New approaches in managing bipolar depression

Historically, the pharmacologic treatment of bipolar depression has not been well studied. New data are beginning to emerge regarding the efficacy of new medications and the use of combinations of mood stabilizers and antidepressants in acute and long-term treatment of bipolar depression. We reviewed data from recent randomized, controlled trials of mood stabilizers and antidepressants in the treatment of bipolar depression and naturalistic studies examining the risk of switching and depressive relapse with ongoing antidepressant treatment.     

Antidepressants for bipolar disorder——A meta-analysis of randomized,double-blind,controlled trials

OBJECTIVE： To examine the efficacy and safety of short-term and long-term use of antidepres- sants in the treatment of bipolar disorder. DATA SOURCES： A literature search of randomized, double-blind, controlled trials published until December 2012 was performed using the PubMed, ISI Web of Science, Medline and Cochrane Central Register of Controlled Trials databases. The keywords ＂bipolar disorder, bipolar I disorder, bipolar II disorder, bipolar mania, bipolar depression, cyclothymia, mixed mania and depression, rapid cycling and bipolar disorder＂, AND ＂antidepressant agent, antidepressive agents second- generation, antidepressive agents tricyclic, monoamine oxidase inhibitor, noradrenaline uptake in- hibitor, serotonin uptake inhibitor, and tricyclic antidepressant agent＂ were used. The studies that were listed in the reference list of the published papers but were not retrieved in the above-mentioned databases were supplemented. STUDY SELECTION： Studies selected were double-blind randomized controlled trials assessing the efficacy and safety of antidepressants in patients with bipolar disorder. All participants were aged 18 years or older, and were diagnosed as having primary bipolar disorder. Antidepressants or antidepressants combined with mood stabilizers were used in experimental interventions. Placebos, mood stabilizers, antipsychotics and other antide pressants were used in the control interventions. Studies that were quasi-randomized studies, or used antidepressants in combination with antipsy- chotics in the experimental group were excluded. All analyses were conducted using Review Man- ager 5.1 provided by the Cochrane Collaboration.     

The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review

BACKGROUND: Current treatment guidelines recommend discontinuation of an antidepressant within 3 to 6 months after remission of depression in patients with bipolar illness. Yet few studies directly compare the impact of antidepressant discontinuation versus antidepressant continuation on the risk for depressive relapse in patients with bipolar disorder who have been successfully treated for a depressive episode. METHOD: In a retrospective chart review, patients with DSM-IV bipolar disorder who were treated for an index episode of depression by adding antidepressant medication to ongoing mood stabilizer medications were identified. The risk of depressive relapse in 25 subjects who stopped antidepressant medications after improvement was compared with the risk of depressive relapse in 19 subjects who continued antidepressants after improvement. RESULTS: Termination of antidepressant medication significantly increased the risk of a depressive relapse. Antidepressant continuation was not significantly associated with an increased risk of mania. CONCLUSION: While this study may have been limited by the retrospective nature of the chart review, nonrandomized assignment of treatment, and reliance on unstructured progress notes, it suggests that antidepressant discontinuation may increase the risk of depressive relapse in some patients with bipolar disorder. Further research is needed to clarify whether maintenance antidepressant treatment may be warranted in some patients with bipolar disorder, especially in those with frequent recurrent depressive episodes.     

Treatment of bipolar depression, a review of the literature and a suggestion for an algorithm

A review of the methodology and results of 9 controlled studies on the acute treatment of bipolar depression and the risk of switches into (hypo)mania is presented. There are indications but no proof for efficacy of mood stabilizers such as lithium, carbamazepine and valproate. Only lamotrigine has been shown to be effective, with a relative low risk of switching. Several antidepressants appear effective as well, but again there is no (placebo-controlled) proof of their efficacy. The only exception is tranylcypromine which has been found to be more effective than imipramine. The switch ratio into (hypo)mania by tricyclic antidepressants seems to be higher than by several other antidepressants, especially the selective serotonin reuptake inhibitors. In the acute treatment of bipolar depression, it is recommended to start with a mood stabilizer, and to add an antidepressant after 4-6 weeks in case of nonresponse. In severer cases, one might consider to start earlier with the combination of a mood stabilizer and an antidepressant, and in refractory patients, there is a place for tranylcypromine. In the maintenance treatment, there are indications that the combined treatment of a mood stabilizer (mostly lithium) and an antidepressant (TCA) is associated with an increased risk of switches into (hypo)mania, when compared to a mood stabilizer alone. Therefore, it is recommended to try whether a monotherapy with a mood stabilizer is effective, before combining it with an antidepressant.     

