Atypical antipsychotics in the treatment of affective symptoms: a review.

Atypical antipsychotics have demonstrated beneficial effects on affective symptoms, in addition to antipsychotic activity. Consequently, their role in the treatment of bipolar disorder and treatment-resistant or psychotic depression has been explored. Adjunctive atypical antipsychotic therapy appears to benefit patients experiencing manic episodes of bipolar disorder, and some studies suggest that monotherapy may also be efficacious. Clinical studies of patients with schizoaffective disorder and major depression support the use of atypical antipsychotics to treat depression. This review focuses on risperidone, olanzapine, quetiapine, and ziprasidone and provides evidence that these drugs demonstrate activity against manic episodes of bipolar disorder when used as adjunctive therapy and possibly as monotherapy and that depression in patients with schizoaffective disorder also responds to these agents.     

Clinical research on antipsychotics in bipolar disorder

Antipsychotics are commonly used in bipolar disorder, both for acute mania and in maintenance treatment. The authors review available clinical research concerning the use of both conventional and atypical antipsychotics in bipolar disorder and present recommendations for a number of key clinical situations based on this review. They also consider a number of important related questions, including whether there is evidence for an increased risk of tardive dyskinesia (TD) in patients with bipolar disorder, the potential role for antipsychotics in the treatment of bipolar depression, the role of antipsychotics in maintenance treatment of bipolar disorder, the potential for antipsychotics to induce depression in bipolar illness, and whether antipsychotics can be considered mood stabilizers with a place as monotherapy for bipolar mania. They conclude that standard treatment for acute mania should begin with a mood stabilizer, with benzodiazepines used as an adjunct for mild agitation or insomnia and antipsychotics used as an adjunct for highly agitated, psychotic, or severely manic patients. They also conclude that atypical antipsychotics are preferable to conventional antispychotics because of their more favorable side effect profile and reduced risk of tardive dyskinesia. They review the evidence for using atypical antipsychotics as first-line monotherapy for mania and conclude that more evidence concerning the risk of TD and their efficacy as maintenance treatment in bipolar disorder is needed before a conclusion can be made. Should the eventual risk of TD associated with atypical antipsychotics be found to be minimal and their efficacy in maintenance treatment found to be high, they could eventually be considered first line monotherapy for bipolar disorder. They conclude that treatment with an antipsychotic during bipolar depression should be limited to those patients who have psychosis and that atypical antipsychotics are preferred over conventional antipsychotics in this situation, not only because of their reduced risk of side effects but also because theoretically they may have antidepressant efficacy due to their effects on the serotonin system. The clinical research findings summarized in the article are, for the most part, supported by a recently published guideline based on a consensus of clinical experts.     

Risperidone for bipolar disorders

Atypical antipsychotic medications are a relatively new, increasingly prominent component of the treatment armamentarium for bipolar disorder -- a development that provides more options for potentially improved outcomes for patients and families affected by bipolar disorder. The US Food and Drug Administration-approved bipolar indications for risperidone include monotherapy for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. Risperidone is also approved in over 30 countries worldwide for bipolar mania either as monotherapy, adjunct therapy, or both monotherapy and adjunct therapy. A number of controlled and open-label treatment trials have shown risperidone's efficacy and tolerability in the manic phase of bipolar disorder. Risperidone has also been reported to be useful in the longer-term treatment of bipolar disorder. This drug profile of risperidone for bipolar disorder will address the chemistry, pharmacodynamics, pharmacokinetics and metabolism of risperidone, clinical trials in bipolar disorder, postmarketing surveillance, safety, tolerability and regulatory issues. Finally, a discussion of potential future directions, a summary of key issues and information resources are provided.     

