The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th

The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th
CNS Drugs 2008; 22 (8): 671-692 REVIEW A RTICLE 1172-7047/08/0008-0671/$48.00/0 © 2008 Adis Data Information BV. All rights reserved. Efficacy and Tolerability of Pharmacotherapies for Borderline Personality Disorder Silvio Bellino, Erika Paradiso and Filippo Bogetto Unit of Psychiatry, Department of Neurosciences, Service for Personality Disorders, University of Turin, Turin, Italy Contents Abstract…………………………………………………………………………671 1. Efficacy and Tolerability of Antidepressant Agents…………………………………….673 1.1 MAOIs……………………………………………………………………673 1.2 Tricyclic and Heterocyclic Antidepressants………………………………………674 1.3 SSRIs……………………………………………………………………..675 2. Efficacy and Tolerability of Mood Stabilizers………………………………………….677 2.1 Lithium……………………………………………………………………677 2.2 Carbamazepine……………………………………………………………678 2.3 Oxcarbazepine…………………………………………………………….679 2.4 Valproate Semisodium………………………………………………………679 2.5 Lamotrigine……………………………………………………………….680 3. Efficacy and Tolerability of Antipsychotics…………………………………………..681 3.1 First-Generation Antipsychotics……………………………………………….. 681 3.2 Atypical Antipsychotics………………………………………………………683 4. Meta-Analyses…………………………………………………………………687 5. Conclusions………………………………………………………………….. 687 Borderline personality disorder is a pervasive pattern of instability of inter- Abstract personal relationships, affects and self-image, as well as marked impulsivity. Although psychotherapy is needed to attain lasting improvements in a patient’s personality and overall functioning, practice guidelines state that pharmacother- apy is indicated to manage state symptoms and trait vulnerabilities. Three psycho- pathological dimensions are the main targets for pharmacotherapy of borderline personality disorder: affective dysregulation, impulsive-behavioural dyscontrol and cognitive-perceptual symptoms. Guidelines recommend the use of antidepres- sant agents and mood stabilizers for affective dysregulation and impulsive- behavioural dyscontrol, and antipsychotics for cognitive-perceptual symptoms. 672Bellino et al. This review aims to report and discuss data from clinical trials, reviews and meta-analyses concerning drug efficacy and tolerability in the treatment of borderline personality disorder. Investigations that considered antidepressant agents mainly focused on SSRIs, which are recommended as first-line treatments for affective instability and impulse dyscontrol. Both open-label and randomized controlled studies have been performed, predominantly concerning the efficacy of fluoxetine and fluvoxamine. Other classes of antidepressants, such as TCAs and MAOIs, were investigated as alternative treatments for borderline personality disorder, but the risk of adverse effects and toxicity is a limitation to their use in clinical practice. Increasing amounts of data have recently been collected on the use of mood stabilizers to control mood instability and impulsivity in patients with borderline personality disorder. More substantial data were derived from control- led trials of valproate semisodium, although other drugs such as lithium, carbama- zepine, oxcarbazepine and lamotrigine were tested with promising results. Several first-generation antipsychotics were studied in open-label and controlled trials, with good effects on behavioural dyscontrol and psychotic-like symptoms. Selec- tion biases and heterogeneity of drugs and methods somewhat limited the value of these results. More recent investigations have examined atypical antipsychotics, with most of these studies being open-label trials with small sample sizes; however, a few controlled studies have been performed using olanzapine, show- ing improvements in impulsivity, anger and hostility. In conclusion, a large number of different drugs have been evaluated in the treatment of patients with borderline personality disorder. Initial findings are encouraging for many of these drugs. However, data need to be replicated in further controlled studies with head-to-head comparisons and long-term follow- ups. Many questions remain to be answered. The essential feature of borderline personality evidence that some personality dimensions of pa- disorder is a pervasive pattern of instability of inter- tients appear to be mediated by dysregulation of personal relationships, affects and self-image, as neurotransmitter physiology and are responsive to well as marked impulsivity that begins by early medication. [5,6] Symptoms exhibited by patients adulthood and appears in a variety of contexts. [1] with borderline personality disorder often fall within Although psychotherapy is needed to attain and three psychopathological dimensions that are a tar- maintain lasting improvements in a patient’s person- get for pharmacotherapy: affective dysregulation, ality, interpersonal problems and overall function- impulsive-behavioural dyscontrol and cognitive- ing, [2,3] American Psychiatric Association (APA) perceptual symptoms. APA guidelines [4] recom- guidelines state that pharmacotherapy is indicated to mend choosing antidepressant agents, in particular manage state symptoms during periods of acute SSRIs and MAOIs, and mood stabilizers for affec- decompensation, as well as trait vulnerabilities. [4] tive dysregulation; SSRIs and mood stabilizers for The pharmacological approach to the treatment impulsive-behavioural dyscontrol; and antipsychot- of borderline personality disorder is based on the ics for cognitive-perceptual symptoms. Although © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 673 medications are widely used to treat patients with1. Efficacy and Tolerability of Antidepressant Agents borderline personality disorder, the US FDA has not approved any medications specifically for the treat- ment of this disorder. 1.1 MAOIs This article reviews available data concerning efficacy and tolerability of agents that have been studied in the treatment of borderline personality Three placebo-controlled studies have tested the disorder. A systematic search of published open- efficacy of MAOIs in the short-term treatment of label and randomized, placebo-controlled trials con- borderline personality disorder. [7-9] cerning pharmacotherapy of borderline personality In the trial by Cowdry and Gardner [7] tranyl- disorder was performed on the online database cypromine, trifluoperazine, alprazolam and carba- PubMed using the key words ‘borderline personality mazepine were compared with placebo in a group of disorder’, ‘pharmacotherapy’, ‘antidepressants’, patients with borderline personality disorder and ‘mood stabilisers’, ‘anticonvulsants’ and ‘antipsy- concomitant hysteroid dysphoria. Tranylcypromine chotics’. Data from open-label studies and from (40 mg/day) had significant effects on a variety of randomized controlled studies were distinguished mood symptoms, such as depression, anger and sen- for each class of drugs, in order to make clear the sitivity to rejection (table I). This drug also reduced different level of evidence. the severity of impulsivity and suicide intentions, Table I. Double-blind controlled trials of antidepressants in the treatment of borderline personality disorder Drug and study Study design No. of Treatment Results with antidepressant drug (comparator drugs) patients duration (wk) MAOIs Tranylcypromine Cowdry and Gardner [7] db, pc (alprazolam, 16 6↓ Anger/hostility, ↓ depression, trifluoperazine,↓ impulsivity/suicidality vs placebo carbamazepine) Phenelzine Soloff et al. [9] co, pc (haloperidol) 108 5↓ Anger/hostility vs placebo TCAs Amitriptyline Soloff et al. [10] db, pc (haloperidol) 90 5↓ Depression, hostility, ↑ self-control vs placebo Desipramine Links et al. [11] co, pc (lithium) 10 6 No significant differences between desipramine and placebo SSRIs Fluoxetine Coccaro and Kavoussi [12] db, pc 40 12↓ Irritability, ↓ aggressiveness vs placebo Markovitz [13] db, pc 17 14↓ Anxiety/depression, ↓ global symptoms vs placebo Salzman et al. [14] db, pc 27 12↓ Anger/hostility, ↓ depression, ↑ global functioning vs placebo Fluvoxamine Rinne et al. [15] co, pc 38 12↓ Affective instability vs placebo co = crossover; db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 674Bellino et al. while the effect on behavioural dyscontrol was close sonality disorder present high levels of impulsivity to a significant level. and poor compliance; therefore, psychiatrists should carefully explain the serious consequences of violat- Parsons et al. [8] compared phenelzine (60 mg/ ing dietary restrictions, describe the picture of day) and imipramine (200 mg/day) in outpatients MAOI intoxication and give emergency instructions with atypical depression and secondary co-morbidi- in case a hypertensive crisis occurs. [4] Moreover, ty with borderline personality disorder. Global im- patients must be carefully informed that they must provement was reported by 92% of patients admin- discontinue an SSRI a long time (up to 5 weeks for istered phenelzine compared with 35% of patients fluoxetine) before beginning MAOI therapy, to administered imipramine. avoid the risk of serotonin syndrome. Phenelzine was administered by Soloff and col- In summary, available controlled studies indicate leagues [9] in inpatients with borderline personality that MAOIs can be useful in treating borderline disorder and co-occurrence of major depression personality disorder, with main effects on symptoms (53%), hysteroid dysphoria (44%) or atypical de- of atypical depression, anger and impulsivity. These pression (46%). The results of this controlled study effects are considered to be independent of the an- indicated that phenelzine significantly decreased tidepressive action of these drugs, [9] although a self-rated anger and hostility, but was not effective study found that patients with a history of major in reducing hysteroid dysphoria or atypical depres- depression or bipolar II disorder showed a non- sion compared with haloperidol or placebo. significant trend to a better response. [7] The three reported studies of MAOIs in border- line personality disorder had a short duration (5–6 1.2 Tricyclic and weeks). [7-9] When a 5-week treatment with phen- Heterocyclic Antidepressants lezine 90 mg/day was continued for a further 16 weeks in a continuation study, only a modest The TCAs amitriptyline, imipramine and desi- reduction of depression and irritability was obtained pramine have been tested in randomized controlled in comparison with placebo. [16] trials of inpatients and outpatients with borderline personality disorder. Concerning tolerability, phenelzine can provoke weight gain, [9] but the most serious adverse event Soloff et al. [10] examined a group of inpatients related to MAOI administration is hypertensive cri- with borderline personality disorder, comparing the sis. Although hypertensive crises may be fatal, the effects of amitriptyline (mean dosage 149 mg/day) risk of these events in patients with psychiatric with haloperidol and placebo. Amitriptyline was disorders is estimated to be <1%, [17] and no cases of found to be superior to placebo in treating depres- hypertensive episodes have been reported in patients sive symptoms and indirect hostility, and signifi- with borderline personality disorder who failed to cantly improved self-control. It is notable that the comply with tyramine dietary restrictions. MAOI core symptoms of the Hamilton Depression Rating toxicity is characterized by delirium, agitation, Scale did not improve with amitriptyline, while the hyper-reflexia, hallucinations, tachycardia, tachy- antidepressant was effective on the associated pnoea, dilated pupils, diaphoresis and convulsions. symptoms of diurnal variation, depersonalization, Hyperpyrexia is a very serious symptom associated paranoid symptoms, obsessive-compulsive symp- with MAOI toxicity. [18] Adherence to dietary restric- toms, helplessness, hopelessness and worthlessness. tions is of primary importance and must be the focus No significant differences were found between pa- of patient education. Patients with borderline per- tients with and without co-morbid major depression. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 675 On the contrary, schizotypal and paranoid symp- In conclusion, available data suggest that the response to TCAs in patients with borderline per- toms were associated with a poorer treatment res- sonality disorder appears modest. The risk of behav- ponse. ioural toxicity and the potential lethality of TCAs in A few studies of TCAs in patients with borderline overdose support the preferential use of SSRIs or personality disorder showed less favourable re- related antidepressants for treating these patients. sults. [8,11] Desipramine was not found to be better than 1.3 SSRIs placebo in treating depression, anger and suicide behaviours, when it was examined in a crossover A considerable number of studies have focused comparison of this drug (mean dosage 162.5 mg/ on the central serotonergic system as a possible day) with lithium carbonate (mean dosage target for psychopharmacological intervention for 985.7 mg/day) and placebo in outpatients with bor- impulsive-aggressive and suicidal patients. [12,20-25] derline personality disorder and a low level of co- On the basis of these pharmacological hypo- morbidity with mood disorders. Moreover, no dif- theses, open-label and randomized controlled trials ferences were found between desipramine and pla- have been performed to test the efficacy of SSRIs in cebo in the psychiatrist and patient perceptions of the treatment of symptoms of affective lability, im- global improvement at 3 and 6 weeks. [11] pulsivity and aggressiveness of patients with border- line personality disorder. [12-15,26-37] Findings of these In a group of outpatients with atypical depression trials showed that fluoxetine, sertraline and venla- and concomitant borderline personality disorder, the faxine (a reuptake inhibitor of serotonin and norad- TCA imipramine was less efficacious than the renaline [SNRI]) induced a significant decrease in MAOI phenelzine. [8] Imipramine 200 mg/day had a symptoms of affective instability, dyscontrol of im- 35% response rate, versus 92% for phenelzine. [8] pulsivity, cognitive-perceptual abnormalities and Symptoms of borderline personality disorder pre- global functioning in patients with borderline per- dicted a poor response to imipramine, but a good sonality disorder. [12-15,28,30,32,34,35,37] Fluoxetine (up response to phenelzine. to 80 mg/day), sertraline (up to 200 mg/day) and TCAs induce frequent adverse effects, such as venlafaxine (up to 400 mg/day) produced effects on sedation, dry mouth, constipation and weight gain. [1] aggressiveness, depression, dysphoria and self-inju- These drugs present a considerable risk of toxicity rious tendencies after treatments of 8–12 weeks. [13] and particular caution is needed when they are ad- Some of these trials reported that improvement of ministered in patients with suicidal intentions. [4] Fa- impulsivity occurred in a short time, usually in the tal arrhythmias are possible in patients with first week of treatment, and was not related to ef- heart conduction disturbances. Blood concentra- fects on depression or anxiety. [12] Furthermore, tions should be measured to minimize the risk of some authors found that the lack of response to one toxicity. SSRI was not a negative predictor of response for all Some authors have reported that the use of ami- SSRIs. They suggested switching patients who did triptyline in patients with borderline personality dis- not respond to a first trial with a serotonergic antide- order may be associated with behavioural toxici- pressant to another drug of the same class. [26] In fact, ty. [19] This term referred to the increase of such some patients who did not respond to fluoxetine symptoms as impulsivity, aggressive behaviours, 80 mg/day had good results with sertraline paranoia and suicidal intentions. 100–200 mg/day. [13] Other patients who did not © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 676Bellino et al. respond to SSRIs improved significantly after re- der were excluded, but dysthymic disorder, depres- ceiving the SNRI venlafaxine. Higher doses of the sive disorder not otherwise specified, anxiety disor- same SSRI and a longer duration of treatment (24 ders, and alcohol and substance abuse were weeks instead of the usual 12 weeks) can also con- common. Fluoxetine had significant effects on ver- vert a substantial proportion of patients from poor to bal aggression and aggression against objects after good response, as was the case in a group of patients 10 weeks of treatment. However, global improve- receiving sertraline. [13] ment was already significant at week 4 and irritabili- ty decreased at week 6. [12] To date, four double-blind, placebo-controlled studies are available on the efficacy and tolerability In a later study, Rinne et al. [15] tested the efficacy of SSRIs in the treatment of borderline personality of fluvoxamine (mean dosage 166 mg/day) versus disorder. [12-15] placebo in a sample of 38 women with borderline personality disorder. Results of the study showed Markovitz [13] conducted the first of these trials in that fluvoxamine, but not placebo, produced a robust a group of 17 patients with borderline personality and long-lasting reduction in the subscale scores for disorder and high co-occurrence of mood/anxiety rapid mood shifts. In contrast, no difference between disorders and somatic symptoms. The trial lasted 14 the fluvoxamine and placebo groups was observed weeks. Patients who received fluoxetine 80 mg/day with regard to the effect on impulsivity and aggres- had significantly better results in global symptoms, sion scores. Rinne et al. [15] suggested that this latter depression and anxiety in comparison with patients finding may be because of gender-specific differ- receiving placebo. Impulsivity and aggression were ences in impulsivity and aggression. not assessed. Some patients taking fluoxetine show- ed an improvement in somatic symptoms, such as In summary, SSRIs (particularly fluoxetine and premenstrual symptoms and headache. fluvoxamine) were found to be efficacious in treat- ing borderline personality disorder in available con- In the same period, a 12-week, double-blind trial trolled studies. The effects of these drugs concerned of fluoxetine (20–60 mg/day) was performed by symptoms of affective instability (depression, [13-15] Salzman and colleagues [14] in 27 patients with bor- anxiety [12-14] and anger [14] ), impulsive dyscontrol derline personality disorder or traits. Patients had a (verbal aggression and aggression against ob- good level of functioning (a mean score of 74 on the jects, [12] and global severity of the disorder [12-14] ). Global Assessment Scale) and did not present co- morbidity with Axis I or II disorders. Fluoxetine Concerning tolerability, SSRIs present a lower induced a significant improvement in symptoms of incidence and milder severity of adverse effects than anger and depression, and increased the level of tricyclic and heterocyclic antidepressants and global functioning in the 22 patients completing the MAOIs. Risk of toxicity is also lower. The highly trial. Reductions in anger and depression were inde- specific actions of SSRIs in enhancing serotonergic pendent of each other. neurotransmission appear to explain their benefit, while the lack of direct actions on other neurotrans- In a 12-week, double-blind trial of fluoxetine mitter systems is responsible for their superior toler- (20–60 mg/day), Coccaro and Kavoussi [12] studied a ability profile compared with older antidepres- group of 40 patients with severe symptoms of im- sants. [39,40] pulsivity and aggression in the context of a personal- ity disorder (approximately one-third had a DSM- Double-blind controlled trials of antidepressants III-R [38] diagnosis of borderline personality disor- in the treatment of borderline personality disorder der). Co-morbid major depression or bipolar disor- are summarized in table I. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 677 2. Efficacy and Tolerability ofality disorder affective instability and bipolar disor- Mood Stabilizersder rapid mood cycling could be a rationale for the use of mood stabilizers in patients with borderline The concept of mood stabilizers is widely applied personality disorder. [48] by clinicians and researchers to indicate a range of To date, several open-label and controlled trials compounds used in the treatment of bipolar disor- have been performed to test the efficacy and tolera- der, although international regulatory authorities do bility of these agents in borderline personality disor- not recognize mood stabilizing as a specific mecha- der, and to specify their effects on different dimen- nism of action. [41-46] A consensus definition of the sions of borderline psychopathology (table II). term has not yet been established. [47] Nevertheless, mood stabilizers have been operationally described 2.1 Lithium as agents that are efficacious in at least one of the three phases of bipolar disorder (mania, bipolar de- In three reviews since the late 1980s, [54-56] lithium pression or long-term maintenance), while not in- was reported to be an effective treatment for patients creasing the frequency or severity of any of the other with borderline personality disorder. Its activity in- phases of the illness. [41] No drugs used as mood volves three interacting systems: (i) modulation of stabilizers have been approved by the FDA for the neurotransmitters, which may contribute to neuro- treatment of borderline personality disorder; how- protection by readjusting excitatory and inhibitory ever, these drugs are often prescribed off-label in activity balance; (ii) modulation of signals im- clinical practice and are suggested by the APA pacting on the cytoskeleton, including glycogen guidelines for the treatment of borderline personali- synthase kinase-3β, cyclic adenosine monophos- ty disorder. [4] phate-dependent kinase and protein kinase C, which Some investigators have suggested that a com- may be critical for the neural plasticity involved in mon mechanism underlying both borderline person- mood stabilization; and (iii) regulation of second Table II. Double-blind controlled trials of mood stabilizers in the treatment of borderline personality disorder Drug and study Study design No. of Treatment Results with mood stabilizers (comparator drugs) patients duration Lithium Links et al. [11] co (desipramine) 10 6 wk↓ Irritability/anger, ↓ self-mutilation vs desipramine Carbamazepine Gardner and Cowdry [49] co, pc 14 6 wk↓ Behavioural dyscontrol vs placebo Cowdry and Gardner [7] db, pc (alprazolam, 16 6 wk↓ Behavioural dyscontrol vs placebo trifluoperazine, tranylcypromine) Valproate semisodium Hollander et al. [50] db, pc 16 10 wk↓ Global symptomatology, ↓ irritability/ aggressivity, ↑ social functioning vs placebo Hollander et al. [51] db, pc 52 12 wk↓ Impulsive aggression vs placebo Frankenburg and Zanarini [52] db, pc 30 6 mo↓ Interpersonal sensitivity, ↓ anger/ hostility, ↓ aggressiveness vs placebo Lamotrigine Tritt et al. [53] db, pc 24 8 wk↓ Anger vs placebo co = crossover; db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 678Bellino et al. messengers, transcription factors and gene expres- thyroid function, ECG, blood counts and biochemis- try, should be undertaken before treatment. sion. [57] Periodic monitoring of plasma lithium concentra- A review by Stein, [58] regarding lithium and the tions, as well as thyroid and kidney function, is antiepileptic drug carbamazepine in the treatment of indicated with prolonged lithium use. patients with borderline or antisocial personality disorder, suggested the effectiveness of both agents 2.2 Carbamazepine on behavioural dysregulation and aggressiveness. The only controlled trial of lithium in borderline Carbamazepine acts by blocking voltage-gated personality disorder was a crossover comparison sodium channels and is indicated by the FDA for use with desipramine performed in a group of ten pa- as an anticonvulsant drug. [63] Although this agent is commonly used by clinicians in the treatment of tients for 6 weeks. [11] Results showed the efficacy of borderline personality disorder, its use for this indi- lithium on core features of borderline personality cation has not been officially approved. disorder psychopathology, such as irritability, anger A clinical practice survey performed by Denicoff and self-mutilation. [11] and colleagues [64] compared carbamazepine with Lithium can be toxic to many organs, particularly many other agents (lithium, valproate sodium, anti- after long-term use; however, most adverse effects psychotics, clonazepam, phenytoin, calcium chan- are not severe and can be reduced or eliminated by nel antagonists) and electroconvulsive therapy in lowering the dose or changing the dosage sched- 1257 patients with different neurological and psy- ule. [59] Metabolic adverse effects are particularly chiatric disorders. These investigators reported that dangerous and include hypothyroidism (up to 36% carbamazepine led to significant global improve- of patients in the study of bipolar I disorder patients ment in the subgroup of patients with borderline by Fagiolini et al. [60] ), hyperparathyroidism and cal- personality disorder. cium level changes, weight gain and nephrogenic In a crossover trial of carbamazepine in 14 fe- diabetes insipidus (almost 20% of patients accord- male outpatients with borderline personality disor- ing to Van Gerven and Boer [61] ). In addition, pa- der, Gardner and Cowdry [49] demonstrated its effi- tients may report other adverse effects related to the cacy in decreasing the frequency and severity of cardiovascular