Have some guidelines for the treatment of acute bipolar depression gone too far in the restriction of antidepressants?

This paper gives a critical review of recommendations concerning the drug treatment of acute bipolar depression. The suggestions of different guidelines and consensus papers, especially in US-American and Canadian psychiatry, have a strong tendency against antidepressants in bipolar depression; they prefer mono-therapy with mood stabilizers and, in the case of co-medication with mood stabilizers and antidepressants in severe depression, to withdraw the antidepressant as early as possible. The intention of this restrictive use is to avoid the risk of mania and the risk of rapid cycling induced by antidepressants. However, apparently the risk of suicidal acts, which is as prominent in bipolar depression as in unipolar depression, has been totally neglected. Furthermore, the fact that none of the mood stabilizers have proven their antidepressive efficacy leads not only to the risk of depression-related suicidal behavior but also to the risk of chronicity of depressive symptoms due to undertreatment. Altogether the view expressed in some guidelines and consensus papers appears not well balanced. Furthermore, the fact that apparently the selective serotonin re-uptake inhibitors and possibly some other modern antidepressants have only a low risk of inducing a switch to mania should stimulate a rewriting of the guidelines on drug treatment in acute bipolar depression in a less restrictive way concerning the use of antidepressants. Received: 3 January 2000 / Accepted: 2 February 2000     

Antidepressant treatment in bipolar versus unipolar depression

OBJECTIVE: Antidepressant responses were compared in DSM-IV bipolar and unipolar depression. METHOD: The authors analyzed clinical records for outcomes of antidepressant trials for 41 patients with bipolar depression and 37 with unipolar depression, similar in age and sex distribution. RESULTS: Short-term nonresponse was more frequent in bipolar (51.3%) than unipolar (31.6%) depression. Manic switching occurred only in bipolar depression but happened less in patients taking mood stabilizers (31.6% versus 84.2%). Cycle acceleration occurred only in bipolar depression (25.6%), with new rapid cycling in 32.1%. Late response loss (tolerance) was 3.4 times as frequent, and withdrawal relapse into depression was 4.7 times less frequent, in bipolar as in unipolar depression. Mood stabilizers did not prevent cycle acceleration, rapid cycling, or response loss. Modern antidepressants, in general, did not have lower rates of negative outcomes than tricyclic antidepressants. CONCLUSIONS: The findings suggest an unfavorable cost/benefit ratio for antidepressant treatment of bipolar depression.     

Mental Health Collaborative Care and its Role in Primary Care Settings

Bipolar depression is considered the most difficult-to-treat phase of bipolar disorder, in relation to its pervasiveness and efficacy and/or tolerability limitations of available treatments. Indeed, most mood stabilizers and atypical antipsychotics are not as effective in ameliorating depressive compared with manic symptoms, and entail substantial tolerability limitations. However, the use of antidepressants is highly controversial, as their efficacy appears less robust in bipolar compared with unipolar depression. In addition, antidepressants, in spite of generally having adequate somatic tolerability, in BD may be associated with a higher risk of manic/hypomanic switch, suicidality and rapid cycling. Among alternative pharmacological strategies, compounds with stimulant and pro-dopaminergic effects, such as methylphenidate, modafinil, armodafinil and pramipexole, have showed potential antidepressant activity, even though their use in clinical practice has been limited by the paucity of controlled evidence. This article seeks to review available evidence about the use of the aforementioned compounds in the treatment of bipolar depression. Findings from reviewed studies suggested that pro-dopaminergic compounds, such as pramipexole and stimulants/stimulant-like agents, deserve consideration as adjunctive therapies in bipolar depressed patients, at least in some subgroups of patients. Nevertheless, caution regarding their use is recommended as further clinical trials with larger samples and longer follow-up periods are necessary to clarify the roles of these medications in bipolar depression.     

Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up

OBJECTIVE: While guidelines for treating patients with bipolar depression recommend discontinuing antidepressants within 6 months after remission, few studies have assessed the implications of this strategy on the risk for depressive relapse. This study examined the effect of antidepressant discontinuation or continuation on depressive relapse risk among bipolar subjects successfully treated for an acute depressive episode. METHOD: Eighty-four subjects with bipolar disorder who achieved remission from a depressive episode with the addition of an antidepressant to an ongoing mood stabilizer regimen were followed prospectively for 1 year. The risk of depressive relapse among 43 subjects who stopped antidepressant treatment within 6 months after remission ("discontinuation group") was compared with the risk among 41 subjects who continued taking antidepressants beyond 6 months ("continuation group"). RESULTS: A Cox proportional hazards regression analysis indicated that shorter antidepressant exposure time following successful treatment was associated with a significantly shorter time to depressive relapse. Furthermore, patients who discontinued antidepressant treatment within the first 6 months after remission experienced a significantly shorter period of euthymia before depressive relapse over the length of 1-year follow-up. One year after successful antidepressant response, 70% of the antidepressant discontinuation group experienced a depressive relapse compared with 36% of the continuation group. By the 1-year follow-up evaluation, 15 (18%) of the 84 subjects had experienced a manic relapse; only six of these subjects were taking an antidepressant at the time of manic relapse. CONCLUSIONS: The risk of depressive relapse in patients with bipolar illness was significantly associated with discontinuing antidepressants soon after remission. The risk of manic relapse was not significantly associated with continuing use of antidepressant medication and, overall, was substantially less than the risk of depressive relapse. Maintenance of antidepressant treatment in combination with a mood stabilizer may be warranted in some patients with bipolar disorder.     

Antidepressants for bipolar depression: a systematic review of randomized, controlled trials

OBJECTIVE: This study reviewed the evidence from randomized, controlled trials on the efficacy and safety of antidepressants in the short-term treatment of bipolar depression. METHOD: The authors performed a systematic review and meta-analysis of randomized, controlled trials. They searched the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX, and LILACS. The main outcome measures were the proportion of patients who clinically responded to treatment and the rate of switching to mania. RESULTS: Twelve randomized trials were included, with a total of 1,088 randomly assigned patients. Five trials compared one or more antidepressants with placebo: 75% of these patients were receiving a concurrent mood stabilizer or an atypical antipsychotic. Antidepressants were more effective than placebo. Antidepressants did not induce more switching to mania (the event rate for antidepressants was 3.8% and for placebo, it was 4.7%). Six trials allowed comparison between two antidepressants. The rate of switching for tricyclic antidepressants was 10%, and for all other antidepressants combined, it was 3.2%. CONCLUSIONS: Antidepressants are effective in the short-term treatment of bipolar depression. The trial data do not suggest that switching is a common early complication of treatment with antidepressants. It may be prudent to use a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic antidepressant as first-line treatment. Given the limited evidence, there is a compelling need for further studies with longer follow-up periods and careful definition and follow-up of emerging mania and partial remission.     

Antidepressants in bipolar disorder: the case for caution

The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15–20% of bipolar depressed patients).     