Antipsychotics in bipolar disorders

This article is a review of the various treatments that are currently available, in particular in France, for the treatment of bipolar disorders. This article specifically addresses the use of novel antipsychotic agents as alternative therapy to a lithium therapy and/or the use of conventional antipsychotics. The prevalence of bipolar disorder over a lifetime is around 1% of the general population. Bipolar disorder consists of alternating depressive and manic episodes. It mainly affects younger subjects, and is often associated with alcohol and drug addictions. There are two main subtypes of bipolar disorder. According to the DSM IV-R, type 1 of bipolar disorder is characterised when at least one manic episode (or a mixed episode) has been diagnosed. Type 2 of bipolar disorder is related to patients enduring recurrent depressive episodes but no manic episode. Type 2 affects women more frequently as opposed to type 1 affecting individuals of both sexes. Manic-depressive disorder (or cyclo-thymic disorder) appears in relation to patients who has never suffered manic episode, mixed episode or severe depressive episode but have undergone numerous periods with some symptoms of depression and hypomanic symptoms over a two-year period during which any asymptomatic periods last no longer than two months. The average age of the person going through a first episode (often a depressive one) is 20 years-old. Untreated bipolar patients may endure more than ten manic or depressive episodes. Finally, in relation to 10 to 20% of patients, the bipolar disorder will turn into a fast cycle form, either spontaneously or as a result of certain medical treatments. Psychiatrists are now able to initiate various treating strategies which are most likely to be effective as a result of the identification of clinical subtypes of the bipolar disorder. Lithium therapy has been effectively and acutely used for patients with pure or elated mania and its prophylaxis. However, lithium medication may worsen depressive symptoms when used for a long term maintenance therapy. Additionally, mixed mania, rapid cycling type patients and bipolar disorder associated with substance abuse do not respond well to lithium therapy. In addition to the lithium therapy or in place of a lithium therapy, one can report the frequent use of antipsychotic agents in respect of patients with bipolar disorder during both the acute and maintenance phases of treatment. Antipsychotic agents have been used for almost forty years and may be used in combination with a lithium therapy. Conventional antipsychotics are effective but they may induce late dyskinesia, weight gain, sedation, sexual dysfunction and depression. These adverse side effects often lead to non compliance in particular in circumstances where antipsychotic agents are combined with a lithium therapy. A number of alternative somatic treatment approaches have been reported for patients who do not respond well or who are intolerant to lithium therapy. As such, valproate has received regulatory approval for the acute treatment of mania and carbamazepine has been indicated for this condition in a number of countries. Divalproex (Depakote) has recently obtained the authorization to market in France and may be prescribed for manic states or hypomanic states that do not tolerate lithium therapy or for which lithium therapy is contraindicated. A number of other anticonvulsants (lamotrigine, gabapentin and topiramate) are currently being tested. Because of the side effects of the conventional antipsychotic agents, atypical antipsychotic agents are currently on trial and appear to be of interest in the treatment of bipolar disorders. Currently, a number of prospective studies are available with clozapine, risperidone and olanzapine in the treatment of bipolar disorder. Most are short-term studies. Recent randomised, double-blind, placebo-controlled studies have shown clozapine, risperidone and olanzapine to be effective with antimanic and antidepressive effects, both as monotherapy and as add-on maintenance therapy with lithium or valproate. They also have a favorable side effect profile and a positive effect on overall functioning. Similarly, valproate combined