system (syncope, ECG abnormali- behavioural dyscontrol. These preliminary findings ties, circulatory failure), nervous system (blurred were confirmed by further investigations: a 6-week vision, tremors, vertigo, ataxia, nystagmus), kidney placebo-controlled study comparing carbamazepine (renal impairment) and gastrointestinal disturbance (mean dosage 820 mg/day), alprazolam (4.7 mg/ (nausea, vomiting, diarrhoea). [62] Concomitant ad- day), trifluoperazine (7.8 mg/day) and tranyl- ministration of NSAIDs, diuretics, renin-angioten- cypromine (40 mg/day) in the treatment of patients sin inhibitors, theophylline and antibacterials has with borderline personality disorder and co-morbid been reported to cause elevations in serum lithium hysteroid dysphoria; [7] and a review of double-blind concentrations. Furthermore, lithium is potentially trials of drug therapy for personality disorders that fatal in overdose, and current guidelines suggest that reported a marked improvement in impulsive ag- it should be used with caution in patients at risk of gression following treatment with carbamaze- suicide. [4] pine. [65] A full medical history, as well as laboratory Further controlled trials suggested the effective- investigations, including renal and liver function, ness of carbamazepine on a wider range of symp- © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 679 toms, including not only impulsive-aggressive be- Two patients withdrew from the study in the first 4 haviours [66] but also affective dysregulation, [67,68] weeks of treatment as a result of noncompliance. A which is often the main goal of the use of mood statistically significant improvement was observed stabilizers when treating patients with borderline in global psychopathology, anxiety, interpersonal personality disorder. relationships and borderline personality disorder core features, including impulsivity, affective insta- Carbamazepine can induce several adverse ef- bility and outbursts of anger. These initial findings fects, including CNS disturbances (diplopia, blurred appear promising and provide preliminary evidence vision, ataxia), fatigue and nausea. [69] Less common of a broad spectrum of action of this drug in patients are skin rash, mild leukopenia or thrombocytopenia, with borderline personality disorder; however, con- and hyponatraemia. [70] Idiosyncratic, potentially fa- trolled trials of larger patient groups are needed to tal events have rarely been reported: agranulocyto- replicate these data. sis, aplastic anaemia, exfoliative dermatitis, and se- rious hepatic and pancreatic toxicity. Overdose of Concerning tolerability, the most frequent ad- carbamazepine may have fatal effects. Periodic verse events during treatment with oxcarbazepine measurement of the white blood cell count is recom- are dizziness, nausea, headache, somnolence and mended. [4] fatigue. [86] Hyponatraemia may occur (albeit often asymptomatically), particularly in the elderly. How- Data from a single study of patients with border- ever, serum sodium level monitoring is not neces- line personality disorder related the use of carbama- sary, unless relevant risk factors exist. [87] Severe zepine to the onset of melancholic depression. [49] haematological dyscrasias have not been report- 2.3 Oxcarbazepine ed. [86] The enzyme-inducing interaction of ox- carbazepine with ethinylestradiol and levonorgestrel Oxcarbazepine is an antiepileptic agent structur- requires additional precautions for women using ally related to carbamazepine, and shares the same hormonal contraception. [87] mechanism of action of blocking voltage-gated so- dium channels, but is less likely to induce cyto- 2.4 Valproate Semisodium chrome P450 enzymes and to cause drug interac- tions. [63] Valproate semisodium is an antiepileptic drug Several trials have shown the efficacy of ox- facilitating the transmission of GABA. [88] This drug carbazepine in the treatment of psychiatric disor- has been extensively studied in patients with border- ders, such as bipolar disorder, substance abuse dis- line personality disorder. order, resistant psychosis and schizoaffective disor- Initial findings regarding possible efficacy of this der; [71-84] however, as in the case of carbamazepine, agent in treating patients with borderline personality oxcarbazepine has been approved by the FDA for disorder came from open-label studies. Firstly, Wil- treating seizure disorders only. cox [89] tested valproate semisodium in a group of No randomized controlled trials are available that patients with psychomotor agitation due to different investigate the use of oxcarbazepine in the treatment underlying psychiatric disorders and observed a of borderline personality disorder. Initial data can be particularly marked reduction of agitation after drawn from an open-label trial that was performed treatment in patients with bipolar disorder or border- by our group, which investigated the 12-week treat- line personality disorder. Wilcox [90] then replicated ment of 13 borderline personality disorder outpa- these data in a further trial that focused on borderline tients with oxcarbazepine 1200–1500 mg/day. [85] personality disorder treatment. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 680Bellino et al. Another 8-week, open-label trial of valproate tors found significant effects on interpersonal sensi- tivity, anger, hostility and aggressiveness. semisodium (daily dose titrated to reach blood con- centrations of 50–100 µg/mL) in 11 patients with Valproate semisodium causes dose-related ad- verse effects, such as gastrointestinal dysfunction borderline personality disorder by Stein and col- (nausea), mild transaminase elevations, tremor, se- leagues [91] suggested the effect of the molecule on dation and weight gain. [93] Less common adverse clinician-rated measures of overall psychopath- events are asymptomatic leukopenia and thrombo- ology, mood, anxiety, anger, impulsivity and rejec- cytopenia. Idiopathic and potentially fatal events are tion sensitivity in four of the eight patients who represented by rare agranulocytosis, and hepatic and completed the study. pancreatic toxicity. [94] Periodic monitoring of blood Kavoussi and Coccaro [92] studied the efficacy of cell count and hepatic function should be pro- 8-week valproate semisodium therapy (up to 2000 vided. [4] After long-term treatment of women, poly- mg/day) in ten patients with several axis II diagno- cystic ovaries and hyperandrogenism can occur. ses who had not responded to a previous trial with an SSRI (two patients met the criteria for borderline 2.5 Lamotrigine personality disorder). They reported a reduction in irritability and impulsive aggressiveness after treat- The antiepileptic lamotrigine has recently been ment. employed in the treatment of depressive episodes of bipolar disorder and in the prevention of recurrences More reliable data derive from three placebo- of this disorder. This agent inhibits neuronal excita- controlled trials. [50-52] bility and modifies synaptic plasticity by inhibiting In a 10-week, double-blind trial of valproate voltage-activated sodium channels. Indirectly, these semisodium (medium plasma concentration 80 µg/ effects would be expected to regulate aberrant intra- mL) in 16 patients with borderline personality disor- cellular and intercellular signalling in critical re- der, Hollander and colleagues [50] found a marked gions of the limbic forebrain. [95] improvement in global symptomatology, social The use of lamotrigine in patients with borderline functioning and borderline personality disorder fea- personality disorder was firstly reported by Pinto tures, such as depressive symptoms, aggressiveness, and Akiskal [96] in a 1-year open-label trial of the irritability and suicidal ideation or behaviour. How- drug (daily dose up to 300 mg), suggesting an im- ever, a high dropout rate (ten patients) precluded provement in global functioning, sexual impulsive- finding any significant differences between val- ness, substance abuse and suicidal behaviour. proate semisodium and placebo treatment groups. A review by Green [97] of patients with mood More recently, in a 12-week, double-blind trial, disorders also suggested the efficacy of this agent in the same authors confirmed the efficacy of valproate treating mood instability of borderline personality semisodium (mean daily dose 1325 mg) on impul- disorder. sive aggression in 52 outpatients with borderline More recently, Preston and colleagues [98] investi- personality disorder. [51] gated the frequency of co-morbid borderline person- Frankenburg and Zanarini [52] performed a ality disorder in 35 patients with bipolar disorder 6-month, placebo-controlled study of valproate who had previously undergone two open-label trials semisodium (plasma concentration 50–100 µg/mL) with lamotrigine, in order to evaluate the effects of in 30 women with borderline personality disorder this drug on borderline personality disorder symp- and co-morbid bipolar II disorder. These investiga- tom dimensions. Borderline personality disorder © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 681 was retrospectively diagnosed in 40% of the pa- symptoms (mood instability, anxiety, anger) and tients. Lamotrigine was reported to be efficacious in somatic complaints. [4] all borderline personality disorder-related symp- 3.1 First-Generation Antipsychotics toms, with a marked improvement of impulsivity and mood instability. Early studies of antipsychotics targeted the Only one double-blind trial of lamotrigine in psychotic-like symptoms of patients with borderline borderline personality disorder is currently avail- personality disorder. able. In 2005, Tritt and colleagues [53] compared the Thioridazine was tested at a mean dosage of efficacy of lamotrigine versus placebo in the treat- 92 mg/day in 13 patients with borderline personality ment of aggression in 24 women with borderline disorder. The open-label study lasted 12 weeks personality disorder. A highly significant improve- (with three patients withdrawing) and showed fa- ment in anger was observed after 8 weeks of the vourable effects on the global severity of symptoms, trial. overall borderline psychopathology and impulsive The most common adverse events associated behaviours. [102] Flupentixol produced similar results with lamotrigine are dizziness, diplopia and head- at the mean dosage of 3 mg/day in a group of ache, [99] while the only serious adverse event is a adolescents with borderline personality disorder. [103] rare hypersensitivity reaction primarily presenting In particular, there was a decrease in depressive and as a rash (the Stevens-Johnson syndrome), which is impulsive symptoms and an improvement of global potentially fatal (0.1% incidence in the study by functioning. Bowden et al. [100] ). Hirsch et al. [101] pointed out a More reliable indications were provided by initial correlation between lamotrigine serum concentra- comparison trials of antipsychotics, which were tion and tolerability: adverse effects requiring a dose found to be effective on a wide range of symptoms. change are uncommon with the most frequently Loxapine (mean dosage 14.5 mg/day) and chlor- encountered lamotrigine concentrations (<10 µg/ promazine (mean dosage 110 mg/day) were both mL) and occur in only 7.4% of patients at concentra- found to be effective in reducing depression, anxie- tions obtained during the majority of clinical trials ty, anger and suspiciousness. [104] (<5 µg/mL). Lamotrigine did not appear to destabi- A double-blind comparison of tiotixene (mean lize mood and was not associated with sexual ad- dosage 9.4 mg/day) and haloperidol (mean dosage verse effects, weight gain or withdrawal symp- 3 mg/day) indicated that both drugs decreased the toms. [101] severity of a series of symptoms, including depres- sion, anxiety, derealization, ideas of reference and 3. Efficacy and Tolerability overall borderline psychopathology (table III). [105] of Antipsychotics More recent trials with a placebo control mostly confirmed these data. Nevertheless, it should be noticed that many studies of antipsychotics in pa- Antipsychotics are widely used in clinical prac- tients with borderline personality disorder present tice for treating borderline personality disorder-re- biases in sample selection that can affect both clin- lated symptoms. Although this use has not been ical picture and treatment outcome. approved by the FDA, APA treatment guidelines recommend the use of antipsychotics, primarily for In a 12-week, double-blind study of patients with their effects on cognitive perceptual disturbances, borderline or schizotypal personality disorder and but also for their efficacy in reducing affective concomitant psychotic-like symptoms, tiotixene © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 682Bellino et al. Table III. Double-blind controlled trials of first-generation antipsychotics in the treatment of borderline personality disorder Drug and study Study design No. of Treatment Results with antipsychotics (comparator drugs) patients duration Tiotixene Serban and Siegel [105] db (haloperidol) 52 3 mo Tiotixene = haloperidol: ↓ global symptomatology, ↓ depression/anxiety, ↓ paranoid ideation vs baseline Goldberg et al. [106] db, pc 50 12 wk↓ Psychotic symptoms, ↓ obsessive- compulsive symptoms, ↓ phobic anxiety vs placebo Trifluoperazine Cowdry and Gardner [7] db, pc (alprazolam, 16 6 wk↓Depression/anxiety, ↓ rejection sensitivity, tranylcypromine,↓ suicidal attempts vs placebo carbamazepine) Haloperidol Soloff et al. [10] db, pc (amitriptyline) 90 5 wk↓Depression, ↓ hostility, ↓ schizotypal symptoms, ↓ impulsiveness, ↑ global functioning vs placebo Soloff et al. [9] db, pc (phenelzine) 108 5 wk No significant differences vs placebo db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased; = indicates equivalent efficacy. (mean dosage 8.7 mg/day) was significantly effec- age 4.8 mg/day) was significantly superior to place- tive in treating illusions, ideas of reference, and self- bo on all symptom clusters, [19] including global se- rated obsessive-compulsive and phobic symptoms, verity of symptoms, self- and clinician-rated depres- but not depression and global functioning. [106] The sion, anger, impulsivity, schizotypal symptoms and choice of patients with psychotic-like symptoms psychoticism. [10] In this group of patients, haloperi- biased the effects of treatment towards cognitive- dol induced the same improvement of depression as perceptual distortions. amitriptyline. A placebo-controlled, crossover comparison was These results indicating the efficacy of haloperi- performed by Cowdry and Gardner [7] in a group of dol on a wide range of symptoms of borderline outpatients with borderline personality disorder. personality disorder were not replicated in another Four drugs were administered in a 6-week trial: trial by the same authors. [9] In the second study, the trifluoperazine, mean dosage 7.8 mg/day; alprazo- same design was used to compare haloperidol (mean lam, mean dosage 4.7 mg/day; carbamazepine, dosage 3.9 mg/day) with phenelzine and placebo. mean dosage 820 mg/day; and tranylcypromine, The antipsychotic had only modest and nonsignifi- mean dosage 40 mg/day. Trifluoperazine signifi- cant effects on hostility and impulsive aggression. cantly decreased depression, anxiety, rejection sen- A subgroup of patients in the above-cited trial of sitivity and suicide attempts. As these patients had a haloperidol, phenelzine or placebo [9] who had re- co-diagnosis of hysteroid dysphoria and a history of sponded to treatment received a 16-week continua- impulsive dyscontrol, results could be biased to- tion of treatment. [16] Haloperidol treatment produced wards affective symptoms and impulsivity. further significant improvement in irritability, but A double-blind comparison of haloperidol and not hostility. Depression significantly increased in amitryptyline was conducted by Soloff and col- severity during prolonged haloperidol treatment, in leagues [10,19] in the 5-week acute treatment of a part as a consequence of akinesia. Global clinical group of inpatients. Haloperidol (mean dos- improvement was of modest importance. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 683 A 6-month continuation treatment was provided nin-2 (5-HT 2) receptors, has been associated not to patients with borderline or histrionic personality only with antipsychotic properties, but also with disorder and a history of recurrent parasuicidal be- antimanic and antidepressant effects. [100] These ef- haviours. [107] In this study, depot flupentixol 20 mg fects have been supported by the results of a number was administered once monthly to control for of studies. [47,110-114] Early studies regarding treat- nonadherence. A significant reduction in suicidal ment of borderline personality disorder with atypi- behaviours was obtained compared with placebo cal antipsychotics suggested the efficacy of cloza- Data on withdrawal rates in samples of outpa- pine. An initial report by Frankenburg and tients with borderline personality disorder who re- Zanarini [115] concerned the beneficial effects of this ceived treatment with antipsychotics depended on drug (mean dosage 253.3 mg/day) on positive and the duration of the trial: 13.7% in a 6-week trial, [104] negative psychotic symptoms and overall function- 48.3% in a 12-week trial [106] and 87.5% in a 22-week ing in 15 patients with a co-diagnosis of borderline continuation study. [16] In short-term treatments, lack personality disorder and psychotic disorder not oth- of compliance can be a consequence of adverse erwise specified. Patients had been resistant or intol- effects induced by typical antipsychotics, partic- erant to previous antipsychotic therapies. The relia- ularly extrapyramidal symptoms (EPS), sedation bility of these results is limited as it is difficult to and hypotension. [100,106,108,109] Some patients who ascertain whether psychotic symptoms were an ex- have obtained a clinical improvement with low pression of borderline personality disorder or were doses of antipsychotics in the acute treatment may due to co-morbidity with psychotic disorders. withdraw when experiencing adverse effects in Benedetti and colleagues [116] tried to address this longer continuation therapy. [4] Clinicians must take issue. They selected a sample of patients with bor- into account the risk of tardive dyskinesia before derline personality disorder who were resistant to deciding to administer first-generation antipsychot- treatment (they had not responded to at least 4 ics for a long period. [4] months of prior treatment with medication and psy- Administration of thioridazine is not recommen- chotherapy) but did not meet the criteria for ded as this drug increases the duration of the QT psychotic disorders. The open-label study focused interval and can induce arrhythmias. [108,109] on psychotic-like symptoms, which were considered A reassuring doctor-patient relationship that more typical of personality disorder. A combination carefully considers problems related to adverse ef- of clozapine (mean dosage 43.8 mg/day) and psy- fects and compliance can be useful to prevent with- chotherapy was administered for 4 months to 12 drawal during antipsychotic treatment. [4] patients, and induced an improvement in all symp- Double-blind controlled trials concerning first- tom clusters – affective symptoms, impulsivity and generation antipsychotics in the treatment of border- cognitive-perceptual distortions. line personality disorder symptoms are summarized Chengappa et al. [117] performed a similar investi- in table III. gation, administering clozapine to seven female in- patients with borderline personality disorder and 3.2 Atypical Antipsychotics concomitant refractory psychosis, who had not re- sponded to previous treatment with other antipsy- Atypical antipsychotics represent a new treat- chotics. Patients were treated for up to 1 year and ment tool for borderline personality disorder. In fact, reported a reduction in self-destructive and aggres- their double mechanism of action, characterized by the antagonism of both dopamine-2 (D 2) and seroto- sive behaviours, isolation, drug intake and abuse. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 684Bellino et al. When considering the efficacy of risperidone in More extensive data have been reported for olan- zapine and quetiapine. the treatment of borderline personality disorder, data are sparse and derive from some case reports and Olanzapine is a thienobenzodiazepine with a high two initial investigations. [118-122] affinity for D 2 through D 4 and 5-HT 2A receptors, and a lower affinity for histamine (H 1), muscarinic In their 8-week, open-label trial of risperidone (M 1 through M 5) and α 1-adrenergic receptors. Ant- (3.3 mg/day) in 15 outpatients with borderline per- agonism at D 2 through D 4 and 5-HT 2A receptors is sonality disorder, Rocca and colleagues [122] outlined thought to be the basis for its therapeutic efficacy, the efficacy of this agent on aggressive behaviour, while antagonism at H 1, M 1–M 5 and α 1-receptors is affective instability and global psychopathology. probably responsible for its adverse effects. [127] Two patients discontinued treatment before the end The first open-label study of olanzapine in bor- of the trial because of lack of compliance. derline personality disorder was conducted by Szighethy and Schulz [119] published the initial Schulz and colleagues [120] in a sample of 11 outpa- data of a double-blind comparison of risperidone tients with a co-diagnosis of dysthymic disorder. (mean dosage 2.5 mg/day) and placebo. Twenty- The nine patients who completed the 8 weeks of seven patients with borderline personality disorder treatment presented a decrease in impulsivity, hos- were included and treated for 8 weeks (see table IV). tility, overall psychopathology and global function- ing. Risperidone was not more effective than placebo in increasing global functioning, but produced an im- Since the completion of this study, several con- provement in psychoticism, paranoid ideas, phobias trolled trials have been published on this and interpersonal sensitivity. drug. [37,123-125] Table IV. Double-blind controlled trials of atypical antipsychotics in the treatment of borderline personality disorder Drug and study Study design No. of Treatment Results with antipsychotics (comparator drugs) patients duration Risperidone Szighethy and Schulz [119] db, pc 27 8 wk No significant differences vs placebo Olanzapine Zanarini et al. [37] db (fluoxetine, olanzapine 45 8 wk↓ Impulsive aggression, ↓ chronic + fluoxetine) dysphoria vs baseline (olanzapine = olanzapine + fluoxetine > fluoxetine) Zanarini and Frankenburg [123] db, pc 28 6 mo↓ Anxiety/paranoid ideation, ↓ interpersonal sensitivity vs placebo Bogenschutz and Nurnberg [124] db, pc 40 12 wk↓ Global symptomatology, ↓ anger vs placebo Soler et al. [125] db, pc (dialectical behaviour 60 12 wk↓ Impulsive aggression, therapy, olanzapine +↓ depression/anxiety vs placebo dialectical behaviour therapy) Aripiprazole Nickel et al. [126] db, pc 52 8 wk↓ Global psychopathology, ↓ depression/anxiety, ↓ anger vs placebo db = double-blind; pc = placebo-controlled; ↓ indicates decreased; = indicates equivalent efficacy; > indicates better efficacy. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 685 Two studies investigated the effects of olanza- of adverse events such as EPS, prolactin elevation and weight gain. [128-130] pine compared with placebo. [123,124] A 6-month double-blind, placebo-controlled trial of olanzapine Hilger and colleagues [131] described the effects of (mean dosage 5.33 mg/day) in 28 women with bor- this agent (400–800 mg/day) on two women with derline personality disorder was performed by borderline personality disorder with severe episodes Zanarini and Frankenburg, [123] who pointed out the of self-mutilation, and found it to be efficacious in efficacy of this agent on anxiety, paranoid ideation improving impulsive behaviour and overall func- and interpersonal sensitivity. Bogenschutz and tioning. Nurnberg [124] reported findings of a 12-week, doub- A few pilot studies on quetiapine in the treatment le-blind, placebo-controlled trial of olanzapine of borderline personality disorder have recently (5–10 mg/day) in 40 outpatients with borderline been performed, with mostly concordant and prom- personality disorder. From the fourth week of treat- ising conclusions being reached. Adityanjee and ment, these investigators observed a significant im- Schulz [132] tested the efficacy of quetiapine (25–300 provement in borderline psychopathology and an- mg/day) in ten patients who completed an 8-week ger. open-label trial. Results showed an improvement in overall symptomatology, hostility, impulsivity and Other studies considered combinations of olanza- functioning. pine with another drug or psychotherapy. Zanarini and colleagues [37] compared the efficacy of fluoxe- Villeneuve and Lemelin [133] replicated these find- tine, olanzapine and the olanzapine-fluoxetine com- ings. They investigated the effects of quetiapine bination in the treatment of 45 women meeting the (175–400 mg/day for 12 weeks) in a group of 23 criteria for borderline personality disorder. In their outpatients with borderline personality disorder and 8-week, randomized, double-blind study, the inves- found a significant improvement in impulsivity, tigators found that all three treatment options signif- hostility, depression, anxiety and social functioning. icantly improved chronic dysphoria and impulsive Perrella et al. [134] recently tested open-label que- aggression. However, olanzapine monotherapy and tiapine (400–800 mg/day) in 29 patients with bor- the olanzapine-fluoxetine combination were found derline personality disorder for 12-weeks. Six pa- to be superior to fluoxetine monotherapy in treating tients withdrew from the study because of adverse both features of borderline psychopathology. Soler effects. In the final sample of 23 patients, these et al. [125] recently compared the efficacy of olanza- investigators found a significant improvement in pine and placebo in a combined treatment with global symptoms, depressive symptoms, hostility/ dialectical behavioural therapy. In their 12-week suspiciousness, aggressiveness and functioning. double-blind study of a group of 60 outpatients with Our group [135] performed a 12-week pilot study borderline personality disorder, they found that on the efficacy of quetiapine (mean dosage 309 mg/ olanzapine (mean dosage 8.83 mg/day) led to a day) for the treatment of 14 patients with borderline significant reduction of impulsive-aggressive beha- personality disorder. Three patients withdrew from viour, depression and anxiety compared with place- the study because of noncompliance. Results were bo. mostly concordant with previous findings and con- Quetiapine is a dibenzothiazepine characterized firmed the improvement of global symptomatology, by low affinity for and rapid dissociation from post- impulsivity, outbursts of anger, anxiety and social synaptic D 2 receptors, which reduces the incidence functioning. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 686Bellino et al. Aripiprazole, an atypical antipsychotic with par- use of growth factors can reduce the risk of infec- tial agonist activity at D 2 and 5-HT 1A receptors, has tions. Transient leukocytosis and eosinophilia can recently been introduced for the treatment of schizo- also be observed, but these do not usually have any phrenia, schizoaffective disorder and bipolar disor- serious clinical effects. [145] der. [136-140] Aripiprazole augmentation of various The incidence of EPS differs among the atypical SSRIs has been reported to have good effects in antipsychotics, with risperidone being associated refractory unipolar depression. [141,142] with the highest incidence, and clozapine and que- tiapine with the lowest incidence. [146] The likelihood Data concerning the use of aripiprazole in the of developing EPS depends not only on the specific treatment of borderline personality disorder are very agent chosen, but also on the rapidity of dose escala- preliminary. tion, the target dose and the vulnerability of the Three patients with borderline personality disor- patient to this adverse effect. [146] der and psychotic symptoms were treated with When taking into account metabolic effects, ris- aripiprazole, with heterogeneous results shown in peridone has a relatively low risk of causing obesity clinical response and tolerability. [143] and diabetes mellitus. [147] Nickel et al. [126] performed a double-blind, place- Data on the tolerability of atypical antipsychotics bo-controlled trial of aripiprazole (15 mg/day) in 52 specifically collected in samples of patients with patients with borderline personality disorder, find- borderline personality disorder are limited. In the ing the molecule to be efficacious after 8 weeks in study by Soler and colleagues, [125] patients with reducing global psychopathology, depression, anxi- borderline personality disorder treated with olanza- ety and anger. Drug therapy was well tolerated. In pine experienced significant weight gain, but there order to assess the long-term effects of the molecule was no dose-dependent relationship. on borderline personality disorder, these investiga- tors performed an 18-month follow-up trial [144] of Some data concerning the tolerability of que- the sample of patients included in the previous in- tiapine in borderline personality disorder can be vestigation. [126] According to the intent-to-treat ana- drawn from the study performed by our group, [135] lysis, all scales of global psychopathology, depres- showing that the most common adverse effects were sion and anxiety showed a significant improvement, somnolence, dry mouth and dizziness. Adverse ef- suggesting that aripiprazole can be considered an fects were mild to moderate in most cases, but two effective agent in the long-term treatment of patients patients discontinued treatment because of excess- with borderline personality disorder. ive somnolence. The pattern of adverse effects ap- peared to be in accordance with other investigations Concerning adverse effects, the newer antipsy- of quetiapine in patients with schizophrenia or bi- chotics present a more favourable tolerability profile polar disorder. [148,149] compared with first-generation antipsychotics. More common adverse effects of aripiprazole are Clozapine presents a serious risk of blood dyscra- headache, insomnia and anxiety. This pattern of sia. Neutropenia and agranulocytosis can occur in a adverse effects can be found in patients affected by small percentage of patients (0.9% and 0.7%, re- other psychiatric disorders, [137,149,150] as well as in spectively, according to Lambertenghi De- patients with borderline personality disorder. [143] liliers [145] ), mainly during the first 18 weeks of clo- zapine treatment, and can lead to serious complica- Double-blind controlled trials of atypical anti- tions. Drug discontinuation usually results in the psychotics in borderline personality disorder are normalization of haematological parameters, and the summarized in table IV. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 687 4. Meta-Analysesity and psychotic symptoms. The only difference seen between MAOIs and placebo was that patients In recent years, a few reviews and meta-analytic receiving MAOIs were less hostile. The compari- studies have evaluated the available pharmacologi- sons of MAOIs with antipsychotics did not show cal interventions for borderline personality disorder, convincing differences, although some results were with the aim of defining which evidence supports significant. Antipsychotics may have some benefits the efficacy of pharmacotherapy on measures of for people with paranoid and psychotic symptoms, symptoms and functional level. but there was little evidence for the advantage of one To date, we found two meta-analyses of random- antipsychotic over another. Mood stabilizers, such ized controlled trials of pharmacotherapy for pa- as valproate semisodium, may induce some change tients with borderline personality disorder. Both in clinical global scores, but data are not conclusive. studies pointed out that the evidence for efficacy is These authors concluded that well designed, clini- very limited and a series of methodological limita- cally meaningful trials are needed and that the posi- tions affect the reliability of results. tive effects of antidepressants could be considerable The meta-analysis by Nos` e et al. [151] included 20 and should be addressed first. articles, reporting 22 placebo-controlled investiga- tions: eight studies involved antipsychotics, seven 5. Conclusions involved antidepressants and seven involved mood stabilizers. Antidepressants and mood stabilizers Investigations on psychotropic agents in the were found to be efficacious in reducing affective treatment of borderline personality disorder have instability and anger, but did not produce significant recently tested several new drugs belonging to the effects on impulsivity and aggression, unstable rela- classes of antidepressants, mood stabilizers and anti- tionships, suicidality or functioning. Antipsychotics psychotics. Results are promising and suggest that significantly improved impulsive aggression, inter- these medications can be useful in clinical practice, personal relationships and global functioning. No particularly to control impulsive aggression and af- difference was found between pharmacotherapy and fective instability. placebo in terms of dropout rates. The authors con- However, available studies show a series of cluded that pharmacotherapy has shown modest methodological limitations, such as small sample beneficial effects on core traits of borderline person- sizes, the short duration of most trials, the lack of ality disorder. long-term follow-up evaluations, the heterogeneity Binks et al. [152] presented evidence from the of selection criteria and outcome measures, and the Cochrane Database of Systematic Reviews, and in- high rates of dropouts. Sometimes, authors do not cluded all randomized trials comparing psycho- describe the reasons for patients withdrawing from active drugs with any other treatment for people trials, although a large proportion of withdrawals with borderline personality disorder. They found ten appear to be related to insufficient compliance small studies (n = 554) involving eight comparisons. among these patients. Furthermore, sponsorship Data on antidepressants indicated that fluoxetine concerns might have led to a bias in the objective may offer some improvement in ratings of anger. A evaluation of the effects of drugs. Considering these study investigating the effects of mianserin on at- limitations, meta-analyses have concluded that tempted suicide found no difference between drug pharmacological treatment of borderline personality and placebo. Data indicated that haloperidol may disorder may be of use but is not currently based on provide better results than antidepressants on hostil- good evidence from trials. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 688Bellino et al. 7. Cowdry RW, Gardner DL. Pharmacotherapy of borderline per- Forthcoming investigations should therefore fo- sonality disorder: alprazolam, carbamazepine, trifluoperazine, cus on a series of relevant topics such as: pilot and tranylcipromine. Arch Gen Psychiatry 1988; 45: 111-9 8. Parsons B, Quitkin FM, McGrath PJ, et al. Phenelzine, imipram- studies of new agents; controlled trials of drugs ine, and placebo in borderline patients meeting criteria for already tested in open-label case series; compari- atypical depression. Psychopharmacol Bull 1989; 25: 524-34 sons of new antiepileptic agents with better known 9. Soloff PH, Cornelius J, George A, et al. Efficacy of phenelzine and haloperidol in borderline personality disorder. Arch Gen mood stabilizers, such as lithium or valproate semi- Psychiatry 1993; 50 (5): 377-85 sodium; head-to-head comparisons of atypical and 10. Soloff PH, George A, Nathan S, et al. Amitriptyline versus haloperidol in borderlines: final outcomes and predictors of traditional antipsychotics to verify which differ- response. J Clin Psychopharmacol 1989; 9: 238-46 ences in clinical effects and adverse events specifi- 11. Links P, Steiner M, Boiago I, et al. Lithium therapy for border- cally occur in borderline personality disorder; defi- line patients: preliminary findings. J Personal Disord 1990; 4: 173-81 nition of appropriate doses to treat borderline per- 12. Coccaro EF, Kavoussi RJ. Fluoxetine and impulsive aggressive sonality disorder symptoms; maintenance studies to behaviour in personality disordered subjects. Arch Gen Psy- chiatry 1997; 54: 1081-8 assess persistence of therapeutic effects in a long- 13. Markovitz P. Pharmacotherapy of impulsivity, aggression, and lasting disorder such as borderline personality disor- related disorders. In: Hollander E, Stein DJ, editors. Impulsivi- der; add-on trials of mood stabilizers and atypical ty and aggression. New York: John Wiley & Sons, 1995: 263-87 antipsychotics in samples of patients with borderline 14. Salzman C, Wolfson AN, Schatzberg A, et al. Effect of fluoxe- personality disorder who do not respond to first-line tine on anger in symptomatic volunteers with borderline per- sonality disorder. J Clin Psychopharmacol 1995; 15: 23-9 therapy with SSRIs; and defining the relationship 15. Rinne T, de Kloet ER, Wouters L, et al. Hyperresponsiveness of between clinical subtypes of patients with border- hypothalamic-pituitary-adrenal axis to combined dexameth- line personality disorder (e.g. affective labile, self- asone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sus- injurious, psychotoform) with response to different tained childhood abuse. Biol Psychiatry 2002; 52: 1102-12 medications. 16. Cornelius JR, Soloff PH, George A, et al. Haloperidol vs phenelzine in continuation therapy of borderline disorder. Psychopharmacol Bull 1993; 29 (2): 333-7 Acknowledgements 17. Lavin MR, Mendelowitz A, Kronig MH. 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The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th
CLINICAL PSYCHOPHARMACOLOGY UPDATE Rafael A. Rivas-Vazquez, Editor Pharmacologic Treatment of Personality Disorders Rafael A. Rivas-VazquezNeurologic Center of South Florida and Miami Research Associates Mark A. Blais Harvard Medical School and Massachusetts General Hospital The era of evidence-based medicine has fostered heightened scrutiny of the manner in which therapeutic interventions are formulated, taught, and implemented. In psychopharmacology, this has translated into an emerging paradigm of developing re- search activities on the basis of specific neurobiological theories and subsequently utilizing the results of well-controlled trials to guide clinical practice. Such data ultimately inform the develop- ment of health care policy and guidelines for treating specific disorders. The application of this paradigm to the pharmacologic treatment of personality disorders (PDs) has introduced some challenges based primarily on the inherent complexities of these pathological entities. Long since felt to be the purview of psycho- social treatments, PDs are increasingly being investigated to de- termine the impact that psychotropic medications may have on their expression and course. Concern has been raised as to the underdetection and undertreatment of PDs, particularly in light of their resultant functional impairment and disability, their adverse impact on the treatment of comorbid Axis I disorders, and the increased use of health resources associated with their presence (compared with patients without an Axis II disorder; Bender et al., 2001). In this article, we review the recent literature on pharma- cologic treatment of PDs, discussing the existing models that guide pharmacotherapy of these disorders and reviewing specific classes of medications that appear to play a beneficial role. Existing Paradigm for Pharmacological Treatment of Personality Disorders Treatment of PDs has traditionally been viewed with some pessi- mism. The deeply ingrained nature of personality characteristics pro- duced a sentiment that root-cause treatment—typically psychothera- py—would have to be long-term, intensive, and guarded in its prognosis. From this perspective, pharmacotherapy was secondary, short-term, and highly symptom-oriented. Over the past 10 –15 years, pharmacological and biological studies— coupled with clinical expe- rience— have prompted a reconsideration of pharmacotherapy forPDs. Medications are now considered as important as psychotherapy in the treatment of PDs, particularly given findings that 81% of patients with PDs report that they have received psychotropic medi- cations at some time during their treatment (Bender et al., 2001). Medications are now clearly valued and used in the treatment of borderline PDs, to the point that some psychiatrists consider it uneth- ical to withhold medications from these patients; psychologists as a group are also highly prone to advocate for the use of medications in their treatment of borderline PDs (Gunderson, 2001). The current pharmacotherapeutic paradigm for PDs has evolved along three separate lines of reasoning (Cloninger & Svrakic, 2000; Kapfhammer & Hippius, 1998; Siever & Davis, 1991): 1.Pharmacotherapy directly influences PDs. The central as- sumption of this approach (also referred to as causal pharmaco- therapy) is that medications alter underlying neurobiological dis- positions that cause maladaptive traits. From this perspective, pharmacological manipulation of the neurobiological systems modifies the disposition and promotes better functioning (includ- ing enhanced learning and experiential events), gradually produc- ing long-term changes in behavior and adaptation. 2.Pharmacotherapy exerts an effect over core or nuclear symptom clusters.This approach targets core or nuclear symptom clusters felt to be highly characteristic of certain PDs. A body of literature sup- ports the presence of four factors or dimensions reflecting fundamen- tal dysfunction in the areas of cognition or perceptual organization, behavioral control, affective stability, and anxiety suppression (Siever & Davis, 1991). This approach appears to be the one most often implemented in current clinical practice. 3.Pharmacotherapy exerts its therapeutic effect by treating comor- bid Axis I disorders.This view is based upon the finding that Axis I disorders are commonly found to be comorbid with PDs. In this model, the therapeutic effect of medications occurs primarily at the comorbid Axis I level, which improves the clinical status of the patient and increases the probability of better outcome produced by other forms of therapy. This view, although valid and practical, is probably most consistent with the traditional approach of treating PDs with medications and has received the least amount of attention in the reconceptualized paradigm (Cloninger & Svrakic, 2000). Identifying the Target: Neurobiology of Clusters and Dimensions A basic tenet of pharmacology is that of clearly identifying the target symptoms at which intervention is aimed and for which data will be collected and monitored over time to determine response and efficacy. In the case of treating PDs pharmacologically, this may CORRESPONDENCE CONCERNING THIS COLUMN should be addressed to Rafael A. Rivas-Vazquez, Neurologic Center of South Florida, Baptist Medical Arts Building, 8940 North Kendall Drive, 802-E, Miami, Florida 33176. E-mail: [email protected] M ARK A. B LAIS received his PsyD in clinical psychology from Nova Southeastern University in 1990 and is chief psychologist of inpatient service at Massachusetts General Hospital and associate professor at Har- vard Medical School. Professional Psychology: Research and Practice, 2002, Vol. 33, No. 1, 104 –107 Copyright 2002 by the American Psychological Association, Inc. 0735-7028/02/$5.00 DOI: 10.1037//0735-7028.33.1.104 104 require a bit of a conceptual shift. A PD is defined as a pattern of inner experience and external behavior (manifested by cognitive processing of the environment, affective regulation, interpersonal functioning, and impulse control) that remains inflexible over time, impairs social and occupational functioning, and pervades across a wide range of situations (American Psychiatric Association [APA], 2000). In the current classification system, a categorical approach (which assumes that PDs are qualitatively distinct syndromes) groups the disorders into three clusters:Cluster A,including paranoid, schizoid, and schizotypal PDs, which may manifest in cognitive distortions and an interpersonal style that is odd, eccentric, or detached;Cluster B, consisting of antisocial, borderline, histrionic, and narcissistic PDs, which often involve behavior that appears dramatic, erratic, impul- sive, aggressive, or affectively dysregulated; andCluster C,which includes avoidant, dependent, and obsessive-compulsive PDs that tend to involve fear, anxiety, apprehension, or perceived avoidance of harm (APA, 2000). A review of the literature reveals that the greatest number of biological and pharmacologic studies have focused almost exclusively on borderline, schizotypal, and antisocial PDs. Research geared at identifying specific neurobiological markers for various PDs has yielded interesting—albeit preliminary—results. A consistent finding with borderline PD is serotonin dysregulation, manifested by reduced levels of serotonin metabolites in cerebrospinal fluid, blunted neuroendocrine responses to serotonergic agonists, and diminished levels of serotonin synthesis and reactivity in prefrontal cortex and corticostriatal pathways, as evidenced by positron emission tomography (PET) imaging (Gurvits, Koenigsberg, & Siever, 2000; Leyton et al., 2001). This finding may correlate with impulsive, aggressive, and self-injurious activity, including suicidal behaviors. Anatomically, volumetric analysis of magnetic resonance imaging (MRI) scans conducted on a small series of patients with borderline PD revealed some structural variability in the frontal lobes and hip- pocampus (the latter is most prominent in borderline patients report- ing a history of abuse; Driessen et al., 2000). Studies of patients with schizotypal PD, often described as a clinical entity existing along the schizophrenia spectrum, have consistently yielded a pattern of processing deficits—sensory gat- ing, working memory, verbal learning, and sustained attention— that are similar to those noted with schizophrenic patients, al- though the pattern of dysfunction may be less severe and more focal (Cadenhead, Light, Geyer, & Braff, 2000; Kirrane & Siever, 2000). Results from MRI studies have suggested abnormalities in the temporal lobe, corpus callosum, and thalamic nuclei (Byne et al., 2001). Furthermore, schizotypal patients do not demonstrate the same degree of diminished frontal lobe volume as do patients with schizophrenia, which may correlate with the comparably less severe pattern of cognitive and social deterioration demonstrated by schizotypal patients (Kirrane & Siever, 2000). There is less neurobiological data appearing in the recent liter- ature regarding antisocial PD, although data continue to implicate subtle frontal dysfunction (as measured by imaging, neuropsycho- logical, and evoked potentials studies) and reduced autonomic arousal and reactivity in the face of distressing stimuli. Recently, Raine, Lencz, Birhle, LaCasse, and Colletti (2000) identified an 11% reduction in prefrontal gray matter volume in patients with antisocial PD (who had no history of acquired brain lesions or insult), and they asserted that this finding may subserve the clin- icopathological features observed with this disorder. Although the categorical approach is used in the present diag- nostic system, this may not be the most useful paradigm whenapplying pharmacological principles to PDs (Cloninger & Svrakic, 2000). Bolstered in part by biological studies, a dimensional ap- proach organized around specific core symptoms—rather than a specific diagnosis—may have greater utility for initiating and monitoring pharmacotherapy with PDs. As noted above, four dimensions of PD symptom clusters have been characterized that show some degree of correspondence to the current PD categories and assume a neurobiological substrate that can potentially serve as a rationale for treatment selection (Siever & Davis, 1991): 1. Thecognitive–perceptual dimension,generally correlating with Cluster A disorders, includes psychosis, unusual perceptual experiences, dissociation, suspiciousness, and odd or magical thinking. Behaviors from this dimension may be the result of dysfunction within the dopaminergic system. 2. Theimpulsive–aggressive dimensionserves as a prominent factor for Cluster B PDs. Anger, aggression, and behavioral dis- inhibition constitute primary impairments in this dimension and may implicate dysfunction in the serotonergic system. 3. Theaffective instability dimensionis also closely tied with the Cluster B disorders and consists of mood dysregulation, depres- sion, dysphoria, and emotional lability. These behaviors may have broad neurotransmitter underpinnings, possibly related to dysfunc- tion in serotonergic, cholinergic, or noradrenergic systems. 4. Theanxiety–inhibition dimension,predominantly associated with Cluster C disorders, consists of anxiety, fear, and manifesta- tions of behavioral inhibition geared at reducing exposure to anxiety-provoking situations. This dimension may reflect a distur- bance in autonomic function and may be mediated by serotonergic and noradrenergic systems. Speculation and identification of specific neurotransmitters sub- serving the PD dimensions translate into important pharmacolog- ical targets (Soloff, 2000). It should be noted that while a certain degree of concordance exists between clusters and dimensions, the heterogeneity of PDs may result in expression of behaviors from several different dimensions within a single PD. For example, although patients with borderline PD typically demonstrate behav- iors from the impulsive–aggressive and affective instability dimen- sions, some borderline patients may exhibit behaviors along the cognitive–perceptual dimension (APA, 2001). This reinforces the notion of basing treatment selection on target-symptom groups rather than on a specific diagnosis. Although results from clinical trials reported in the literature typically refer to the application of a medication to a specific PD diagnosis, efficacy data are typically collected on one of the dimensions noted above (in addition to ratings of effect on global functioning). Application of Specific Classes of Medications to PDs Antipsychotics One of the earliest reports of applying medications to PDs involved the antipsychotic trifluoperazine (Vilkin, 1964). 1Since 1Drug names for the medications discussed in this article are as follows: alprazolam (Xanax), carbamazepine (Tegretol), chlorpromazine (Thor- azine), clonazepam (Klonopin), clozapine (Clozaril), divalproex sodium (Depakote), fluoxetine (Prozac), haloperidol (Haldol), loxapine (Loxitane), naltrexone (ReVia), olanzapine (Zyprexa), perphenazine (Trilafon), risperi- done (Risperdal), sertraline (Zoloft), thiothixene (Navane), trifluoperazine (Stelazine), and venlafaxine (Effexor). 