A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network

Objectives: The risk‐to‐benefit ratio of the use of unimodal antidepressants (ADs) as adjuncts to mood stabilizers continues to be an area of controversy and disagreement among experts in the field. This paper reviews new data on: (1) depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD discontinuation that are pertinent to the ongoing discussion and recommendations. Methods: In the first study reviewed, 258 outpatients with bipolar illness were assessed prospectively on a daily basis using the National Institute of Mental Health‐Life Chart Method^TM (NIMH‐LCM) for 1 year. In the second study, 127 bipolar depressed patients were randomized to 10 weeks of sertraline, bupropion, or venlafaxine, as adjuncts to mood stabilizers; non‐responders were re‐randomized and responders were offered a year of continuation treatment. In the final study, Altshuler et al. retrospectively and prospectively assessed the risk of depressive relapses in patients who remained on ADs after 2 months of euthymia compared with those who discontinued ADs. Results: Despite intensive naturalistic treatment, the 258 outpatients with bipolar illness followed prospectively for 1 year showed three times as many days depressed as days manic, re‐emphasizing the considerable depressive morbidity that remains in bipolar disorder despite the number of treatment options available. In the study of bipolar depressed patients randomized to one of three ADs, a range of severities and durations of hypomanic to manic switches were discerned following 175 trials of AD augmentation of treatment with a mood stabilizer. Of the acute 10‐week trials, 9.1% were associated with switches into hypomania or mania and another 9.1% with a week or more of hypomania alone (with no to minimal dysfunction). In 73 continuation phase AD trials, 16.4 and 19.2% were similarly associated with hypomanic to manic and hypomanic switches, respectively. In the Altshuler et al. studies, those who remained well on any AD for more than 2 months (only 15–20% of those initially treated) and who continued on ADs showed a lesser rate of relapse into depression over 1 year (35 and 36% in the first and second study, respectively) compared with those who discontinued their ADs (68 and 70% relapsing into depression). Surprisingly, this continuation of ADs was associated with no increase in the rate of switching into mania compared with those stopping ADs. Conclusions: These data reveal that depression and depressive cycling remain a substantial problem in some two‐thirds of intensively treated bipolar outpatients. Acute AD augmentation was associated with a modest response rate and 18.2% switched into a hypomanic to manic episode, and 35.6% of the continuation trials showed these two types of switches. Two separate studies suggest that in the very small subgroup who remain well on ADs for at least 2 months, one should consider continuation of this AD augmentation treatment, because AD discontinuation appears associated with a substantially increased risk of depression relapse over the subsequent year with no reduced risk of switching into mania.     

Quetiapine monotherapy for bipolar depression

Bipolar depression is more common, disabling, and difficult-to-treat than the manic and hypomanic phases that define bipolar disorder. Unlike the treatment of so-called "unipolar" depressions, antidepressants generally are not indicated as monotherapies for bipolar depressions and recent studies suggest that -even when used in combination with traditional mood stabilizers - antidepressants may have questionable value for bipolar depression. The current practice is that mood stabilizers are initiated first as monotherapies; however, the antidepressant efficacy of lithium and valproate is modest at best. Within this context the role of atypical antipsychotics is being evaluated. The combination of olanzapine and the antidepressant fluoxetine was the first treatment to receive regulatory approval in the US specifically for bipolar I depression. Quetiapine was the second medication to be approved for this indication, largely as the result of two pivotal trials known by the acronyms of BOLDER (BipOLar DEpRession) I and II. Both studies demonstrated that two doses of quetiapine (300 mg and 600 mg given once daily at bedtime) were significantly more effective than placebo, with no increased risk of patients switching into mania. Pooling the two studies, quetiapine was effective for both bipolar I and bipolar II depressions and for patients with (and without) a history of rapid cycling. The two doses were comparably effective in both studies. Although the efficacy of quetiapine monotherapy has been established, much additional research is necessary. Further studies are needed to more fully investigate dose-response relationships and comparing quetiapine monotherapy to other mood stabilizers (lithium, valproate, and lamotrigine) in bipolar depression, both singly and in combination. Head-to-head studies are needed comparing quetiapine to the olanzapine-fluoxetine combination. Longer-term studies are needed to confirm the persistence of response and to better gauge effects on metabolic profiles across months of therapy. A prospective study of patients specifically seeking treatment for rapid cycling and those with a history of treatment-emergent affective shifts also is needed. Despite the caveats, as treatment guidelines are revised to incorporate new data, the efficacy and tolerability of quetiapine monotherapy must be given serious consideration.     

Can antidepressants cause mania and worsen the course of affective illness?

Several investigators have recently challenged the belief that antidepressants can precipitate mania or rapid cycling between mania and depression. With one exception, there appear to be no placebo-controlled studies of switches into mania in bipolar patients during antidepressant treatment. Patients most likely to switch into mania during antidepressant therapy have probably been excluded from maintenance treatment studies and are probably overrepresented in studies at special research facilities. On balance, the available evidence suggests that some bipolar patients become manic, and a few experience rapid cycling, when they are treated with antidepressants. The prevention of these responses will require further research on risk factors and on the antimanic efficacy of coadministered lithium or other mood stabilizers.     