with antipsychotics provides greater improvement in mania than antipsychotic medication alone and results in lower dosage of the antipsychotic medication. There is currently no double-blind study regarding the use of clozapine for bipolar disorders. However, based on the results of a number of open-label studies, clozapine appears to be effective in relation to schizo-affective and bipolar patients including those with rapid cycling or those who respond inadequately to mood stabilizers, carbamazepine, valproate or conventional antipsychotics. Clozapine seems to be more appropriate for bipolar and schizo-affective patients than schizophrenics. In particular, studies show that patients with manic and mixed-psychotic state of illness are better responders than patients with major depressive syndromes. Four open studies suggest the efficacy of clozapine in the maintenance treatment of bipolar disorder and three prospective, open-label studies show the efficacy of clozapine in the manic state of the illness. However, the number of patients in the studies was not important and these studies are not controlled. Clozapine has also adverse side affects, one of which consisting of a major risk of agranulocytosis and, potentially, death. In addition, clozapine has been shown to produce significant weight gain and sialorrhea as well as significant anticholinergic effects. As a result, clozapine should not be prescribed in the first place. As opposed to clozapine, there are open-label reports and controlled studies in respect of risperidone and olanzapine. Two recent double-blind studies of acute mania found olanzapine to be more effective than placebo. Based on these two studies, olanzapine has recently been approved for the indication of mania. The effects of olanzapine and divalproex in the treatment of mania have also been compared in a large randomized clinical trial. The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission. Significantly more weight gain and cases of dry mouth, increased appetite and somnolence were reported with olanzapine while more cases of nausea were reported with divalproex. The comparison of olanzapine with lithium for the treatment of mania has also been the subject of a double-blind randomized controlled trial. That study shows no differences between the two drugs. While these studies support the idea that olanzapine has direct acute anti-manic effects, a number of authors are of the opinion that olanzapine may have specific prophylactic mood-stabilizing properties. Olanzapine would appear to be effective in the maintenance treatment, as it exhibited both antimanic and antidepressant effects. Systematic trials have shown that risperidone may be effective and safe in the treatment of acute mania, as an add-on therapy with lithium or valproate (open studies and two controlled double-blind studies) and as monotherapy (open studies). In an open, multi-center, 6-month study, risperidone seems to be effective and safe as long-term adjunctive therapy in treatment-resistant bipolar and schizo-affective disorders, with no exacerbation of manic symptoms. Risperidone had few adverse side effects (and where there were any, they were mostly mild), mostly consisting of APS and weight gain. A naturalistic comparison of clozapine, risperidone and olanzapine in the treatment of bipolar disorder suggests that the efficacy and tolerability of the three treatments are similar. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. However, this may partially be caused by the use of mood-stabilizing agents. Bipolar and schizo-affective patients now require combination therapy approach because of the cyclic nature of these disorders. Many studies report the combination of mood-stabilizing agents with conventional antipsychotics and atypical antipsychotics. Combination therapies produce a number of adverse side effects. Atypical antipsychotics (other than clozapine) are now rated as first-line agents for adjunctive treatment of mania because they produce less adverse side effects. Atypical antipsychotics are also rated as first-line agents for combined treatment of psychotic depression and they are strongly preferred when an antipsychotic is required for long-term maintenance.     