105 CLINICAL PHARMACOLOGY UPDATE then, several conventional antipsychotics, including haloperidol, perphenazine, thiothixene, chlorpromazine, and loxapine, have been investigated with variable and modest therapeutic efficacy in PDs (Coccaro, 1998). Patients in these studies demonstrated either borderline or schizotypal PDs. Efficacy was noted for cognitive– perceptual distortions, as would be expected, but also for symp- toms from other dimensions, including the impulsive–aggressive and affective instability dimensions (Kapfhammer & Hippius, 1998; Soloff, 2000). The advent of the atypical antipsychotics (with their relatively decreased tendency to produce motor side effects and expanded efficacy for improving negative symptoms [e.g., alogia, avolition, apathy, affective flattening] associated with schizophrenia) has prompted a decrease in the use of the conven- tional antipsychotics with PDs. Several studies have provided preliminary data supporting the efficacy of the atypical antipsychotic clozapine for treating psy- chotic symptoms demonstrated by borderline PD, as well as for treating impulsivity, aggression, and self-mutilation (Benedetti, Sforzini, Colombo, Maffei, & Smeraldi, 1998; Chengappa, Ebel- ing, Kang, Levine, & Parepally, 1999). However, given clozap- ine’s tendency to produce agranulocytosis, clinicians are increas- ingly beginning to use the other atypical antipsychotics (APA, 2001). Case reports and open-label trials have suggested that olanzapine and risperidone may have efficacy in patients with borderline PD who exhibit either self-mutilation or mild depres- sion (Coccaro, 1998; Hough, 2001; Schulz, Camlin, Berry, & Jesberger, 1999). There has been one report of risperidone reduc- ing aggression and impulsivity associated with antisocial PD (Hirose, 2001). Mood Stabilizers As a group, this class of medications shows particular promise for treating patients with PDs that load high on the impulsive– aggressive and affective instability dimensions. Lithium was the first mood stabilizer to be studied, with results suggesting thera- peutic efficacy for aggression and emotional lability displayed by patients with PDs (Coccaro, 1998). The anticonvulsant carbamaz- epine has also been studied for PDs associated with behavioral impulsivity, but it has demonstrated equivocal results (Soloff, 2000). Recent attention has focused on another mood-stabilizing anticonvulsant—divalproex sodium—with results from several open-label studies indicating efficacy for borderline patients who demonstrate affective instability, irritability, and impulsive– aggressive behavior (Kavoussi & Coccaro, 1998; Townsend, Cam- bre, & Barbee, 2001). These findings have recently been supported by results from a double-blind, placebo-controlled trial in which divalproex sodium was more effective than placebo in reducing aggression and depression in patients with borderline PD (Hol- lander et al., 2001). Antidepressants Older antidepressants—the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs)—have demon- strated variable results with PDs. With the advent of newer anti- depressants, coupled with the cardiotoxicity and other undesirable side effects associated with the MAOIs and TCAs, these older agents have fallen into relative disuse. The selective serotonin reuptake inhibitors (SSRIs) have received the most attention, pri-marily with borderline PD. These agents are thought to represent the usual starting point as first-line agents for impulsive– aggressive symptoms and affective dysregulation (APA, 2001; Gunderson, 2001). Fluoxetine has been the most extensively stud- ied, with results from three randomized, placebo-controlled studies of primarily borderline patients demonstrating efficacy on mea- sures of anger, rage, aggression, depression, irritability, and self- mutilation (APA, 2001). Data are also available for sertraline, primarily from case reports and open trials. A similar pattern of response should be expected from the other SSRIs, and there is no reason to suspect that one SSRI will have significantly greater efficacy over another. The application of the novel antidepressant venlafaxine, which has both serotonin and norepinephrine reuptake blockade, should be of interest. One open trial has noted a decrease in self-injurious behavior and overall symptomatology in a group of patients with borderline PD (Markovitz & Wagner, 1995). SSRI treatment of avoidant PD has been discussed in the literature, although there is some difficulty in overlap between this PD and a generalized form of the Axis I disorder social phobia (which has been found to be responsive to SSRIs and other newer antidepressants). Benzodiazepines Despite an early finding of efficacy for diazepam in patients with PDs (Vilkin, 1964), this class of agents has not been consis- tently or systematically studied. Case reports and open-label trials of alprazolam and clonazepam suggest some efficacy in decreasing anxiety and fear-related symptoms associated primarily with bor- derline PDs (Kapfhammer & Hippius, 1998; Soloff, 2000). How- ever, there is at least one report that application of these agents to PDs can lead to behavioral disinhibition and dyscontrol (Coccaro, 1998). This, in conjunction with the high potential for abuse and dependence, has served as a bit of contraindication for using this class with PDs (Cloninger & Svrakic, 2000). Application of these antianxiety agents to PDs associated with the anxiety–fear dimen- sion, most notably avoidant, dependent, and obsessive-compulsive PD, has not been reported. Opioid Antagonists On the basis of findings that self-injurious behavior may be partially produced by dysregulation of endorphins (endogenous opioid-like neuropeptides), the opioid antagonist naltrexone has been used with some success in various populations (e.g., children with mental retardation and other developmental disabilities). There is one case report of naltrexone reducing self-mutilation in a patient with borderline PD (McGee, 1997). Results from an open-label trial of 13 patients with borderline PD suggested that naltrexone may reduce the duration and intensity of cognitive– perceptual symptoms of dissociation (Bohus et al., 1999). Summary Mounting data would appear to justify more than a secondary role for medications in the overall treatment strategies for PDs. The current paradigm posits that pharmacological intervention impacts either underlying neurobiological dysfunction or core symptoms that are fundamental aspects of these PDs (rather than simply treating comorbid Axis I symptoms). Of the recognized 106 CLINICAL PHARMACOLOGY UPDATE disorders in the current classification system, borderline, schizo- typal, and antisocial PDs have been investigated to the greatest degree, with little if any work being done with the other PDs. Dimensions of symptom clusters represent the most likely phar- macological targets, and these include cognitive–perceptual dis- tortions, aggression–impulsivity, affective instability, and fear– anxiety. Of the currently available agents, preliminary data suggest that the atypical antipsychotics and mood stabilizers may provide the broadest spectrum of efficacy in the most troublesome dimen- sions (notably, cognitive distortions, aggression–impulsivity, and affective instability). However, algorithms developed for guiding the pharmacological treatment of borderline PD indicate that the SSRIs and newer antidepressants occupy a first-line position for affective instability and aggression–impulsivity (APA, 2001). In light of the current data and clinical application, there is general agreement that more well-controlled studies are needed to better elucidate the efficacy, safety, and application of medications to various PDs. Initiation of pharmacotherapy with this population also requires increased vigilance regarding risk-management issues. Medication abuse, in the form of overdose or noncompliance, takes place at least 50% of the time during the treatment of patients with bor- derline PD (Gunderson, 2001), requiring that clinicians be active in monitoring for adverse and potentially lethal events. Psycho- therapy and psychosocial interventions remain critical for many PDs, and it has been well stated that the art of pharmacotherapy for PDs involves employing the concurrent use of nonpharmacologi- cal therapies, addressing potentially unrealistic expectations, and emphasizing that medications are not a panacea (Janicak, Davis, Preskorn, & Ayd, 1997). References American Psychiatric Association. (2000).Diagnostic and statistical man- ual of mental disorders(4th ed., rev.). Washington, DC: Author. American Psychiatric Association. (2001). Practice guideline for the treat- ment of patients with borderline personality disorder.American Journal of Psychiatry, 158,1–52. Bender, D. S., Dolan, R. T., Skodol, A. E., Sanislow, C. A., Dyck, I. R., McGlashan, T. H., et al. (2001). Treatment utilization by patients with personality disorders.American Journal of Psychiatry, 158,295–302. Benedetti, F., Sforzini, L., Colombo, C., Maffei, C., & Smeraldi, E. (1998). Low-dose clozapine in acute and continuation treatment of severe bor- derline personality disorder.Journal of Clinical Psychiatry, 59,103– 107. Bohus, M. J., Landwehrmeyer, G. B., Stiglmayr, C. E., Limberger, M. F., Bohme, R., & Schmahl, C. G. (1999). Naltrexone in the treatment of dissociative symptoms in patients with borderline personality disorder: An open-label trial.Journal of Clinical Psychiatry, 60,598–603. Byne, W., Buchsbaum, M. S., Kemether, E., Hazlett, E. A., Shinwari, A., Mitropoulou, V., & Siever, L. J. (2001). Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder.Archives of General Psychiatry, 58, 133–140. Cadenhead, K. S., Light, G. A., Geyer, M. A., & Braff, D. L. (2000). Sensory gating deficits assessed by the P50 event-related potential in subjects with schizotypal personality disorder.American Journal of Psychiatry, 157,55–59. Chengappa, K. N., Ebeling, T., Kang, J. S., Levine, J., & Parepally, H. (1999). Clozapine reduces severe self-mutilation and aggression in psy- chotic patients with borderline personality disorder.Journal of Clinical Psychiatry, 60,477–484.Cloninger, C. R., & Svrakic, D. M. (2000). Personality disorders. In B. J. Sadock & V. A. Sadock (Eds.),Comprehensive textbook of psychiatry (7th ed., pp. 1723–1764). Philadelphia: Lippincott/Williams & Wilkins. Coccaro, E. F. (1998). Clinical outcome of psychopharmacologic treatment of borderline and schizotypal personality disordered subjects.Journal of Clinical Psychiatry, 59(Suppl. 1), 30–35. Driessen, M., Herrmann, J., Stahl, K., Zwaan, M., Meier, S., Hill, A., et al. (2000). Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization.Archives of General Psychiatry, 57,1115–1122. Gunderson, J. G. (2001).Borderline personality disorder: A clinical guide. Washington, DC: American Psychiatric Publishing. Gurvits, I. G., Koenigsberg, H. W., & Siever, L. J. (2000). Neurotransmit- ter dysfunction in patients with borderline personality disorder.Psychi- atric Clinics of North America, 23,27–40. Hirose, S. (2001). Effective treatment of aggression and impulsivity in antisocial personality disorder with risperidone.Psychiatry & Clinical Neurosciences, 55,161–162. Hollander, E. H., Allen, A., Prieto Lopez, R., Bienstock, C. A., Grossman, R., Siever, L. J., et al. (2001). A preliminary double-blind, placebo- controlled trial of divalproex sodium in borderline personality disorder. Journal of Clinical Psychiatry, 62,199–203. Hough, D. W. (2001). Low-dose olanzapine for self-mutilation behavior in patients with borderline personality disorder.Journal of Clinical Psy- chiatry, 62,296–297. Janicak, P. G., Davis, J. M., Preskorn, S. H., & Ayd, F. J. (1997). Principles and practice of psychopharmacotherapy.Baltimore: Wil- liams & Wilkins. Kapfhammer, H.-P., & Hippius, H. (1998). Pharmacotherapy in personality disorders.Journal of Personality Disorders, 12,277–288. Kavoussi, R. J., & Coccaro, E. F. (1998). Divalproex sodium for impulsive aggressive behavior in patients with borderline personality disorder. Journal of Clinical Psychiatry, 59,676–680. Kirrane, R. M., & Siever, L. J. (2000). New perspectives on schizotypal personality disorder.Current Psychiatry Reports, 2,62–66. Leyton, M., Okazawa, H., Diksic, M., Paris, J., Rosa, P., Mzengeza, S., et al. (2001). Brain regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder.American Jour- nal of Psychiatry, 158,775–782. Markovitz, P. J., & Wagner, S. C. (1995). Venlafaxine in the treatment of borderline personality disorder.Psychopharmacology Bulletin, 31,773– 777. McGee, M. D. (1997). Cessation of self-mutilation in a patient with borderline personality disorder treated with naltrexone [Letter].Journal of Clinical Psychiatry, 58,32–33. Raine, A., Lencz, T., Birhle, S., LaCasse, L., & Colletti, P. (2000). Reduced prefrontal gray matter volume and reduced autonomic activity in antisocial personality disorder.Archives of General Psychiatry, 57, 119–127. Schulz, S. C., Camlin, K. L., Berry, S. A., & Jesberger, J. A. (1999). Olanzapine safety and efficacy in patients with borderline personality disorder and comorbid dysthymia.Biological Psychiatry, 46,1429– 1435. Siever, L. J., & Davis, K. L. (1991). A psychobiological perspective on personality disorders.American Journal of Psychiatry, 148,1647–1568. Soloff, P. H. (2000). Psychopharmacology of borderline personality dis- order.Psychiatric Clinics of North America, 23,169–192. Townsend, M. H., Cambre, K. M., & Barbee, J. G. (2001). Treatment borderline personality disorder with mood instability with divalproex sodium: A series of ten cases.Journal of Clinical Psychopharmacol- ogy, 21,249–251. Vilkin, M. I. (1964). Comparative chemotherapeutic trial in treatment of chronic borderline patients.American Journal of Psychiatry, 120,1004. 107 CLINICAL PHARMACOLOGY UPDATE
The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th
ORIGINAL PAPER Lamotrigine in the Treatment of Unipolar Depression with and Without Comorbidities: A Literature Review Adam Daniel Zavodnick •Rizwan Ali Published online: 10 February 2012 Springer Science+Business Media, LLC 2012 AbstractTo review the available data behind the use of lamotrigine in unipolar depression and common comorbid conditions. A PubMed based literature review was conducted using keywords related to lamotrigine, depression, anxiety, post traumatic stress disorder (PTSD), obsessive–compulsive disorder (OCD), and personality disorders. A large number of trials using lamotrigine for unipolar depression and various comorbid conditions were reviewed. A major limitation behind the majority of studies was a limited course of the treatment phase. The most robust data was found among studies that followed patients for over 8 weeks, and used higher dosages. Patients with comorbid anxiety states appeared to bene t. Patients with borderline personality disorder also appeared to bene t. The bene ts of lamotrigine in unipolar depression have been inconsistently noted in a number of studies. This is due in part to short treatment phases, atypical domains of bene t and different patient populations across studies. Patients with more treatment-resistance, comorbid anxiety and borderline personality disorder may be more able to bene t from lamotrigine. Introduction The history of lamotrigine in the management of psychiatric illness is complex. Initially developed as an anticonvulsant, its effectiveness was at rst thought to be due to its antagonism of folate synthesis [1]. However its antagonism in this regard was modest and it was subsequently found to block voltage dependent sodium channels and modulate the A. D. Zavodnick (&) Department of Psychiatry and Behavioral Medicine, Carilion Clinic-Virginia Tech Carilion School of Medicine, Roanoke, VA, USA e-mail: [email protected] A. D. Zavodnick Veterans Affairs Medical Cente, 1970 Roanoke Boulevard—116A7, Salem, VA 24153, USA R. Ali Psychiatry Service, Veterans Affairs Medical Center, Salem, VA, USA 123 Psychiatr Q (2012) 83:371–383 DOI 10.1007/s11126-012-9208-4 release of the excitatory neurotransmitter glutamate. Calcium channel blockade as well as other properties of this compound also may contribute to its effect on mood [2]. There have been a variety of studies using lamotrigine in the treatment of bipolar disorder and treatment-resistant unipolar depression. Fewer studies have looked at con- ditions which are often comorbid with affective illness such as anxiety disorders and personality disorders. Some of the more recent double blind placebo controlled studies on lamotrigine in mood disorders have not shown bene t in some of the primary outcome measures, however there have been notable limitations with these studies, the most prominent being the short duration of the trials. In addition, many of the comorbid conditions such as personality disorders had been selected out through exclusion criteria. To our knowledge, there have been no articles analyzing all of the studies in unipolar depression and comorbid anxiety or personality disorders. The present review is performed to assess what was known about the effects of lamotrigine in the treatment of unipolar depression, anxiety disorders and borderline personality disorder. This literature review includes the following objectives: 1. What is known about the effects of lamotrigine in unipolar depression, both in acute treatment and long-term maintenance trials? 2. Which outcome measures are altered by treatment with lamotrigine? 3. Are there other conditions which are often comorbid with unipolar depression that are effected by treatment with lamotrigine? Method A PubMed based literature search was conducted. Relevant keywords such as ‘‘lamotri- gine’’ ‘‘depression’’ ‘‘borderline personality disorder’’ ‘‘PTSD’’ and ‘‘OCD’’ were used. Several hundred studies were found, with the majority excluded as they did not meet the objectives of the study. Review articles were studied and reference lists were searched for additional studies for inclusion. A total of 13 published articles using lamotrigine in the treatment of unipolar depression were reviewed and categorized in Table1. Unpublished studies were reviewed and discussed but were not categorized in Table1. In addition, 3 studies assessing the role of lamotrigine in the management of borderline personality disorder and 3 studies assessing the role of lamotrigine in anxiety disorders were also reviewed. Additional studies of interest are also cited where relevant to the discussion. Results The History of Lamotrigine and Psychiatric Disorders Lamotrigine and its effect on mood was a serendipitous discovery, observed by neurolo- gists nearly 20 years ago. Smith et al. [3] demonstrated this effect in a study in 1993. Domains such happiness, self-esteem, sense of mastery, anxiety, depression and appetite were included. It was through this comprehensive evaluation that a strong bene t was observed in the spheres of happiness and mastery. This bene t was not explained by better seizure control and was highly signi cant with a p value of .003. It is worth noting that the bene ts of lamotrigine in that patient population might not have been appreciated had the 372 Psychiatr Q (2012) 83:371–383 123 Table 1Comparison of trials of lamotrigine in unipolar depression StudyNtype of study limitations Other pertinent observationsLength Dosage Measurement Result Conclusion Smith et al. [3]N81 Cross over Excluded sev mental illness16–18 weeks 400 mg (AED adjunct) 200 mgHealth related questionnaire (affect, mood, esteem, mastery)Happiness mastery Signi cance independent of seizure control Kumar and Khanna [20]N8 Case series4 weeks Max 100 mg YBOCS, CGI-S, and CGI-I1 pt improved NS Barbee and Jamhour [10]N31 Retrospect Chart review No placebo Pts had been tried on an average of 13.27 past antidepressants. [90% with comorbid anxiety disordersAvg 41.80 weeksAvg dose 112.90CGI and GAF 40.5% much improved 21.6% mildly improved 37.8% unchangedEffective especially in less depressed, fewer failed trials, comorbid anxiety Obrocea et al. [8]N45 35 bipolar 10 unipolar Placebo controlled double-blind randomized controlled trial Mixed patient population LTG was used as monotherapy rather than an adjunct6 weeks Avg dose 274 Max dose 500 mg Abrupt titrationCGI Response LTG 51% vs 28% Gabapen vs 21% PboResponse associated w/bipolar diagnosis, male gender, fewer med trials Normann et al. [9]N40 Placebo controlled double-blind randomized controlled trial9 weeks 200 mg/day Ham-D and CGI Selected response (depressed mood, guilt, work/interest) CGI, fewer benzos, fewer withdrawalsExcel response to SSRI Rocha and Hara [11]N25 Retrospective chart review1 mont at target doseAvg 155 mg/ dayCGI 76% improved Comorbidity decreased response Barbosa et al. [12]N 13-LTG N10-Pbo Placebo controlled double-blind randomized controlled trial BP II and unipolar patients25–100 mg over 6 wks100 mg/day HAM-D, MADRS, and CGICGI HAM-D MADRSImproved CGI No improvement in HAM-D or MADRS. No signi cant difference between mdd/bp II Psychiatr Q (2012) 83:371–383 373 123 Table 1continued StudyNtype of study limitationsOther pertinent observationsLength Dosage Measurement Result Conclusion Gutierrez et al. [13]N34 Retrospect chart review356 days Avg dose 43 mg Max dose 113 mg/day‘‘Med Visit by MD’’ Improvement in multiple domains Improvement in multiple domains by 30 days Gabriel [14]N14 Open study Heterogeneous population Highly resistant population—use of MAOIs, TCAs, antipsychotics, 1 past hospitalization 2 failed ECT/TMS trials6 months Max 200 mg/ dayCGI-S and MADRS Improvement in CGI MADRS Social/Occ FunctioningImprovement by 8 weeks Schindler and Anghelescu [15]N34 Open study No placebo Li vs LTG8 weeks Max dose 250 mg Avg dose 152.94HAM-D Improvement in both arms Improvement in both arms Santos et al. [16]N34 Treatment resistant depression with at least 2 failed med trials High rate of placebo response No details on benzo use No details on anxiety No HAM-D No suicidality No psychosis No Axis II8 weeks 200 mg/day for the last 4 weeksMADRS, CGI-S, and CGI-INS NS 3 pts left LTG arm b/c of adverse effects and non- compliance 2 left placebo arm b/c of worsening dep. 1 left b/c of mania 374 Psychiatr Q (2012) 83:371–383 123 Table 1continued StudyNtype of study limitationsOther pertinent observationsLength Dosage Measurement Result Conclusion Barbee et al. [17]N48-LTG N48-Pbo Placebo controlled double-blind randomized controlled trial More past episodes and anxiety in the LTG arm10 weeks At least 100 mg/day for 5 weeks At least 200 mg/day for last 4 weeksMADRS, HDRS-17, CGI-S, and CGI-IPrimary outcome measures negative Post hoc analysis suggested bene t in severely depressed patients. Completer analysis suggested bene t LTGLamotrigine Psychiatr Q (2012) 83:371–383 375 123 only measures of well being been restricted to the Hamilton Rating Scale for Depression (HAM-D) or the Montgomery-A sberg Depression Rating Scale (MADRS). Subsequent studies into the use of lamotrigine in a variety of psychiatric ill- nesses followed. The most robust and consistent ef cacy was found for bipolar depression [1,4–6]. As observations regarding lamotrigine and improvement in mood were being noted, GlaxoSmithKline became interested pursuing an indication for lamotrigine in the treatment of bipolar disorder. It sponsored three relatively brief (7–8 week) studies investigating lamotrigine in the management of unipolar depression. 1All were negative and in one instance neither lamotrigine nor desipramine was able to separate from placebo. Investi- gation was done as part of the process for obtaining a bipolar indication. 2Subsequent published studies showing ef cacy of lamotrigine in unipolar depression followed. Unipolar Depression, Anxiety Disorders, Personality Disorders and Lamotrigine Over the past decade there have been several published studies evaluating lamotrigine in the treatment of unipolar depression [7–17]. Also studied have been conditions which are frequently comorbid with depression such as anxiety disorders [18], speci cally general- ized anxiety disorder (GAD) [19], OCD [20], PTSD [21] as well as borderline personality disorder [22–24]. Preliminary Case Reports and Retrospective Chart Reviews of Lamotrigine in Unipolar Depression Maltese [25] wrote a case report in which a patient with treatment-resistant depression responded to lamotrigine in 1999. Following that piece there were several retrospective chart reviews [10,11,13] and open studies [14,15] in depression. In a retrospective chart review Barbee and Jamhour [10] found bene t in less severely depressed patients and in those with comorbid anxiety, however all patients were treatment-refractory. In a sub- sequent retrospective chart review, Rocha and Hara [11] found bene t with lamotrigine but no association between treatment response and current depressive morbidity or past epi- sodes. He found comorbidity adversely predicted response to lamotrigine, again all patients were treatment-refractory to some extent. 1Unpublished studies available online. GlaxoSmithKline. An eight-week, multicenter, double-blind, randomized, xed-dose evaluation of the ef cacy and safety of lamotrigine (200 mg/day), desipramine (200 mg/d and, and placebo in outpatients with unipolar depression (result summary for the study SCAA2011 [105-613]).http://download.gsk-clinical studyregister.com/ les/1666.pdf. Ver ed December 12, 2011. GlaxoSmithKline. A randomized, multicenter, double-blind, placebo-controlled, xed-dose, 7-week evaluation of the ef cacy and safety of lamotrigine in patients with major depression (result summary for study SCA20022.http://download.gsk-clinicalstudyregister.com/ les/1661.pdf. Veri ed December 12, 2011. GlaxoSmithKline. A randomized, multicenter, double-blind, placebo-controlled, xed-dose, 7-week evaluation of the ef cacy and safety of lamotrigine in treatment of a major depressive episode in unipolar depressed patients (result summary for study SCA20025).http://download.gsk-clinicalstudyregister.com/ les/1663.pdf. Veri ed December 12, 2011. 