Management of the depressive component of bipolar disorder

Acute bipolar depression (ABD) and breakthrough depression occurring during maintenance therapy of bipolar disorder are associated with significant morbidity and an increased risk of suicide. Lithium is an effective mood stabilizer for ABD, but its onset of antidepressant action is slow and additional antidepressant therapy is often prescribed. The extent to which other mood stabilizers (e.g., carbamazepine and valproate) have antidepressant activity is unclear. Preliminary initial research suggests three potential advantages that selective serotonin reuptake inhibitors have over tricyclic antidepressant for ABD: possibly greater efficacy, fewer adverse effects, and a lower frequency of antidepressant-induced mania. Bupropion may also have significant advantages. However, further research is needed to confirm these findings. Monoamine oxidase inhibitors are the antidepressant of choice for atypical bipolar depression. Electroconvulsive therapy (ECT) has the highest response rate of all treatments for ABD. Further research is needed to explore combination treatments with mood stabilizers and antidepressants for the effective treatment of ABD. Depression and Anxiety 4:190–198, 1996/1997. © 1997 Wiley-Liss, Inc.     

Antidepressants and suicidal behavior in bipolar disorder

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167–181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.     

Mood state at study entry as predictor of the polarity of relapse in bipolar disorder.

Of the placebo-controlled maintenance studies conducted in bipolar disorder, few have enrolled patients who present depressed. In fact, only lithium and lamotrigine have been studied over the long term with placebo-controlled designs in recently manic and recently depressed bipolar patients. Given the magnitude of the unmet medical need and the data suggesting that symptomatic patients with bipolar disorder spend the majority of their time depressed, this is unfortunate. Our review of the pre-lithium literature and more recent publications suggests that mood state at study entry predicts the polarity of relapse and the response to treatment. Accordingly, a need exists to enroll recently depressed patients in maintenance studies to elucidate the complete spectrum of efficacy of putative mood stabilizers and improve the long-term treatment of bipolar depression. Patients presenting depressed for a maintenance study tend to relapse into depression; those presenting manic, into hypomania/mania/mixed states. This is particularly true during the first several months of the randomized treatment. The polarity of the index episode tends to predict the polarity of relapse into a subsequent episode in a ratio of about 2:1 to 3:1. We conclude that putative mood stabilizers must be tested in recently manic and recently depressed patients to determine their spectrum of prophylactic efficacy.     

Women and bipolar disorder: an update

The major clinical challenges facing women with bipolar illness, and the practitioners who care for them, are the management of rapid cycling and of the postpartum period. Among patients with rapid cycling bipolar disorder, the treatment of depression is particularly problematic. The most commonly prescribed mood stabilizers are more potent antimanic than antidepressant agents, and the use of antidepressants may precipitate mania or rapid cycling. The availability of new anticonvulsant medications that may have both mood-stabilizing and antidepressant effects is an important development in this regard. In the postpartum period, women with bipolar illness are at uniquely high risk for relapse. The possible reasons for this high risk, and options for the management of pregnancy and the postpartum period in bipolar women, are discussed.     

Traitement pharmacologique du trouble bipolaire chez l’enfant et l’adolescent

Objective

To review the options for acute and maintenance pharmacological treatment of bipolar disorder in children and adolescents.

An overview of recent findings of the Stanley Foundation Bipolar Network (Part I)

Aim and Methods: Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed.
Results: Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted.
Conclusions: Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.     

When do antidepressants worsen the course of bipolar disorder?

Bipolar disorder may be more prevalent than previously believed. Because a substantial number of patients with bipolar disorder present with an index depressive episode, it is likely that many are misdiagnosed with unipolar major depression. Even if a correct diagnosis is made, depressive symptoms in bipolar disorder are notoriously difficult to treat. Patients are often treated with antidepressants, which, if used improperly, are known to induce mania and provoke rapid cycling. This article explores diagnostic conundrums in bipolar depression and their possible solutions, based on current research evidence. It also elucidates current evidence regarding the risks and benefits associated with antidepressant use and evaluates alternative treatment regimens for the depressed bipolar population, including the use of traditional mood stabilizers such as lithium, novel anticonvulsants such as lamotrigine, and atypical antipsychotics.