Acute and maintenance treatment of bipolar mania: the role of atypical antipsychotics

Abstract:  Bipolar disorder is a complex condition including depression, mania, and in many cases associated with comorbid anxiety symptoms and substance abuse. Mood stabilizers including lithium and divalproex have been considered standard therapy for the treatment of patients with bipolar disorder, but remission rates remain inadequate. Conventional antipsychotics have demonstrated efficacy for acute mania, but they appear to have little role in the maintenance treatment of bipolar disorder. Despite substantial evidence of efficacy and recent guideline recommendations, atypical antipsychotics remain underused for the treatment of bipolar disorder. Data from double-blind, controlled trials are available for a number of clinically meaningful efficacy measures, including improvement in manic symptoms, onset of action, response rates, remission rates, improvement in comorbid depressive symptoms, and induction/worsening of mania or depression. Atypical antipsychotics are effective both as alternatives to lithium or divalproex as monotherapy, or in combination with these mood stabilizers, in the acute and likely the maintenance treatment of mania. The atypical antipsychotics represent an effective and relatively safe addition to our armamentarium for the treatment of bipolar disorder.     

Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials

BACKGROUND: Randomized, controlled trials have demonstrated efficacy for atypical antipsychotics in the treatment of mania in bipolar disorder, either as monotherapy or adjunctive treatment. However, there are no published comparisons of individual atypical antipsychotics for mania. DATA SOURCES AND STUDY SELECTION: We conducted a systematic review and meta-analysis of randomized, placebo-controlled monotherapy and adjunctive therapy trials of atypical antipsychotics for acute bipolar mania. Studies published through 2004 were identified using searches of PubMed/MEDLINE with the search terms mania, placebo, and each of the atypical antipsychotics, limited to randomized, controlled clinical trials; review of abstracts from the 2003 meetings of the American College of Neuropsychiatry, American Psychiatric Association, and International Conference on Bipolar Disorder; and consultations with study investigators and representatives of pharmaceutical companies that market atypical antipsychotics. DATA EXTRACTION: Analyses were performed on the changes in Young Mania Rating Scale or Mania Rating Scale total scores from baseline to endpoint, using last observation carried forward and computing the difference in change scores between each drug and its corresponding placebo arm. A random-effects model with fixed drug effects was used to combine the studies and make comparisons of the antipsychotics to each other and to placebo. DATA SYNTHESIS: Data from 12 placebo-controlled monotherapy and 6 placebo-controlled adjunctive therapy trials involving a total of 4304 subjects (including 1750 placebo-treated subjects) with bipolar mania were obtained. Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone all demonstrated significant efficacy in monotherapy (i.e., all confidence intervals exclude zero). However, after adjusting for multiple comparisons, pairwise comparisons of individual effects identified no significant differences in efficacy among antipsychotics. Magnitude of improvement was similar whether the antipsychotic was utilized as monotherapy or adjunctive therapy. CONCLUSIONS: The 5 newer atypical antipsychotics were all superior to placebo in the treatment of bipolar mania. For monotherapy and add-on therapy, cross-trial comparisons suggest that differences in acute efficacy between the drugs, if any, are likely to be small.     

Risperidone in the treatment of bipolar mania

Atypical antipsychotic medications have assumed growing importance for the treatment of bipolar disorder, an illness that affects approximately 1.2%–3.7% of the general population in a given year. Current practice guidelines for the treatment of bipolar mania support the use of atypical antipsychotic medications as monotherapy or as a component of polytherapy, and in clinical settings the use of atypical antipsychotics to treat bipolar disorder is widespread. Risperidone is an atypical antipsychotic, sometimes referred to as a second-generation antipsychotic. The receptor-binding profile of risperidone, which includes potent antagonism of the serotonin 5-HT2_A, dopamine D₂, and alpha-adrenergic receptors, is believed to be related to positive effects on mood. The FDA-approved bipolar indications for risperidone include: 1) monotherapy for short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and 2) combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. This review of risperidone for bipolar mania will address the chemistry, pharmacodynamics, pharmacokinetics, and metabolism of risperidone, use with concomitant medications, clinical trials in bipolar mania, as well as safety and tolerability issues. Finally, dosing and administration are addressed as well as use for bipolar mania in geriatric, child, or adolescent patients.     

Ziprasidone-associated mania: a case series and review of the mechanism

Atypical antipsychotics are now commonly used in the treatment of bipolar disorder, as they have been shown to have effects on mania as well as psychosis. Shortly after the introduction of atypical antipsychotics, several cases of associated hypomania and mania were reported. Ziprasidone is an atypical antipsychotic recently approved by the Food and Drug Administration for the treatment of psychosis. Although ziprasidone has also been shown to be effective in treating mania, it may be associated with the induction of mania or hypomania. We report four cases of mania associated with initiation of ziprasidone, which, to our knowledge, are the first reported for this drug in bipolar patients. As ziprasidone has substantial serotonergic and noradrenergic action, we hypothesize, it may more likely induce mania than other atypical antipsychotics. We advocate future studies to evaluate ziprasidone's efficacy in treating bipolar disorder and caution clinicians that induction of mania or hypomania may be possible with this agent.     

Tolerability profiles of atypical antipsychotics in the treatment of bipolar disorder

Atypical antipsychotics have unequivocally advanced the pharmacotherapy of bipolar disorder. These broad-spectrum medications offer efficacy against core symptoms of mania, and evidence supports the use of several agents as treatment options in depressed and maintenance phases of the disorder. Atypical antipsychotics also have a reduced propensity for provoking acute or tardive neurologic adverse events compared with their therapeutic predecessors, the conventional antipsychotics. These agents are not, however, a panacea and are associated with several problematic tolerability and safety concerns. Although classified together, atypical antipsychotics are heterogeneous in their tolerability and safety profiles, an issue that is relevant to individualizing treatment selection. This article reviews relevant adverse events attributable to the use of atypical antipsychotic agents, with particular consideration of the bipolar disorder population.     