2GlaxoSmithKline internal data. 376 Psychiatr Q (2012) 83:371–383 123 Open Studies Gabriel [14] performed an open study in treatment-resistant depression in 2006. He found a robust response to lamotrigine as early as 8 weeks, however patients were followed for 6 months. Strangely there was an appreciable response in some domains as early as week 2 when the dosage was quite low. This could be attributed to placebo response or a syner- gistic effect between lamotrigine and selective serotonin reuptake inhibitor (SSRI), which would be consistent with the ndings of Normann et al. [9], who found that lamotrigine may have accelerated the response to SSRI treatment. Schindler and Anghelescu [15] performed an open trial comparing lamotrigine augmentation to lithium augmentation in treatment-resistant depression. That study found no signi cant difference between the two treatment arms at 8 weeks. The nature of these studies such as absence of placebo arm make them more prone to bias. However they also allow for longer follow up than many of the prospective studies. For example Barbee and Jamhour [10] retrospectively followed patients for over 41 weeks while Gutierrez et al. [13] followed patients for almost a full year. Double-Blind Studies There have been 5 published separate double-blind randomized placebo-controlled studies of lamotrigine in depression [7,9,12,16,17]. Obrocea et al. [8] performed a subsequent analysis on patients rst investigated by Frye et al. [7]. Unfortunately all studies were relatively brief (6–10 weeks) and this time period included the lengthy lamotrigine titra- tion. This was also true of the three unpublished studies from GlaxoSmithKline footnoted above. With the exception of the study by Frye et al. [7] and Obrocea et al. [8] all were negative regarding primary outcome measures such as composite HAM-D and MADRS scores. However, the outcome measure Clinical Global Impression Scale (CGI) consis- tently showed improvement in the majority of published studies [7–9,12]. Normann et al. [9] showed bene t in speci c elements of HAM-D and potential acceleration of the response to SSRI in addition to improved CGI score. In contrast to the retrospective and open studies previously mentioned, Barbee et al. [17] found bene t among more treatment- resistent patients and in those with comorbid anxiety. Only Santos et al. [16] found no bene t in realms assessed, MADRS and CGI. Individual Study Analysis Obrocea et al. [8] followed patients rst investigated by Frye et al. [7]. That study investigated lamotrigine monotherapy in patients with unipolar depression (N10) and depression due to bipolar disorder type II (N35). While unipolar patients did improve, a more robust effect was seen in those with bipolar disorder type II. Fewer failed medication trials and male gender were also associated with a favorable response. Only 6 weeks in duration, it was fairly brief, however the titration schedule was more aggressive (maximum dosage of 500 mg/day with mean dosage of 274 mg/day) than subsequent studies; thus patients were on a therapeutic concentration for a longer period of time. This might explain why lamotrigine was so prominently superior to placebo (51% vs 21%) and why there were more drop outs secondary to intolerance among the lamotrigine group. Investigating lamotrigine augmentation of paroxetine for depression in unipolar and bipolar type II depression, Normann et al. [9] found improvement in CGI and also speci c domains of HAM-D (depressed mood, guilt, work/interest). More patients in the Psychiatr Q (2012) 83:371–383 377 123 lamotrigine arm remained in the study and there were fewer benzodiazepines used among the lamotrigine group. This is consistent with the retrospective study by Barbee and Jamhour [10], showing improvement among those with anxiety and with the works by Masdrakis et al. [19] and Hertzberg et al. [21], both of which showed bene cial effects of lamotrigine for anxiety disorders (GAD and PTSD respectively). Barbee and Jamhour [10] performed a retrospective chart review of 37 individuals with treatment-resistant unipolar depression, 35 of whom had comorbid anxiety disorders. Using CGI as the principle ef cacy measure, 62% of patients showed some degree of improvement, 40.5% of which were much/very much improved. Those with fewer failed trials and those with comorbid anxiety disorders appeared to bene t more. Barbosa et al. [12] investigated lamotrigine with concomitant uoxetine administration in those with unipolar depression and those with depressive episodes of bipolar disorder type II. He found improvement in CGI, however here too no differences were seen in the MADRS or HAM-D. There was no difference between unipolar and bipolar type II depression in respect to response to lamotrigine. Santos et al. [16] found no signi cant differences in all domains assessed, inclusive of CGI and MADRS. There were several limitations of the study. HAM-D was not assessed. There was no mention of, need for or number of prior inpatient hospitalizations, use of ECT or past suicidality. Quantity of benzodiazepines used and frequency of comorbid anxiety were not reported. Exclusion criteria included those with organic illness, ‘‘severe clinical disease,’’ acute depression with risk of suicide, psychosis, bipolar disorder, per- sonality disorders and disorders related to alcohol and other drugs. As will be further discussed below, the treatment-resistance was not as pronounced as some of the earlier studies. The most recent double-blind randomized control trial was performed by Barbee et al. [17]. After being started on Paroxetine or Paroxetine CR, patients were randomized to either lamotrigine (N48) or placebo (N48) and followed for 10 weeks. Administering lamotrigine or placebo for 10 weeks, it was the longest running double-blind randomized controlled trial of lamotrigine treating exclusively unipolar depressed patients. While primary outcome measures (MADRS, HAM-D, CGI) did not show a statistical difference, the signi cantly greater chronicity in the lamotrigine arm (14.33 prior episodes of depression vs 3.93 episodes in placebo arm) may have skewed the ndings. Twice the number of patients with anxiety were in the lamotrigine arm (13 patients vs 6 patients). Indeed, post hoc analyses found that among the more severely ill patients the bene ts of lamotrigine approached signi cance (P=.06). Completer analysis favoring lamotrigine neared signi cance as well. Exclusion criteria included severe personality disorders, psychosis and substance abuse in the 6 months prior to study initiation. Comorbid Diagnoses As was alluded to earlier, comorbid conditions are often excluded from prospective trials in an effort to eliminate confounding variables. For example, the studies by Santos et al. [16] and Barbee et al. [17] excluded those with prominent personality disorders. This has the potential to limit the assessment of an agent’s utility in common comorbid states, such as borderline personality disorder and anxiety disorders. Such may have been the case for lamotrigine, as it had been found to be effective for both speci c anxiety disorders, such as GAD [19], PTSD [21] and symptoms associated with borderline personality disorder [22–24]. 378 Psychiatr Q (2012) 83:371–383 123 Anxiety Disorders While Kumar and Khanna [20] did a small case series on 8 patients af icted with OCD in which no bene t was found, it was very brief (4 weeks), relatively low dose (100 mg/day) and included the lamotrigine titration. A more persuasive, albeit small study evaluating lamotrigine in PTSD was conducted by Hertzberg et al. [21]. 10 patients received lamotrigine and 4 patients received placebo over 12 weeks. 50% of the lamotrigine group compared with 25% of the placebo group responded to treatment, with improvements in re-experiencing, detachment and numbing. Patients were on 100 mg by the beginning of week 5 and dosages were increased to a maximum of 500 mg/day by week 10. A more recent case series by Masdrakis et al. [19] demonstrated improvement in 3 of 4 patients with panic disorder with agoraphobia. Lamotrigine was titrated up to 200 mg/day over 6 weeks and kept at this dosage for an additional 8 weeks. This is yet another example in which bene t was shown when patients were followed for an extended period of time beyond initial titration. Borderline Personality Disorder There have been three double-blind randomized placebo controlled studies evaluating the use of lamotrigine in borderline personality disorder (BPD). The rst was by Tritt et al. [22] in 2005, in which 24 patients were assigned to lamotrigine or placebo in a 2:1 manner for 8 weeks. Primary outcome measures were self-reported changes on the anger scales of the Trait Anger Expression Inventory (STAXI). There was a highly signi cant reduction in this measure when compared to placebo. Leiberich et al. [23] performed an 18 month follow up study in 2008, demonstrating that gains associated with lamotrigine were maintained. The most recent study evaluating lamotrigine in borderline personality disorder was by Reich et al. [24] in 2009. That study speci cally evaluated the affective lability associated with borderline personality disorder. 15 patients received lamotrigine and 13 were assigned to placebo over 12 weeks. Affective instability was assessed by the Affective Lability Scale (ALS) and the affective instability score of the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). Both scores were reduced (P.05). Discussion The Inconsistencies in the Studies Referenced Above Are Challenging to Interpret. How Can These Findings Be Reconciled? Clearly there are many potential confounding variables. The clearest element is the pro- longed titration schedule that is needed to minimize the risk of Stevens-Johnsons Syn- drome. However it is also possible that the antidepressant effects of this medication take longer than most studies are equipped to run for. For example, among bipolar studies there were many negative short-term trials but lamotrigine often separated from placebo among trials that ran for over 20 weeks or involved aggregate data [4–6]. One unpublished double-blind placebo-controlled ran- domized study by GlaxoSmithKline (Study 611), which was referenced by Goldsmith et al. [26] followed rapid cycling patients for 32 weeks. While non-signi cant in the primary outcome measure of time to intervention for an emerging mood episode, fewer lamotrigine Psychiatr Q (2012) 83:371–383 379 123 recipients required intervention for a depressive episode compared with those receiving placebo (P=0.007). Lamotrigine was signi cantly more effective than placebo at delaying time to an emerging depressive episode (P=0.047), however not at delaying time to an emerging manic/hypomanic episode. Among unipolar studies a similar trend was appreciable. In a retrospective study, Guiterrez et al. [13] found bene t as early as one month but followed patients for almost a full year. In an open study, Gabriel [14] found differences appreciable at 8 weeks but followed patients for 6 months. The double-blind studies were not as promising but patients were only on therapeutic quantities for 4–5 weeks. The degree of treatment-resistance is another variable that deserves attention. Barbee and Jamhour [10] examined patients who had failed an average 13.27 different antide- pressants in the past. 9 were on MAOIs, other medications included antipsychotics. The side effects of these medications attest to the highly resistant nature of these patients. Over 90% of patients had comorbid anxiety disorders inclusive of PTSD. 2 of the 14 patients examined by Gabriel [14] had failed ECT or transcranial magnetic stimulation and 1 had been hospitalized in the past. In contrast, a failed trial of ECT was a speci c exclusion criterion in the study by Barbee et al. [17]. Many of the patients who were treatment-resistant in the study by Santos et al. [16] had been on less than 3 antidepressants in the past. Patients were on a variety of agents inclusive of TCAs but there was no mention of past trials with ECT, past use of MAOIs or other agents such at lithium or atypical antipsychotics. This underscores the importance of careful quanti cation of ‘‘treatment-resistance.’’ Patients who fail multiple antidepressant regimens and remain outpatients may be quite different from those who fail two trials of antidepressants and are subsequently hospital- ized for a prolonged period. A full discussion of the different criteria used to assess resistance is beyond the scope of this article. However there are important differences in the Thase Rush Scale [27] and the Massachusetts General Hospital criteria [28] used in these studies. For example, according to the Massachusetts General Hospital criteria, a patient who failed 5 trials of different antidepressants in the same class would have the same score as a patient who had been on a TCA and subsequently went on to fail a trial of ECT. In contrast, Thase Rush categorizes patients based on the various classes of medications used rather than the cumulative number of trials. Among patients with depression, those who are more treatment-resistant are often less likely to respond to augmentation strategies than less severely ill patients [29]. So why would those who are more treatment-resistant appear to bene t more from lamotrigine when compared to those who are less severely depressed? One explanation would be that the effect of lamotrigine is modest, so a more ill patient population is needed to show effect. Alternatively, it could be that those who are more treatment-resistant and those with more past episodes represent a distinct type of unipolar depression, an entity that is more similar to bipolar disorder. Saggese et al. [30] articulates this viewpoint, noting that patients with highly recurrent unipolar depression (HRUP) often have family histories of bipolar disorder and are more likely to respond to mood stabilizers. Concordant with this viewpoint is the observation that highly treatment-resistant MDD patients frequently go on to be treated with atypical antipsychotics, lithium and other mood stabilizers. Another confounding variable has been the range of dosages across trials. Two of the double-blind randomized trials, which showed bene t used higher dosages of lamotrigine. Obrocea et al. [8] used a maximum dosage of 500 mg, while Schneider and Anghelescu [15] used a maximum dosage of 250 mg. Among bipolar studies dosages as high as 380 Psychiatr Q (2012) 83:371–383 123 500 mg have been used [4]. While beyond the scope of this paper, lamotrigine has been used for psychosis in dosages as high as 400 mg/day [31]. Setting aside the parameter of treatment length, dosage and speci c differences in patient populations across studies, it would appear that lamotrigine is a dif cult drug to study. The most common outcome measures frequently fail to capture its bene t and yet there are clearly patients who respond quite well. Why is this the case? Looking back to Smith et al. [3], it was happiness that was statistically signi cant between treatment arms, not depression. In this regard it is worth remembering that lamotrigine’s mechanism of action involves glutamatergic modi cation and is quite dif- ferent than the serotonergic and noradrenergic agents routinely used as rst line medica- tions. It should not be surprising if the course and nature of symptom reduction is differently expressed. As more glutamatergic agents become available, older screening tools may need to be reassessed for sensitivity. It might be that the patients who are best helped by lamotrigine are selected out of the more rigorous studies. Axis II pathology, PTSD, past hospitalizations and suicidality are frequent in routine clinical practice but not in many of the double-blind trials referenced above. The role of cognition deserves mention. While not routinely assessed by HAM-D or MADRS, there is abundant data on the detrimental effects of mood disorders on cognition, both in acute episodes and during interepisode recovery [32]. There is also data behind the neuroprotective properties of mood stabilizers such as lamotrigine [2]. Paradoxically it is also known that many mood stabilizers actually impair cognition. In this respect lamo- trigine appears superior, having little negative impact on cognition [33] and may be demonstrably bene cial [34]. In keeping with this, Tiihonen et al. [35] found bene cial effects of lamotrigine in both negative and positive psychotic symptomatology of Schizophrenic patients resistant to clozapine. Future studies will likely need to be of longer duration and with more sensitive detection modalities to better characterize the bene ts of this compound. At this point it would appear that lamotrigine is somewhat of an atypical antidepressant. When all of the available studies are reviewed, bene t appears most robust in the long-term management of treatment-resistant severe mood disorders. Outcome measures such as HAM-D and MADRS appear to be less sensitive than CGI at recording improvement. Given the data in isolated anxiety disorders such as panic with agoraphobia [19] and PTSD [21], it is quite feasible that those patients with depression and comorbid anxiety disorders will bene t more than others. The study by Barbosa et al. [12] also suggested a role of lamotrigine for depression with comorbid anxiety. Patients with borderline personality disorder often have depressive symptoms in addi- tion to affective instability and aggression. There is strong evidence for the use of lamo- trigine in the treatment of certain aspects of this disorder as well [22–24]. While speculative at this point, the neuro-protective role of lamotrigine may translate into its use among depressed patients with comorbid cognitive disorders such as mild cognitive impairment. Lamotrigine’s unique mechanism of action allows it to be safely added to traditional serotonergic agents without increasing risk of serotonin syndrome. It has been associated with weight loss as well [2]. Patients with comorbid migraine or seizure disorders may also bene t from the dual ef cacy of this agent. Finally lamotrigine may be good option for those depressed patients whose history is less than straightforward and where there are suspicions of borderline personality disorder or bipolar disorder. Going forward let us remember the history of this medication. The effects of lamotri- gine on mood were rst observed by neurologists looking to understand the whole patient Psychiatr Q (2012) 83:371–383 381 123 [3]. Over the course of months, measures of self-esteem, mastery, happiness and anxiety were assessed, alongside seizure frequency and duration. It was because of this meticulous analysis that the bene cial effects of lamotrigine on mood were rst discovered. Sub- sequent studies on mood were not as prolonged or as thorough and this likely contributed to the confusion in reconciling the aforementioned results. There is much that the psychiatric community can learn from the investigations of lamotrigine for affective disorders. The length of trials, the speci c measures used to assess ef cacy, reproducibility of results and impact of comorbid conditions are all essential when going about careful investigation. Overly narrow patient populations can lead to ndings which may not be relevant to the clinician working with a heterogeneous patient popu- lation. The bene ts of lamotrigine are not as a straightforward as other agents and it may be that it will work best for those patients who are also less than straightforward. References 1. Kemp DE, Muzina DJ, Gao K, Calabrese JR, Lamotrigine. In: Schatzberg AF, Nemeroff CB (Eds). The American Psychiatric Publishing textbook of psychopharmacology. Arlington, American Psychiatric, 2009 2. Ketter TA, Manji HK, Post RM. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. Journal of Clinical Psychopharmacology 23(5):484–495, 2003 3. Smith D, Baker G, Davies G, Dewey M, Chadwick DW. Outcomes of add-on treatment with lamo- trigine in partial epilepsy. Epilepsia 34(2):312–322, 1993 4. Calabrese JR, Bowden CL, Sachs G, et al.: A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Journal of Clinical Psychiatry 64:1013–1024, 2003 5. Bowden CL, Calabrese JR, Sachs G, et al.: A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Archives of General Psychiatry 60:392–400, 2003 6. Goodwin GM, Bowden CL, Calabrese JR, et al.: A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. Journal of Clinical Psychiatry 65:432–441, 2004 7. Frye MA, Ketter TA, Kimbrell TA, Dunn RT, Speer AM, Osuch EA, Luckenbaugh DA, Cora-Ocatelli G, Leverich GS, Post RM: A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. Journal of Clinical Psychopharmacology 20(6):607–614, 2000 8. Obrocea GV, Dunn RM, Frye MA, Ketter TA, Luckenbaugh DA, Leverich GS, Speer AM, Osuch EA, Jajodia K, Post RM: Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Biological Psychiatry 51(3):253–260, 2002 9. Normann C, Hummel B, Scha¨ rer LO, Ho¨ rn M, Grunze H, Walden J: Lamotrigine as adjunct to par- oxetine in acute depression: a placebo-controlled, double-blind study. Journal of Clinical Psychiatry 63(4):337–344, 2002 10. Barbee JG, Jamhour NJ: Lamotrigine as an augmentation agent in treatment-resistant depression. Journal of Clinical Psychiatry 63(8):737–741, 2002 11. Rocha FL, Hara C: Lamotrigine augmentation in unipolar depression. International Clinical Psycho- pharmacology 18(2):97–99, 2003 12. Barbosa L, Berk M, Vorster M: A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with uoxetine for resistant major depressive episodes. Journal of Clinical Psychiatry 64(4):403–407, 2003 13. Gutierrez RL, McKercher RM, Galea J, Jamison KL. Lamotrigine augmentation strategy for patients with treatment-resistant depression. CNS Spectr. IEEE Transactions on Pattern Analysis and Machine Intelligence 10(10):800–805, 2005. 14. Gabriel A. Lamotrigine adjunctive treatment in resistant unipolar depression: an open, descriptive study. Depress Anxiety 23(8):485–488, 2006 15. Schindler F, Anghelescu IG: Lithium versus lamotrigine augmentation in treatment resistant unipolar depression: a randomized, open-label study. International Clinical Psychopharmacology 22(3):179–182, 2007 382 Psychiatr Q (2012) 83:371–383 123 16. Santos MA, Rocha FL, Hara C: Ef cacy and safety of antidepressant augmentation with lamotrigine in patients with treatment-resistant depression: a randomized, placebo-controlled, double-blind study. Primary Care Companion to the Journal of Clinical Psychiatry 10(3):187–190, 2008 17. Barbee JG, Thompson TR, Jamhour NJ, Stewart JW, Conrad EJ, Reimherr FW, Thompson PM, Shelton RC: A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. Journal of Clinical Psychiatry 72(10):1405–1412, 2011 18. Mula M, Pini S, Cassano GB: The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. Journal of Clinical Psychopharmacology 27(3):263–272, 2007 (Review) 19. Masdrakis VG, Papadimitriou GN, Oulis P: Lamotrigine administration in panic disorder with agora- phobia. 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A preliminary study of lamotrigine in the treatment of affective instability in borderline personality disorder. International Clinical Psychopharmacology 24(5):270–275, 2009 25. Maltese TM: Adjunctive lamotrigine treatment for major depression. American Journal of Psychiatry 156(11):1833, 1999 26. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM. Lamotrigine: a review of its use in bipolar disorder. Drugs 63(19):2029–2050, 2003 (Review) 27. Thase ME, Rush AJ: When at rst you don’t succeed: sequential strategies for antidepressant nonre- sponders. Journal of Clinical Psychiatry 58(suppl 13): 23–29, 1997 28. Fava M: Diagnosis and de nition of treatment-resistant depression. Biological Psychiatry 53:649–659, 2003 29. Rush AJ, Trivedi MH, Wisniewski SR, et al.: Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry 163(11):1905–1917, 2006 30. Saggese JM, Lieberman DZ, Goodwin FK: The role of recurrence and cyclicity in differentiating mood disorder diagnoses. Primary Psychiatry 13(11):43–48, 2006 31. Kremer I, Vass A, Gorelik I, Bar G, Blanaru M, Javitt DC, Heresco-Levy U: Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biological Psychiatry 56:441–446, 2004 32. Wilder-Willis KE, Sax KW, Rosenberg HL, Fleck DE, Shear PK, Strakowski SM: Persistent attentional dysfunction in remitted bipolar disorder. Bipolar Disorders 3(2):58–62, 2001 33. Gualtieri CT, Johnson LG: Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. MedGenMed 23;8(3):46, 2006 34. Marciani MG, Stanzione P, Mattia D, Spanedda F, Bassetti MA, Maschio M, Bernardi G: Lamotrigine add-on therapy in focal epilepsy: electroencephalographic and neuropsychological evaluation. Clinical Neuropharmacology 21(1):41–47, 1998 35. Tiihonen J, Wahlbeck K, Kiviniemi V: The ef cacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophrenia Research 109(1–3):10–14, 2009 (Review) Author Biographies Adam Daniel Zavodnick, MDis a psychiatry intern with the Department of Psychiatry and Behavioral Medicine Carilion Clinic—Virginia Tech Carilion School of Medicine, Roanoke, Virginia. Rizwan Ali, MDis a staff psychiatrist at Veterans Affairs Medical Center, Salem, Virginia and Assistant Professor with the Department of Psychiatry and Behavioral Medicine Carilion Clinic—Virginia Tech Carilion School of Medicine, Roanoke, Virginia. Psychiatr Q (2012) 83:371–383 383 123 Copyright of Psychiatric Quarterly is the property of Springer Science & Business Media B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder’s express written permission. However, users may print, download, or email articles for individual use.