Atypical antipsychotics: newer options for mania and maintenance therapy

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of bipolar disorder. In the past few years several atypical agents have received regulatory approval for use in bipolar mania. Through a review of randomized controlled trials for five commonly used atypical drugs, olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole, this article evaluates their efficacy in the acute and maintenance phases of bipolar disorder. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored.
Atypical antipsychotics appear to have broadly similar efficacy against manic symptoms of bipolar disorder, but there are important differences in their tolerability profiles, which are likely to be of particular relevance during long-term treatment. A brief assessment of tolerability issues surrounding the use of atypical agents in bipolar disorder and other aspects of treatment that have impact on the clinical effectiveness of the therapy are considered.     

The role of novel antipsychotics in bipolar disorders

Patients with bipolar disorder frequently receive antipsychotic agents during both the acute and maintenance phases of treatment. Conventional antipsychotics are effective against mania, but they may induce depressive symptoms and expose patients with bipolar disorder to increased risks of tardive dyskinesia. Recent studies have shown risperidone to be effective for acute mania, both as monotherapy and in combination with mood stabilizers; this agent has also shown efficacy as add-on maintenance therapy in open-label studies as it exhibited both antimanic and antidepressant effects. Olanzapine, another novel antipsychotic, is also effective against both manic and depressive symptoms and in the maintenance treatment as indicated by an open-label study. Data on other novel agents are more limited.     

Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry

The current statement is a systematic review of the available data concerning the efficacy of medication treatment of bipolar disorder (BP). A systematic MEDLINE search was made concerning the treatment of BP (RCTs) with the names of treatment options as keywords. The search was updated on 10 March 2012. The literature suggests that lithium, first and second generation antipsychotics and valproate and carbamazepine are efficacious in the treatment of acute mania. Quetiapine and the olanzapine-fluoxetine combination are also efficacious for treating bipolar depression. Antidepressants should only be used in combination with an antimanic agent, because they can induce switching to mania/hypomania/mixed states/rapid cycling when utilized as monotherapy. Lithium, olanzapine, quetiapine and aripiprazole are efficacious during the maintenance phase. Lamotrigine is efficacious in the prevention of depression, and it remains to be clarified whether it is also efficacious for mania. There is some evidence on the efficacy of psychosocial interventions as an adjunctive treatment to medication. Electroconvulsive therapy is an option for refractory patients. In acute manic patients who are partial responders to lithium/valproate/carbamazepine, adding an antipsychotic is a reasonable choice. The combination with best data in acute bipolar depression is lithium plus lamotrigine. Patients stabilized on combination treatment might do worse if shifted to monotherapy during maintenance, and patients could benefit with add-on treatment with olanzapine, valproate, an antidepressant, or lamotrigine, depending on the index acute phase. A variety of treatment options for BP are available today, but still unmet needs are huge. Combination therapy may improve the treatment outcome but it also carries more side-effect burden. Further research is necessary as well as the development of better guidelines and algorithms for the step-by-step rational treatment.     

Second generation antipsychotics in bipolar depression: a new therapeutic option?

Bipolar depression, the most common phase of bipolar disorder, causes significant morbidity and mortality. Lithium, anticonvulsants or antidepressants offer some clinical efficacy. However, efficacy can be limited and side effects are sometimes problematic. There is still a major unmet need for effective, well-tolerated agents for the treatment of bipolar depression. The second-generation antipsychotics, with their proven efficacy against manic symptoms, are emerging as candidates for use against the depressive phase of bipolar disorder. Several studies have shown that some second-generation antipsychotics may improve depressive symptoms in mixed episodes in patients with bipolar disorder. More recently, specific studies have been performed in patients with bipolar depressive episodes. Quetiapine or olanzapine, as monotherapy or associated with other compounds, demonstrate an interesting efficacy. The international guidelines for the treatment of bipolar depression have identified quetiapine as a first line treatment in monotherapy. Second generation antipsychotics may prove to be important future treatments for patients with bipolar depression.     