The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th
PSYCHIATRIC ANNALS • Vol. 45, No. 8, 2015 431 The Efficacy of Pharmacotherapy for Borderline Personality Disorder: A Review of the Available Randomized Controlled Trials Dimitry Francois, MD; Steven D. Roth, MD, JD; and Daisy Klingman, MD ABSTRACT Although there are no medications ap – proved by the US Food and Drug Admin – istration for the treatment of borderline personality disorder (BPD), polypharmacy is commonly encountered in individu – als with BPD. This review summarizes the results of randomized controlled trials on the efficacy of pharmacologic agents in BPD. Pharmacotherapy in BPD is an ad – junctive treatment aimed at stabilizing symptoms and behavior in a crisis situa – tion, and it should be avoided whenever possible. Further studies are needed, in – cluding large, randomized controlled tri – als with long-term follow up, to examine the efficacy of psychiatric medications in patients with BPD. [Psychiatr Ann . 2015;45(8):431-437.] Dimitry Francois, MD, is an Assistant Professor of Psychiatry, Weill Cornell Medical Col – lege; an Associate Director, Psychiatry Clerkship, New York-Presbyterian Hospital; and the Site Director, Psychiatry Clerkship, New York-Presbyterian Hospital/Westchester. Steven D. Roth, MD, JD, is an Associate Professor of Clinical Psychiatry, Weill Cornell Medical College; the Acute Division Director and the Unit Chief, Personality Disorders Unit, New York- Presbyterian Hospital/Westchester Division. Daisy Klingman, MD, is an Assistant Professor of Psychiatry, Weill Cornell Medical College; and an Attending Psychiatrist, Personality Disorders Unit, New York-Presbyterian Hospital/Westchester Division. Address correspondence to Dimitry Francois, MD, 21 Bloomingdale Road, White Plains, NY 10605; email: [email protected] Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00485713-20150803-09 © Shutterstock 432 Copyright © SLACK Incorporated B orderline personality disorder (BPD) is present in about 6% of primary care patients 1 and in 15% to 20% of patients in psychi – atric hospitals and outpatient clinics. 2 BPD affects men and women equal – l y, 3 and is associated with increased medical and psychiatric use and health care expenses. 4 Although there are no medications approved by the US Food and Drug Administration (FDA) for the treatment of BPD, polypharmacy is a common occurrence in patients with BPD. Approximately 80% of pa – tients with the disorder take medica – tions regularly, and more than 40% take three or more medications daily. 5 This review summarizes results of ran – domized controlled trials (RCTs) on the efficacy of pharmacologic agents that have been studied in BPD. Results from open trials, case reports, case se – ries, and RCTs rejected from the 2010 Cochrane review 6 were not used. Stud – ies were identified from searches up to December 2014 in PubMed and Med – line. ANTIDEPRESSANTS Selective Serotonin Reuptake Inhibitors Salzman et al. 7 described the results of a 13-week, double-blind, placebo- controlled study of the effects of fluox – etine on anger in patients with BPD or BPD traits. Thirteen patients received fluoxetine and nine received placebo. All patients began with a single 20- mg capsule or identical placebo, and doses were titrated up to a maximum of 60 mg/day. The authors found a re – duction in anger among the fluoxetine recipients but no reduction in depres – sion. In 2004, the therapeutic effect of fluoxetine added to dialectical behav – ior therapy (DBT) for the treatment of BPD was examined by Simpson et al. 8 in a 12-week, randomized, double- blind, placebo-controlled study. Of the 20 patients that completed treatment, 9 were randomly assigned to receive up to 40 mg/day of fluoxetine and 11 were randomly assigned to placebo. The re – sult showed no significant group dif – ferences in scores from pretreatment to posttreatment on any measure. Rinne et al. 9 conducted a double- blind, placebo-controlled, random – ized trial of fluvoxamine (mean dose 150 mg/day) for 6 weeks followed by a blind half-crossover for 6 weeks and an open follow-up for another 12 weeks in 38 women with BPD. Fluvoxamine improved rapid mood shifts (standard – ized mean changes [SMD], -0.646) but not impulsivity and aggression. Jariani et al. 10 compared sertra – line (50-100 mg/day) to olanzapine (5-10 mg/day) for the treatment of BPD in 120 patients on methadone maintenance therapy for heroin de – pendence who were also diagnosed as having BPD. The results (evaluation of Symptom Checklist-90 [SCL-90] questionnaire before treatment and in the 4th, 8th, and 12th weeks of treat – ment) indicated that both drugs could generally ameliorate depression, anxi – ety, hypersensitivity in interpersonal relationships, aggression, obsession, and somatization symptoms in a 12- week treatment. Sertraline was more effective in decreasing symptoms of depression, hypersensitivity in in – terpersonal relationships, and obses – sion. Olanzapine was more useful for anxiety, aggression, and paranoia symptoms. There was no difference in decreasing somatization symptoms between both drugs. In regard to self- mutilation, there was a significant dif – ference in the olanzapine group. Tricyclic Antidepressants Soloff et al. 11 described a 5-week, double-blind, placebo-controlled study of amitriptyline and haloperi – dol in 90 BPD inpatients. They found a significant effect for depression (SMD, -0.596) with amitriptyline, at a mean dose of 149 mg/day. Monoamine Oxidase Inhibitors Soloff et al. 12 examined the data collected in a 5-week, double-blind, placebo-controlled trial of phenelzine (average dose, 60 mg/day), haloperi – dol, or placebo for atypical depression in 108 inpatients with BPD. Three- way comparisons between groups indicated superior efficacy for phen – elzine on measures of depression, bor – derline psychopathologic symptoms, and anxiety. Pair-wise comparisons between medication and placebo re – vealed significant efficacy for phenel – zine against anger and hostility but no efficacy against atypical depression. Mianserin In 1983, Montgomery et al. 13 com – pared 30 mg/day of mianserin to pla – cebo in a 6-month, RCT of 38 indi – viduals with a personality disorder and a history of a suicidal act causing hospitalization. They found no signifi – cant difference in outcome between the groups. (Please note that mianserin is not approved by the FDA for use in the United States; its analogue is mir – tazapine.) Summary of Antidepressants Few antidepressants have been studied in BPD. There seems to be a benefit for tricyclic antidepressants (TCAs) in the reduction of depressive Sertraline was more effective in decreasing symptoms of depression, hypersensitivity in interpersonal relationships, and obsession. PSYCHIATRIC ANNALS • Vol. 45, No. 8, 2015 433 pathology. No statistically significant effects were observed for the selective serotonin reuptake inhibitors (SSRIs), phenelzine, and mianserin. MOOD STABILIZERS Carbamazepine In a double-blind, parallel, placebo- controlled trial involving 20 hospital – ized BPD patients, De la Fuente and Lotstra 14 reported no significant posi – tive effects from carbamazepine. Divalproex Sodium Divalproex sodium has been tested in three small RCTs. In the first, Hollander et al. 15 conducted a 10-week, parallel, double-blind study comparing divalpro – ex sodium to placebo in 16 outpatients with BPD. Only six patients completed the study. Five of the six completers were considered to be responders, as defined by a Clinical Global Impressions (CGI)-I score of 1 or 2 at endpoint. In the second investigation, Franken – burg and Zanarini 16 studied 30 women with BPD in a 6-month, placebo-con – trolled, double-blind trial comparing di – valproex sodium to placebo. Divalproex sodium proved to be superior to placebo in diminishing interpersonal sensitiv – ity (SMD, -1.046) and anger/hostility as measured by the SCL-90, as well as overall aggression as measured by the modified Overt Aggression Scale. In a study by Moen et al., 17 15 patients with BPD received 4 weeks of “con – densed DBT,” and then those patients with SCL-90 scores higher than 150 after this treatment were randomly and blindly assigned to placebo or divalproex extend – ed-release for 12 weeks. There were no significant differences between the par – ticipants assigned to divalproex extend – ed-release compared with placebo. Lamotrigine Reich et al. 18 studied 28 patients with BPD in a 12-week, double-blind, placebo-controlled study of lamotrigine. Patients in the lamotrigine group had sig – nificantly greater reductions of affective instability and impulsivity. A study by Tritt et al. 19 compared the efficacy of lamotrigine versus placebo in the treatment of aggression in women with BPD. In comparison with the pla – cebo group, significant changes on anger (SMD, -1.696) were observed after 8 weeks in those patients treated with la – motrigine. Topiramate Topiramate was evaluated in three RCTs by the same group of researchers. First, Nickel et al. 20 examined the effect of topiramate on aggression in 29 women with BPD. Significant improvements on four subscales of the STAXI (state-anger, trait-anger, anger-out, anger-control) were observed in the topiramate-treated individuals after 8 weeks in comparison with the placebo group. A similar RCT by Nickel et al., 21 this one with 42 male outpatients, also found significant changes on anger. An RCT by Loew et al. 22 aimed to de – termine whether topiramate could influ – ence borderline psychopathology, health- related quality of life, and interpersonal problems in 58 women with BPD. Topi – ramate was found to reduce psychiatric symptoms (SMD, -1.196), anxiety (SMD, -1.406), anger (SMD, -3.006), and inter – personal difficulties (SMD, -0.916), and to improve health-related quality of life at 8 and 10 weeks. Summary of Mood Stabilizers RCTs involving the mood stabilizers were limited by low statistical power. Divalproex sodium shows an effect for anger and interpersonal sensitivity. Topi – ramate and lamotrigine were found to have an effect on anger. No statistically significant effects were found for carba – mazepine. ANTIPSYCHOTICS Loxapine versus Chlorpromazine Leone 23 studied 80 outpatients with BPD in a 6-week, double-blind study of loxapine (mean average dose 14.5 mg/day) and chlorpromazine (mean average dose 110 mg/day). The outcomes measured were BPD sever – ity, affective instability using the Pro – file of Mood State scale, psychotic symptoms using the Brief Psychiatric Rating Scale, and mental health sta – tus using the CGI and the Systematic Nurses’ Observation of Psychopathol – ogy. The author reported both groups improved significantly from baseline, and the individuals prescribed loxap – ine improved significantly more than the individuals prescribed chlorproma – zine in several symptom areas, partic – ularly depression and anger/hostility. Flupenthixol Flupenthixol (which is not ap – proved by the FDA for use in the Unit – ed States) given as depot injections was found to significantly reduce the number of suicide attempts compared to placebo after 4 months and for the remainder of a 6-month RCT of pa – tients with personality disorders (23 of the 30 completers had BPD). 24 Thiothixene In a study by Goldberg et al., 25 50 outpatients with borderline and/or schizotypal personality disorder were randomly allocated to thiothixene or placebo treatment that was continued for 12 weeks (after 1 week of placebo washout). The mean daily dose of thio – thixene in the final week of the study was 8.7 mg. Significant drug-placebo Topiramate and lamotrigine were found to have an effect on anger. 434 Copyright © SLACK Incorporated differences were found for psychotic symptoms but not for depression. Haloperidol Soloff et al. 26,27 published a study of haloperidol in two active drug versus active comparator drug trials. The first one was a 5-week (after 1-week wash – out) double-blind, placebo-controlled study of amitriptyline and haloperidol in 90 symptomatic BPD inpatients. Haloperidol (average dose 5 mg/day) produced significant improvement over placebo in global functioning, de – pression, hostility, schizotypal symp – toms, and impulsive behavior. (For the amitriptyline findings from this study, please refer to the discussion of TCAs earlier in the article.) In the second 5-week (after 1-week washout), dou – ble-blind, placebo-controlled study, the authors compared the efficacy of haloperidol (average dose 4 mg/day) to phenelzine and placebo against the affective, cognitive, and impulsive-ag – gressive symptoms of 108 BPD inpa – tients. The results indicated a tendency for patients receiving haloperidol to suffer less from interpersonal prob – lems as compared to patients receiving phenelzine sulfate. (For the phenelzine findings from this study, please refer to the discussion of monoamine oxidase inhibitors earlier in the article.) Aripiprazole An RCT by Nickel et al. 28 of 52 subjects (43 women and 9 men) with BPD found a large effect of aripipra – zole, 15 mg/day for 8 weeks, for de – pression (SMD, -1.256), interpersonal problems (SMD, -0.77), impulsivity (SMD, -1.846), anger (SMD, 1.146), and paranoid thinking (SMD, -1.056), and a moderate effect for anxiety (SMD, -0.736). Ziprazidone Pascual et al. 29 examined 60 adult patients with BPD in a 12-week, single-center, double-blind, placebo- controlled study of ziprasidone (mean daily dose 84 mg). The CGI scale for use in BPD patients was the primary outcome measure, and other scales and self-reports related to affect, behavior, psychosis, general psychopathology domains, and clinical safety were also included. No statistically significant differences were found between zipra – sidone and placebo. Quetiapine In a recent 8-week RCT compar – ing low (150 mg/day) and moderate (300 mg/day) dosages of extended- release quetiapine to placebo in 95 adults with BPD, Black et al. 30 found that participants treated with 150 mg/ day of quetiapine had a significant re – duction in the severity of the follow – ing BPD symptoms: interpersonal, affectivity, and anger and cognition problems. The effect size was -0.79 for the primary outcome measure (the Zanarini scale total score). No signifi – cant effects were found for impulsiv – ity, depression, and general psychopa – thology. The difference between the moderate-dosage quetiapine group and the placebo group was not statistically significant ( d = 20.41, P = .265). Olanzapine Olanzapine’s effect on BPD has been studied in nine RCTs. Six of these studies compared olanzapine to placebo. These studies are Bogen – schutz and Nurnberg 31 (n = 40); Line – han et al. 32 (olanzapine was added to psychotherapy, n = 24); Schulz et al. 33 (n = 314); Soler et al. 34 (all patients were in DBT, n = 60); Zanarini and Frankenberg 35 (n = 28); and Eli Lil – ly36 (n = 301). Of the remaining three studies, one compared olanzapine to haloperidol (Shafti and Shahveisi, 37 n = 28); one compared olanzapine to sertraline (Jariani et al, 10 n = 120 [all pa – tients were on methadone maintenance therapy]); and one with three different arms of treatment 38 compared olan – zapine to fluoxetine ( n = 30), then olan – zapine to olanzapine plus fluoxetine (n = 31), and finally fluoxetine to fluoxetine and olanzapine ( n = 29). The intervention times ranged from 12 weeks to 6 months. The trials by Zanarini and colleagues 33,35,38 were supported in part by a grant from Eli Lilly (Indianapolis, IN), the maker of olanzapine. Regarding the trials of olanzapine versus placebo, significant decreases in affective instability, anger, psychot – ic paranoid symptoms, and anxiety were found. Of note, two studies 31,33 of olanzapine-treated groups had a sig – nificantly lower degree of amelioration of recurrent suicidal ideation as com – pared to the placebo groups. No sig – nificant differences were found in the comparison of olanzapine with fluox – etine and olanzapine with haloperidol for any pathology-related outcome. In the study by Jariani et al., 10 olanzapine was more useful for anxiety, aggres – sion, paranoia symptoms, and self-mu – tilation. There were no significant dif – ferences indicating any benefits from combined treatment versus treatment with olanzapine or fluoxetine alone. Summary of Antipsychotics Olanzapine has the most supporting data of the antipsychotics; studies have shown its use can lead to reductions in anger, paranoia, anxiety, and interper – sonal sensitivity. Effects were found for aripiprazole on impulsivity, anger, anxiety, psychosis, and interpersonal The difference between the moderate-dosage quetiapine group and the placebo group was not statistically significant. PSYCHIATRIC ANNALS • Vol. 45, No. 8, 2015 435 problems. No significant effect was found for ziprazidone. Regarding the typical antipsychotics, statistically significant effects were found for halo – peridol on anger and for flupenthixol on suicidal behavior. MISCELLANOUS Omega-3 Fatty Acids Zanarini and Frankenburg 40 con – ducted an 8-week, placebo-controlled, double-blind study to compare the ef – ficacy of ethyl-eicosapentaenoic acid (EPA) at a dose of 1 g/day versus place – bo in 30 women with BPD. The results showed there was a significant effect of ethyl-EPA in reducing aggressive behaviors and depressive symptoms (SMD, -0.346). A 12-week RCT by Hal – lahan et al. 41 included 35 patients with BPD and found there was a significant improvement of depressive symptoms, suicidality, and reaction to daily stress – es in the group using EPA (1.2 g/day) and docosahexaenoic acid (DHA, 0.9 g/ day) in addition to standard psychiatric care. A small RCT of EPA, DHA, and vitamin E in 15 adolescents with BPD who also met ultra–high-risk criteria for psychosis found that 1.2 g/day of EPA significantly improved function – ing and reduced psychiatric symptoms (SMD, -1.516) compared with place – bo. 42 Bellino et al. 43 conducted a 12- week controlled trial aimed to assess the efficacy of the association of EPA and DHA with valproic acid compared to valproic acid alone in 43 consecu – tive BPD outpatients. The combination therapy of valproate and omega-3 fatty acids produced significant effects in reducing the severity of characteristic BPD symptoms such as impulsive be – havioral dyscontrol (SMD, -1.6343), outbursts of anger (SMD, -1.7843), and self-mutilating conduct. Naltrexone (Opioid Antagonist) Two small, double-blind, placebo- controlled randomized trials (total N = 25) compared naltrexone (50 or 200 mg/day) to placebo in reducing dissociative symptoms in patients with BPD. 44 In both trials, the intensity and duration of dissociative symptoms were numerically lower with naltrexone than with placebo. However, the effects were too small to reach statistical sig – nificance. Clonidine (Alpha-2 Adrenergic Agonist) Ziegenhorn et al. 45 used a double- blind, randomized, placebo-controlled crossover study to determine whether clonidine (450 mcg/day orally) was ef – fective in reducing hyperarousal in a sample of 18 patients with BPD, with or without comorbid posttraumatic stress disorder (PTSD), and with a prominent hyperarousal syndrome. Hyperarousal, as measured by the clinician-administered PTSD scale, improved significantly (18% decrease) compared with placebo ( P = .003), ir – respective of PTSD comorbidity. Oxytocin In a small RCT, 14 patients with BPD and 13 healthy control adults received 40 IU of intranasal oxytocin or placebo in a double-blind, random – ized order followed by the Trier So – cial Stress Test. 46 The authors noted a greater attenuation of stress-induced dysphoria in the BPD group after oxy – tocin administration. DISCUSSION Results from the RCTs should be examined with caution, as the data were limited by (1) the small size of the trials; (2) short duration (often last – ing between 6 and 12 weeks); (3) high dropout rates; (4) inconsistent outcome measures; (5) enrollment bias (subjects were mostly women, and the hetero – geneity of clinical features, treatment settings, and assessment instruments); and (6) lack of replication (most effect estimates were based on single study effects). In addition, individuals with suicidal ideation or recent suicide at – tempt were excluded from most inves – tigations, which is uncharacteristic of severely ill or hospitalized BPD pa – tients. The American Psychiatric Associa – tion’s practice guidelines’ 47 endorse – ment of SSRIs as first-line therapies for BPD is not supported by the cur – rent literature. The World Federation of Societies of Biological Psychiatry guidelines for biological treatment of personality disorders 48 conclude that there is no evidence at either level of evidence that any drug improves BPD psychopathology in general. The Na – tional Institute for Health and Care Excellence guideline on treatment and management of BPD 49 recommends that “drug treatment should not be used specifically for BPD.” The authors of this review support a symptom-oriented pharmacologic ther – apy, as first recommended by Soloff in 1998. 50 A symptom-specific approach to drug trials for BPD will involve out – come measurements defined for the symptom, not the BPD syndrome as a whole. The three main areas that medi – cations should target are (1) affect, (2) impulse, and (3) cognition. For the af – fective dysregulation symptoms, data indicate beneficial effects for topira – mate, lamotrigine, divalproex sodium, haloperidol, aripiprazole, olanzapine, quetiapine extended-release, omega-3 fatty acids, and amitriptyline. The im – pulsive behavioral dyscontrol symp – toms might be decreased by topiramate, lamotrigine, aripiprazole, and omega-3 fatty acids. In regard to the psychotic symptoms, findings show significant beneficial effects for aripiprazole, olanzapine, and quetiapine extended- release. There is some evidence to sup – port the use of aripiprazole, divalproex sodium, and topiramate in managing interpersonal problems. Omega-3 fatty 436 Copyright © SLACK Incorporated acids show promise in terms of reduc – ing elevated suicidality. CONCLUSION The mainstay of treatment for BPD is still psychotherapy; pharmacothera – py is an adjunctive treatment aimed at stabilizing symptoms and behavior in a crisis situation. A symptoms-specific approach has response overlap. 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The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th
Pharmacotherapy for borderline personality disorder: NICE guideline In their review of drug treatments for borderline personality disorder, Liebet al, 1despite considering similar evidence, draw largely different conclusions from those we drew when developing the National Institute for Health and Clinical Excellence (NICE) guideline. 2Lieb et alrecommend a range of drugs. These include anticonvulsants for affective dysregulation symptoms (topiramate, valproate semisodium and lamotrigine) and impulsive–behavioural dyscontrol symptoms (lamotrigine and topiramate); and anti- psychotics (aripiprazole and olanzapine) for cognitive–perceptual symptoms. In contrast, we do not recommend drug treatment other than for the treatment of comorbid disorders. There are a number of reasons for the disparity. First, we did not consider the evidence from some studies to be usable. 3–7 These trials tended to find large effect sizes favouring treatment compared with effect sizes from other trials. Following further investigation, we considered this evidence for topiramate, lamotrigine or aripiprazole to be unreliable and excluded the trials from our analysis (see p. 218 of the full guideline 2). Second, most other recommendations made by Lieb et alare based on weak and/or low-quality evidence. We do not agree with the interpretation of the evidence for valproate, which Lieb et al claim shows a reduction in interpersonal problems and depression. The apparent effect on interpersonal problems is derived from a trial of 30 participants with more than 60% drop out. The effect on depression, which we noted as not statistically significant (s.m.d. = 70.61 (95% CI 71.29 to 0.07)), is derived from a larger trial with skewed data, in which over 60% of participants were not diagnosed as having borderline personality disorder. We therefore graded this evidence ‘low quality’. The authors also claim ‘favourable results’ for haloperidol and the other antipsychotics on symptoms of affective dysregulation, and for omega-3 fatty acid supplementation and flupentixol decanoate. It is unclear for which ‘symptom constellation’ these latter drugs are recommended. We calculated similar effect sizes, but tended to grade the quality of evidence ‘low’ because of single studies, skewed data and wide confidence intervals. We excluded the trial of flupentixol 8because its inclusion criterion was not specifically a diagnosis of borderline personality disorder. Third, NICE guidelines are developed as a practical synthesis of clinical recommendations based on a pragmatic analysis of the evidence for the clinical effectiveness and cost-effectiveness, including evidence of harm, of particular treatments and approaches to a problem. As far as possible we do not rest NICE guideline development on speculative theory. The American Psychiatric Association 9based their recommendations about selective serotonin reuptake inhibitors and low-dose antipsychotics on a speculative theoretical model which has never been tested in hypothesis-driven studies. Treatment recommendations thus derived are based on post hocreconstructions rather than primary evidence. Lieb et alimplicitly use this model to understand the evidence and to develop recommendations. Fourth, Lieb et almade recommendations regarding a number of drugs on the basis of single trials in which positive findings are restricted to one or two symptoms. They place greater emphasis on simple statistical significance without sufficient consideration of clinical significance, whether the outcome measures used were appropriate – in many cases they are not – or indeed the potential for harm. For example, valproate semisodium is an especially dangerous drug for women of child-bearing years who may unexpectedly become pregnant; and antipsychotics have a wide range of neurological side-effects, some of which can be permanent, as well as metabolic effects leading to weight gain and an increased risk of diabetes. Finally, the NICE guideline considered evidence for non-drug treatments, for example psychological therapies, and looked at the care pathway within the National Health Service (NHS) in England and Wales. Recommendations relating to drug treatment were therefore developed in the context of evidence for the whole range of treatments for, as well as the clinical management of, borderline personality disorder. Consensus-based recommendations for the management of crises and sleep problems, experiences which in the NHS commonly lead to excessive reliance on various pharmacological solutions, were also included. No drug has been licensed in the UK for borderline personality disorder. It is important that drugs that are used commonly within the NHS are subject to post-licensing surveillance by the Medicines and Healthcare products Regulatory Agency. It is therefore unusual for a NICE guideline to recommend the use of any unlicensed drug. There are exceptions to this, for example where there are no other treatments or other treatments are associated with significant harm. These remain exceptions, nevertheless. We hope that readers can see that, with these considerations in mind, the guideline group was correct in deciding not to recommend drug treatments for either the core symptoms of borderline personality disorder or indeed for any symptom clusters. More good-quality evidence is required. 1 Lieb K, Vo ¨llm B, Ru ¨cker G, Timmer A, Stoffers JM. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J Psychiatry 2010;196: 4–12. 2 National Collaborating Centre for Mental Health. Borderline Personality Disorder: The NICE GUIDELINE on Treatment and Management. National Clinical Practice Guideline No. 78 . British Psychological Society & Royal College of Psychiatrists, 2009. 3 Nickel MK, Nickel C, Mitterlehner FO, Tritt K, Lahmann C, Lieberich PK, et al. Topiramate treatment of aggression in female borderline personality disorder patients: a double-blind, placebo-controlled study. J Clin Psychiatry2004; 65 : 1515–9. 4 Nickel MK, Nickel C, Kaplan P, Lahmann C, Muhlbacher M, Tritt K, et al. Treatment of aggression with topiramate in male borderline patients: a double-blind, placebo-controlled study. Biol Psychiatry2005;57: 495–9. 5 Tritt K, Nickel C, Lahmann C, Lieberich PK, Rother WK, Loew TH, et al. Lamotrigine treatment of aggression in female borderline-patients: a randomized, double-blind, placebo controlled study. J Psychopharmacol 2005; 19: 287–91. 6 Loew TH, Nickel MK, Muehlbacher M, Kaplan P, Nickel C, Kettler C, et al. Topiramate treatment for women with borderline personality disorder. A double-blind, placebo controlled study. J Clin Psychopharmacol2006; 26 : 61–6. 7 Nickel MK, Muehlbacher M, Nickel C, Kettler C, Pedrosa G, Bachler E, et al. Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo controlled study. Am J Psychiatry2006;163: 833–8. 8 Montgomery SA, Roy D, Montgomery DB. The prevention of recurrent suicidal acts. Br J Clin Pharmacol 1983;15(suppl 2): 183S–8S. 9 American Psychiatric Association. Practice guidelines for the treatment of borderline personality disorder. Am J Psych2001;158(suppl 10): 1–52. 158 Edited by Kiriakos Xenitidis and Colin Campbell Contents & Pharmacotherapy for borderline personality disorder: NICE guideline & Lithium in drinking water The British Journal of Psychiatry (2010) 196, 158–160 Correspondence Declaration of interest T.K. was a facilitator, R.B. a systematic reviewer and A.B. a guideline development group member for the NICE borderline personality disorder guideline. Tim Kendall, Director, National Collaborating Centre for Mental Health, Royal College of Psychiatrists’ Research Unit, London, and Medical Director and Consultant Psychiatrist, Sheffield Health and Social Care Trust, email: [email protected]; Rachel Burbeck , National Collaborating Centre for Mental Health, London; Anthony Bateman , Consultant Psychiatrist, Barnet, Enfield and Haringey Mental Health NHS Trust, and Visiting Professor at University College London, UK doi: 10.1192/bjp.196.2.158 Lithium in drinking water In their short report, Ohgami et al 1reported lithium levels in drinking water and linked them to the risk of suicide. Despite the report highlighting the pitfalls of drawing simple conclusions from large-scale ecological studies, a Google search shows that these findings have been widely disseminated in scientific and lay media. A major concern, addressed only obliquely by the authors, is the likelihood of confounding in this scenario. As noted by Chandra & Babu, 2sociological factors play an important role in suicide. The lack of accounting for such potential confounders for the different districts in the study is a serious methodological omission, rendering the results of the study untenable from an epidemiological perspective. The demographics of the different areas (beyond age structure) are not addressed, thus ignoring important economic and social factors (like deprivation and unemployment) which contribute to suicide risk. Adjusting for differences in age structures between centres using standardised mortality ratios (SMRs) is unlikely to account for all important sources of confounding, so that the possibility of residual confounding must be considered a major qualifier when considering these results, rather than details to be addressed in future studies. 3 The potential reasons behind the difference in lithium levels in the drinking water samples in the different municipalities are also not explained. Lithium levels in water sampled across a number of districts in New Zealand differ within municipal areas, depending where the sample is sourced. In this context, how valid is it then to use the mean value to represent the lithium exposure in that area? This would require the matching of lithium levels with suicide data from each discrete area of water supply and a loss of statisti- cal power for such a relatively uncommon event as suicide. The duration of exposure to a specific level of lithium in the drinking water was also not addressed. Apart from the issue of dietary intake of lithium noted in the letter by Desai & Chaturvedi, 4there is the question of where people source most of their drinking water, and the use of bottled water. In the context of the short report, it is also difficult to fully assess the suitability of the analysis methods used. It would have been useful to have more detail on the weighting structure used in the regression, alongside frequency data on the number of events observed in each locality. Also, the reported beta coefficient from the regression is not interpretable in the context of the presented figure or reported analysis methods. Although the reported results were indeed intriguing, in the absence of more a developed approach to the research question it seems too early, and indeed misleading for a non-scientist audience, to even start speculating on the relationship between suicide rates and lithium in drinking water sources on the basis of these data. In this era of rapid information dissemination, the publishing of reports without rigorous scrutiny of the statistical method and due consideration of the confounding variables is a concern. 1 Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N. Lithium levels in drinking water and risk of suicide. Br J Psychiatry2009;194: 464–5. 2 Chandra PS, Babu GN. Lithium in drinking water and food, and risk of suicide. Br J Psychiatry 2009;195: 271. 3 Young AH. Invited commentary on . . . Lithium levels in drinking water and risk of suicide. Br J Psychiatry 2009;194: 466. 4 Desai G, Chaturvedi SK. Lithium in drinking water and food, and risk of suicide. Br J Psychiatry 2009;195: 271. Mark A. Huthwaite , Department of Psychological Medicine, University of Otago, Wellington, New Zealand. Email: [email protected]; James Stanley, Department of Public Health, University of Otago, Wellington, New Zealand doi: 10.1192/bjp.196.2.159 In 1990 we reported that the mean suicide rates in 27 Texas counties over a 10-year period were consistently lower in those with ‘high’ natural lithium content in the drinking water (70– 160 mg/l) than in counties with ‘medium’ (12–60 mg/l) or ‘low’ (0–10 mg/l) water lithium levels. 1Ohgami et al 2have since argued, without proof, that these associations may have been spurious owing to what they considered an arbitrary division of the data. It is necessary, therefore, to emphasise that the data were partitioned in accord with accepted methods of statistical trend analysis and not in an arbitrary fashion, and that tests were conducted to assure that the partitioning of the data did not produce spurious associations. Within the same study, 1we found the rates of homicide, rape, robbery, burglary and theft to be also lower in the high-lithium counties. In addition, a statistically significant reciprocal relation- ship between the water lithium levels and the arrest rates for possession of opium, cocaine and their derivatives was observed, while the arrest rates for lesser crimes such as possession of marijuana, drunkenness and driving under the influence showed no consistent dependence on the water lithium levels. The studies were later extended to include arrest rates of juveniles, yielding statistically significant results for possession of narcotic drugs and, interestingly, ‘runaway from home’. 3 In the interest of historical accuracy it needs to be pointed out that in 1972 Dawson et al 4reported mental hospital admissions and homicide rates to be lower in high-lithium Texas counties. They also found the suicide rates to be lower in these counties, but the differences did not reach statistical significance, as incidence data for only a 2-year period (1968–1969) were compared. Thus, the evidence in favour of beneficial effects of low levels of lithium on human behaviour is already strong, and since lithium is close to be officially recognised as a nutritionally essential trace element, 5emphasis should be placed on assuring adequate lithium intakes in populations at risk of developing lithium deficiency. 1 Schrauzer GN, Shrestha KP. Lithium in drinking water and the incidence of crimes, suicides and arrests related to drug addictions. Biol Trace Elem Res 1990; 25: 105–13. 2 Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N. Lithium levels in drinking water and risk of suicide. Br J Psychiatry2009;194: 464–5. 3 Schrauzer GN, Shrestha K. Lithium in drinking water and the incidence of crimes, suicides and arrests related to drug addictions. In Lithium in Biology and Medicine (eds GN Schrauzer, KF Klippel): 191–203. Verlag Chemie, 1991. 4 Dawson EB, Moore TD, McGanity WJ. Relationship of lithium metabolism to mental hospital admissions and homicide. Dis Nerv Syst1972;33: 546–56. 159 Correspondence 5Schrauzer GN. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr 2002;21: 14–21. Gerhard N. Schrauzer , Professor Emeritus, Department of Chemistry and Biochemistry, University of California, San Diego, USA. Email: [email protected]; Krishna P. Shrestha , Department of Arts and Sciences, Mountain State University, West Virginia, USA doi: 10.1192/bjp.196.2.159a Authors’ reply : First, Drs Huthwaite & Stanley point out that a major concern is the likelihood of confounding in this scenario. In our previous research, 1we examined government statistics on suicide in the 47 prefectures in Japan. The overall yearly suicide rate in Japan was 25 per 100 000 population in 1999. Pearson’s correlation was used to calculate correlations of suicide rate with latitude, longitude, yearly mean temperature, yearly total sunshine, yearly mean individual income, and yearly unemployment rate in the 47 prefectures, although lithium levels were not measured in the study. There was a significant correlation with suicide rate for yearly total sunshine, yearly mean temperature, latitude, and yearly mean individual income. By using multiple regression analysis, yearly total sunshine was the only individual variable to predict significant variance in suicide rate. Taking these findings into consideration, we did not use yearly mean individual income or yearly unemployment rate. 2Also, yearly total sunshine was similar between the 18 municipalities of Oita prefecture so we did not use this. Most importantly, only 18 municipalities prevented us from conducting further analyses including confounding factors. We are now planning to perform a large study to consider confounding factors. Second, they state that the potential reasons behind the difference in lithium levels in the drinking water samples in the different municipalities are also not explained and ask how valid it is then to use the mean value to represent the lithium exposure in that area. Lithium levels of drinking water supplies were measured at 26 locations in Oita city and at 53 locations in the other municipalities. The reason for the large difference in lithium levels is unknown, but Oita prefecture may have different geological features between the 18 municipalities and such differences may bring about large differences in lithium levels, although this thought is speculative. Also, instead of the mean value, we used the median value for the analysis and similar results were obtained. Third, Huthwaite & Stanley question the duration of exposure to a specific level of lithium in the drinking water, and where people source most of their drinking water and the use of bottled water. In Japan, most people drink tap water although a small portion of people drink bottled water. Therefore, it is meaningful to measure lithium levels in tap water supplies. Moreover, the duration of exposure to a specific level of lithium is unknown, but if the residents continue to live at the same place, then their age may be associated with the duration. Finally, we agree that in the context of the short report it is difficult to fully assess the suitability of the analysis methods used. Nonetheless, we emphasise that although short reports are not in themselves conclusive, they can provide new findings which lead to comprehensive research to establish a definite conclusion. We would like readers to read short reports with this in mind, so that they are not misled. Although Schrauzer & Shrestha emphasise that their data were partitioned in accordance with accepted methods of statistical trend analysis, in their report 3they said only that the 27 Texas counties were classified into high, medium, and low groups according to the lithium content in the municipal water supplies. There was no explanation of how to divide the high (range 70– 160 mg/l), medium (13–60 mg/l) and low (0–12 mg/l) groups. To avoid the suspicion of an arbitrary division, they should have fully described their method in their full paper. In addition, their results were adjusted only by population density and annual income. Dawson et al 4also investigated suicide rates and lithium in drinking water, classifying lithium levels as high ( 570 mg/l) or low ( 411 mg/l). This division might have derived from their previous study, in which they reported that the lithium levels were clustered into four groups ( 411, 11–29.9, 30.0–69.9 and 570 mg/l), which would provide about equal distribution of the measured values at consistent increments. 5Their results were adjusted by population density, the distance to the nearest state hospitals and rainfall. 4 Taking the nature of these partitions of lithium levels 3–5 into consideration, our method of investigating the association between suicide rates and lithium in drinking water 2is more valid. We used lithium levels as a continuous variable and applied weighted least squares regression analysis adjusted for the size of each population. In any case, as Huthwaite & Stanley pointed out, confounding factors were not sufficiently investigated by Schrauzer & Shrestha 3, Dawson et al 4or us. 2Therefore, beneficial effects of low levels of lithium on human behaviour has not been confirmed and further studies are clearly required. 1 Terao T, Soeda S, Yoshimura R, Nakamura J, Iwata N. Effect of latitude on suicide rates in Japan. Lancet2002;360: 1892. 2 Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N. Lithium levels in drinking water and risk of suicide. Br J Psychiatry2009;194: 464–5. 3 Schrauzer GN, Shrestha KP. Lithium in drinking water and the incidence of crimes, suicides and arrests related to drug addictions. Biol Trace Elem Res 1990; 25: 105–13. 4 Dawson EB, Moore TD, McGanity WJ. Relationship of lithium metabolism to mental hospital admission and homicide. Dis Nerv Syst1972;33: 546–56. 5 Dawson EB, Moore TD, McGanity WJ. The mathematical relationship of drinking water lithium and rainfall to mental hospital admission. Dis Nerv Syst 1970; 31: 811–20. Takeshi Terao , Oita University Faculty of Medicine, Idaigaoka 1-1, Hasama-machi, Yufu, Oita, 879-5593, Japan. Email: [email protected]; Hirochika Ohgami, Ippei Shiotsuki ,Nobuyoshi Ishii , Oita University Faculty of Medicine; Noboru Iwata , Hiroshima International University, Japan doi: 10.1192/bjp.196.2.160 160 Correspondence 10.1192/bjp.196.2.158 Access the most recent version at DOI: 2010, 196:158-159. BJP  Tim Kendall, Rachel Burbeck and Anthony Bateman guideline Pharmacotherapy for borderline personality disorder: NICE References http://bjp.rcpsych.org/content/196/2/158#BIBL This article cites 8 articles, 1 of which you can access for free at: permissions Reprints/ [email protected] write to To obtain reprints or permission to reproduce material from this paper, please to this article at You can respond /letters/submit/bjprcpsych;196/2/158 from Downloaded The Royal College of Psychiatrists Published by on February 18, 2018 http://bjp.rcpsych.org/ http://bjp.rcpsych.org/site/subscriptions/ go to: The British Journal of Psychiatry To subscribe to
The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th
o cTo Be r 2010 T h e Br o w n Un i v e r s iTy Ps y c h o Ph a r m a c o l o g y UPd a Te 7 continued on next page and p=0.0005, respectively), with no sig- nificant between-group differences. There were no serious adverse events reported with fluoxetine, which appeared to be well tolerated, with only 2 participants maintained on less than 40 mg/day. Authors’ conclusions According to George and colleagues, the biological model “was universally well received by perpetrators and contributed to both a reduction in their need to project blame and a willingness to assume respon- sibility for their behavior and participate in IPV treatment.” Although combination treatment with fluoxetine, CBT, and alcohol counseling appeared to reduce aggression signifi- cantly, the degree to which the individual treatments contributed to reductions in physical and nonphysical improvements is not clear. A study with a much larger sample and a different design would be needed to determine the degree to which each of these factors contributed to reduc- tions in aggressive behaviors. The authors report that new studies are underway using functional magnetic resonance imaging to assess fluoxetine’s effects on brain function. The authors report no funding, support, or potential conflicts of interest.  • • • • • • • • • • • • • • • • • • • • • • • • • • • • George DT, Phillips MJ, Lifschitz M, et al.: Fluox- etine treatment of alcoholic perpetrators of domestic violence: A 12-week, double-blind, randomized, placebo-controlled intervention study. J Clin Psy- chiatry 2010 June 29. E-pub ahead of print: DOI: 10.4088/JCP.09m05256gry. E-mail: [email protected] Re f e Re n c e s 1. Trial registration: ClinicalTrials.gov identifier: NCT00011765. Full description (last updated on June 4, 2010) at http://clinicaltrials-lhc.nlm.nih.gov/ ct2/show/NCT00011765. 2. George DT, et al.: Biol Psychiatry 2000; 47(9):804–812. Commentary by lead author David T. George, M.D. This study adds to a growing literature indicating that there is a biological compo- nent to domestic violence. This is important for a number of reasons. First, it places responsibility on the medical community to identify and assist in the treatment of per – petrators of domestic violence just like they would for patients with other biological illnesses such as diabetes or hypertension. Second, presenting the biologically based medical model to the perpetrators pro- vides a nonthreatening means to confront their behavior and help them understand their overreactivity to perceived threats. The model contributes to both a reduction in the perpetrators’ need to project blame, and a willingness to assume responsibility for their behavior and participate in treatment. Third, by addressing the perpetrators’ alcohol consumption in conjunction with the administration of Prozac (or presumably other SSRIs), physicians can significantly im- pact the problem of domestic violence by decreasing the perpetrators’ anger and thus affording them a longer “fuse” before reacting to environmental stimuli. Fourth, these results, if confirmed in larger studies, provide evidence that treatment can impact this major societal problem. ▪ • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • David T. George, M.D., is a psychiatrist at the Laboratory of Clinical and Translational Studies, Na- tional Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland. n e W s n o t e s Escitalopram for treatment- resistant GAD Escitalopram may be an acceptable and potentially efficacious treatment for patients with generalized anxiety disorder (GAD) who still have clinically significant symp- toms following cognitive behavioral therapy (CBT), according to an open-label pilot study. Twenty-four patients with moderate severity of GAD were initially treated with CBT, 15 of whom completed ≥12 sessions. During the CBT phase, there were sig- nificant improvements in GAD, depression, and quality of life. However, 8 completers of CBT continued to experience clinically significant anxiety, 7 of whom started esci- talopram treatment. At endpoint, the esci- talopram dose was 10 mg/day for 5 patients, and 20 mg/day for 2 patients. Four patients completed 12 weeks of escitalopram treat- ment, and 3 discontinued. There was a trend towards improvement with escitalopram in GAD symptoms on the Hamilton Rating Scale for Anxiety (HRSA) but no significant change on the self-rated Penn State Worry Questionnaire. Significant changes also oc- curred in GAD severity on secondary mea- sures, and all 4 completers showed a 50% reduction in HRSA score. However, without a placebo group for comparison, “we cannot rule out the possibility that improvement during escitalopram treatment was attribut- able to delayed benefits from (completed) CBT or nonspecific effects,” the authors write. Side effects leading to discontinua- tion were nausea, increased anxiety, insom- nia, tremor, gastrointestinal symptoms, ner – vousness, and irritability. Controlled studies with larger sample sizes are needed to determine escitalopram efficacy in patients with persistent GAD symptoms following CBT. [Schneier FR, et al.: J Nerv Ment Dis 2010; 198(6):458–461.] Lamotrigine effective for borderline personality disorder A preliminary study suggests that the anticonvulsant lamotrigine may be effec- tive in treating affective instability in pa- tients with borderline personality disorder (BPD). The study randomized 28 patients with DSM-IV BPD to treatment with flex- ibly dosed lamotrigine (N=15) or placebo (N=13) under double-blind conditions for 12 weeks. Seventeen patients (9 lamotri- gine) completed 12 weeks of treatment, and 23 patients (12 lamotrigine) completed 6 weeks. Lamotrigine-treated patients had significantly greater reductions in total Af- fective Lability Scale scores (p<0.05) and in scores on the affective instability item of the Zanarini Rating Scale (ZAN) for BPD (p<0.05) compared with placebo-treated pa- tients. A secondary outcome showed signifi- cantly greater reductions with lamotrigine in impulsivity scores on the ZAN-BPD versus placebo (p=0.001). “To our knowledge, our study is the first to show prospectively that any mood-stabilizing anticonvulsants can effectively treat overall affective in- stability in BPD,” the authors write. The findings are consistent with the only previ- ous study of pharmacotherapy of affective instability in BPD, in which fluvoxamine was modestly effective in reducing affective instability as measured by the Borderline Personality Disorder Severity Index. The 8 T h e Br o w n Un i v e r s iTy Ps y c h o Ph a r m a c o l o g y UPd a Te o c To Be r 2010 c a s e r e p o r t Delirium following addition of adjunctive quetiapine/valproate in BP Case 1: Female, 53 years old Medications: Lithium (Eskalith), sodium valproate, sertraline (Zoloft), quetiapine (Seroquel), haloperidol (Haldol) Comment: A 53-year-old woman with bipolar disorder since age 16, developed permanent mild renal insufficiency following acute lithium intoxication resulting from intentional over – doses 1 year prior to presentation. Valproate was started but despite good compliance she was hospitalized due to ongoing depression. One week after starting valproate 500 mg/day and sertraline 50 mg/day she experienced a manic episode, and sertraline was discontinued. Due to increasing mood instability, valproate was titrated to 1000 mg/day over the next 10 days with adjunctive quetiapine 100 mg/day. The night following quetiapine initiation, she devel- oped visual hallucinations with disorientation, confusion, agitation, and met DSM-IV criteria for delirium. Her valproate plasma level was 103 μg/ml. Results of neurologic, physical, and laboratory tests were normal. Within 2 days of discontinuing quetiapine, her delirium was fully resolved, with the addition of oral haloperidol 5 mg/day, although mania persisted. Case 2: Male, 63 years old Medications: Lithium (Eskalith), quetiapine (Seroquel), sodium valproate Comment: A 63-year-old man with bipolar disorder since age 33, experienced acute lithium intoxication 5 years previously with concomitant use of a diuretic for hypertension and spo- radic use of lithium, resulting in mild renal insufficiency. He was prescribed valproate, which he took irregularly, and was eventually hospitalized for hyperactivity, irritability, pressure of speech, and aggression, and given a diagnosis of bipolar disorder, manic episode. For the next 3 weeks, he received valproate 1000 mg/day and quetiapine titrated up to 300 mg/day. Que- tiapine at 300 mg resulted in confusion and visual hallucinations, and delirium was diagnosed. His plasma valproate level was 43 μg/ml. Consistent with delirium, an electroencephalogram showed diffuse background-slowing. Computerized axial tomography showed no abnormal- ity. Within 1 week of discontinuing quetiapine his delirium was fully resolved. “Although seemingly rare, we report 2 patients with bipolar disorder who developed delirium when pre- scribed quetiapine as an adjunct to valproate for acute mania.” The development of delirium may have been the result of a synergistic effect of valproate and adjunctive quetiapine in the presence of mild renal sufficiency. Alternatively, the mild renal insufficiency that developed following lithium intoxication resulted in an accumulation of quetiapine. One study 1 has re- ported increased plasma quetiapine concentrations associated with older age, as well as a 77% increase in quetiapine plasma concentrations with concomitant use of valproate. Any or all of these factors may have induced anticholinergic delirium in the current cases. ▪ • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Huang CC, Wei IH: Unexpected interaction between quetiapine and valproate in patients with bipolar disor – der. Gen Hosp Psychiatry 2010; 32(4):446.e1–446.e2. E-mail: [email protected] Re f e Re n c e 1. Aichorn W, et al.: Influence of age, gender, body weight, and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol 2006; 21:81–87. Safety alert for lamotrigine A safety alert for lamotrigine (Lamictal) was posted on August 12, warning that the drug can cause asep- tic meningitis. Lamotrigine is com- monly used for treating bipolar disor – der in adults, and seizures in children aged ≥2 years. Meningitis symptoms include headache, fever, stiff neck, nausea, vomiting, rash, and sensitiv- ity to light. Rapid diagnosis is needed to initiate prompt treatment. [www. fda.gov/Safety/MedWatch/Safety Information/SafetyAlertsforHuman MedicalProducts/ucm222269.htm] Drug Safety Changes A list of drug safety labeling changes for June 2010 is available at www.fda.gov/Safety/MedWatch/ SafetyInformation/ucm218813.htm. New Approvals A list of all original, tentative, and supplemental FDA approv- als for the month of July 2010 is available at www.accessdata.fda. gov/scripts/cder/drugsatfda/index. cfm?fuseaction=Reports.Monthly ApprovalsAll. ”Bad Ad” program The FDA’s “Bad Ad” program encourages healthcare providers to play a role in making sure “that prescription drug advertising and promotion is truthful and not mis- leading.” The program asks health- care providers to remain aware of the many ads and promotions they see everyday, and to help stop FDA violations by reporting activities and messages that they consider to be false or misleading. [Further details are available at www.fda.gov/Drugs/ GuidanceComplianceRegulatory Information/Surveillance/Drug MarketingAdvertisingandCommuni cations/ucm209384.htm.] FDA From the n e W s n o t e s authors recommend that future studies in- vestigating lamotrigine in this population be designed with longer treatment dura- tion, larger sample sizes, more severely ill borderline patients including those who are actively suicidal, and provide more infor – mation on lamotrigine’s effectiveness for affective instability in male BPD patients. [Reich DB, et al.: Int Clin Psychopharmacol 2010. E-pub ahead of print: DOI: 10.1097/ YIC.0b013e32832d6c2f] continued from previous page Copyright of Brown University Psychopharmacology Update is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder’s express written permission. However, users may print, download, or email articles for individual use.
The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th
Running head: BORDERLINE PERSONALITY DISORDER 0 Borderline Personality Disorder Heather Yant PSY 630 PsychopharmacologyInstructor: Stefanie Gwaltney-Hausch 2/18/18 . Borderline Personality Disorder Borderline personality disorders is a complex disorder which showcases persistence problem in regulating emotion, controlling impulses and instability in interpersonal relationship and self-image. The purpose of this research on borderline personality disorder is to examine the contribution of neurotransmitter and receptors and other anatomic features associated with disruption of a neurocognitive process and memory system (Rhoads, & Murphy, 2015). As well, the research will outline critical classes of drugs used in treating borderline personality disorder, examining the agonist-antagonist activity of the drug. Also, the study will explore receptors agonist-antagonist action and side effects of drugs and evaluation of risk benefits of drug use for this disorder. Borderlines personality disorder is challenging to diagnose because some of the symptoms associated with the diseases are shared by other mental disorders. Therefore proper evaluation of client longitudinal history and interview is done to identify some of the client symptoms. These procedures help in reducing misdiagnosis. According to DSM-V, (2013), an individual with Borderline personality disorders has to experience the following symptoms. First, the client experiences impairments in self-function (a) and (b). According to APA,( 2013), Impairment (a) associated with unstable self-image, excessive self-criticism, a chronic feeling of emptiness and dissociative states of stress. Impairment (b) associated with instability in goal, aspiration, and value or career plan. Besides, the client experience impairment in interpersonal functional (a) and (b) for example Empathy which is associated with ability interpersonal hypersensitivity. Intimacy which is associated with unstable and conflicted close relationship marked mistrust and others factors. Besides, an individual with borderline disorder experiences emotional liability, for example, frequent mood changes, anxiousness, separation insecurity because of fear of rejection depressive. Pathological personality traits according to DSM V, (2013) include Disinhibition and Antagonism. Disinhibition is associated with impulsivity, for example, acting on the spur of the moment in response to immediate stimuli. Risk-taking includes engagements in dangerous and risky activities. Antagonism involves hostility, for example, persistent and angry feelings. In category C, according to DSM V, (2013), the impairment in personality functioning and individual personality traits is stable across time and consistency across situation. Category D according to DSM V, (2013), entails that, the personality functioning and personality traits expression are associated or understood as normative for individual developmental stages or social environment. Category E according to DSM V, (2013) entails that an individual impairment should not be linked to direct physiological effects of substance abuse or severe brains injury. Therefore if an individual has two or more of the following impairments behaviors he or she qualifies diagnoses of borderline personality disorder. Qualified mental physicians recommend medications and drugs for the borderline personality disorder. Mesolimbic dopaminergic is a pathway in the human brain that carries dopamine from one area of the brain to the other. This pathway associated with the function of movement, preservation, and compulsion. If Mesolimbic dopaminergic is induced by physiological stimuli or psychotropic drugs, then the chemical messages from neurotransmitter are sent to initiate pleasures. Therefore intakes of certain substances result in the intense and fast feeling of pleasure caused by an increase of dopamine in the mesolimbic systems. Some of the antidepressant drugs used to treat borderline disorders include Selective serotonin reuptakes inhibitors (SSRIs), Serotonin-norepinephrine reuptake inhibitors and melatonergic agents. The antidepressant medications for SSRIs can be administered when there is evidence of aminergic systems which is influencing inhibitory control or resisting urge and control of compulsive repetition. The aminergic system includes key biogenic amines responsible regulating emotion, controlling impulses and other variables. Those biogenic amines include serotonin (5-HT), norepinephrine (NE), dopamine (DA), and acetylcholine (ACh). Serotonergic drug work efficiently in serotonergic dysregulation, impulse, and symptoms associated with the obsessive-compulsive spectrum (Kayser, Titulaer, Gresa-Arribas, & Dalmau, 2013). Oppositely, selective serotonin reuptakes inhibitor has insignificant effects on impulsive aggression in Borderline personality disorders, but it has a significant impact on decreasing anxiety and depression. Other researchers indicate that some drugs such as amitriptyline, tricyclic antidepressant have positive effects on borderline symptoms outside major depressive disorders. Amitriptyline in BDP is recommended only to be used on limited occasion because it is highly toxic when an individual overdose. On the other side, monoamine oxidase inhibitor (MAOIs) approved for treating patients with atypical depression. These patients are characterized by rejection sensitivity and efficiently reactivity. MAOIs use improves aggression and anxiety that according to an earlier study on the effects of these drugs to patients. The drug still has side effects if used continuously because it leads to hypertensive crises during dietary indirection. Besides, the drug is limitedly used for patients with severe impulsivity or suicidality (Kayser, Titulaer, Gresa-Arribas, & Dalmau, 2013). All these drugs in one way or the other effect how neurotransmitter communicates with each neuron. When an individual takes certain types drugs, the drugs interact with serotonin, dopamines and other neurotransmitters. As a result s sense of happiness and well-being may be affected in one way or the other because the drugs may interfere with normal secretion of serotonin possible for happiness. SSRIs drugs are said to have mild side effects when used to treat patients with severe symptoms of depression. The drug works by blocking the brain reabsorption of serotonin. It remains in the synaptic cleft where it continues to bind to receptors and activates them. The reason behind keeping a high level of neurotransmitter between the nerve cells is to strengthen circuits in the brain which regulates moods. MAOIs drugs keep the serotonin from being metabolized and excreted from the neurons. The serotonin is converted into melatonin in the pineal glands in the hypothalamus hence helps in controlling sleep patterns and sexual urges. Psychedelic drugs raise serotonin level in the brain which is responsible for moods stabilization and happiness. The agonist is a chemical which initiates psychological response with a receptor while the antagonist is chemical or drugs that bind to receptors to block initiation of psychological response. There are several drugs which help in psychological Responses or blocking initiation of psychological response. For example, opioid receptors antagonist, for example, naltrexone and nalmefene prevent the reinforcing effects of opioids and reduces substance consumptions and craving. The Opioid receptors analogists mainly prescribed for alcoholism and heroin dependence. The second generation antipsychotic drugs and first-generation drugs act as antagonist drugs in the dopamine D2 receptors. These drugs block the types two serotonin (5-HT2) receptors for 5-HT2A and 5- HT2C (Steiner, Teegen, Schiltz, Bernstein, Stoecker, & Bogerts, 2014). Examples of drugs responsible for blockage of 5-HT2A subtypes of receptors include trazodone and nefazodone. The action of blocking type two serotonin receptors effect forebrain norepinephrine and dopamine neurotransmission. On the contrary, 5-HTIA receptors agonist enhances the release of norepinephrine and dopamine. Dopamine regulates emotional and motivation behaviors through the mesolimbic dopaminergic pathways. Some subtypes of serotonin receptors indicate differing effects on impulsive aggression for example Antagonist of 5-HT2A receptors reduces the impulsivity while a typical neuroleptics with prominent 5-HT2A antagonism have anti-aggression efficacy in a clinical population. Agonist, on the other hand, reduces impulsivity at 5-HT2C receptors. This indicates that’s the two receptors subtypes are responsible for regulating aggression. Agonist –Antagonist’s drugs are characterized by lesser tendency to produce physical dependence and by ceiling effects for respiratory depression. These drugs may have some side effects for patients receiving agonist opioids. Some agonist drugs such as Aripiprazole bind to and activate dopamine receptors in the brain (Steiner, Teegen, Schiltz, Bernstein, Stoecker, & Bogerts, 2014). This drug exerts impact through various receptors such as subtypes of serotonin, dopamine, adrenergic, adrenergic, muscarinic acetylcholine and histamine receptors. This drug can be used to treat schizophrenia and bipolar disorders. Also, the drug can be used to treat major depressive disorders, obsessive-compulsive disorders, and irritability. Aripiprazole partial agonistic drug affects dopamine receptors by decreasing dopamine production and stabilizing dopamine system. The side effects associated with the drug include pain in the limbs and headache, nervousness, and many other side effects. Asenapine drug is categorized in the antipsychotic medication. The drug works by changing the action of the chemical in the brain. This drug act as dopamine antagonist drugs which block serotonin receptors subtypes from initiating their function within the human mind. This drug used in treating schizophrenia in adults and bipolar I disorders in adults and children. This drug has many side effects such as high fever, sweating, confusion, tremors, uncontrollable high movement and other effects. Mental specialist recommends some medication for Borderline personality disorders after they have evaluated the risk involved in the drug use. The dangers of taking some drugs can be justified after the drug benefits outweigh its possible benefits. For example, symptoms of borderline personality disorder such as emotional dysregulation and impulsivity can be controlled by use of mood stabilizer which in one way or the other may have side effects to the user. The best method to deal with mood dysregulation is through psychotherapy. The reason for using drugs is because they help in treating mental disorder efficiently because psychotherapy may not be useful because BPD has interlinked symptoms. Drugs associated with SSRIs have fewer side effects to the user, and therefore recommendation of the drug will be effective in stabilizing moods and happiness References American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). 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