Atypical antipsychotic augmentation of mood stabilizer therapy in bipolar disorder

Although monotherapy with lithium or divalproex is the recommended initial therapy for bipolar disorder, these agents are associated with prolonged favorable outcomes in only 30% of patients. Increasingly, the medical literature is demonstrating that augmentation of mood stabilizers with atypical antipsychotics is a more effective therapy. This form of combination therapy is recommended as first-line treatment for severe bipolar mania. Recent clinical studies have shown that augmentation therapy with the atypical antipsychotics risperidone, olanzapine, quetiapine, and ziprasidone is effective in long-term maintenance treatment, and preliminary evidence is emerging that use of atypicals with mood stabilizers can help control the depressive phase of bipolar disorder. The atypical antipsychotics also have relatively mild side effect profiles, although augmentation therapy with some antipsychotics and mood stabilizers has been associated with excessive weight gain.     

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009

The Canadian Network for Mood and Anxiety Treatments (CANMAT) published guidelines for the management of bipolar disorder in 2005, with a 2007 update. This second update, in conjunction with the International Society for Bipolar Disorders (ISBD), reviews new evidence and is designed to be used in conjunction with the previous publications.
The recommendations for the management of acute mania remain mostly unchanged. Lithium, valproate, and several atypical antipsychotics continue to be first-line treatments for acute mania. Tamoxifen is now suggested as a third-line augmentation option. The combination of olanzapine and carbamazepine is not recommended. For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. New data support the use of adjunctive modafinil as a second-line option, but also indicate that aripiprazole should not be used as monotherapy for bipolar depression. Lithium, lamotrigine, valproate, and olanzapine continue to be first-line options for maintenance treatment of bipolar disorder. New data support the use of quetiapine monotherapy and adjunctive therapy for the prevention of manic and depressive events, aripiprazole monotherapy for the prevention of manic events, and risperidone long-acting injection monotherapy and adjunctive therapy, and adjunctive ziprasidone for the prevention of mood events.
Bipolar II disorder is frequently overlooked in treatment guidelines, but has an important clinical impact on patients' lives. This update provides an expanded look at bipolar II disorder.     

Manic/hypomanic symptoms induced by atypical antipsychotics: a review of the reported cases

The widespread use of atypical antipsychotics (APs) in clinical practice has advanced the pharmacotherapy of schizophrenia regarding treatment resistant cases as well as the negative symptoms of the disorder. Atypical antipsychotics manifest a favourable side effect profile compared to the conventional APs. Atypical APs are also being used as adjunct therapy or monotherapy in patients with manic episodes of bipolar and schizoaffective disorder as well as in patients with psychotic (delusional) depression. On the other hand, atypical APs are also used in combination with (selective) serotonin reuptake inhibitors [(S) SRIs] in the treatment of resistant depression. Shortly after the introduction of atypical APs several cases of manic/hypomanic symptoms during treatment with these compounds have been described in the literature. The reported cases and the possible pathogenetic mechanisms involved in their occurrence are reviewed and discussed.     

A Pilot Trial of Adjunctive Gabapentin in the Treatment of Bipolar Disorder

Several antiepileptic drugs (AEDs) have documented efficacy in the manic phase of bipolar disorder. To investigate the efficacy, tolerability, and safety of the new AED, gabapentin, in mania, we treated nine consecutive outpatients with bipolar I or II disorder by DSM-IV criteria who were experiencing hypomanic, manic, or mixed states inadequately responsive to standard mood stabilizers with open-label, adjunctive gabapentin. Response of manic symptoms was assessed monthly as none, minimal, moderate, or marked. Of the nine patients, seven displayed a moderate or marked reduction in manic symptoms by 1 month after addition of gabapentin, and an additional patient displayed moderate improvement after 3 months. Of these eight patients, six displayed continued antimanic responses for follow-up periods ranging from 1 to 7 months. Side effects were most commonly neurological, mild, and transient. Adjunctive gabapentin may have antimanic and mood-stabilizing effects in some patients with bipolar disorder and is generally well tolerated. Controlled studies of gabapentin in bipolar disorder appear to be warranted.     

Comparative efficacy of typical and atypical antipsychotics as add-on therapy to mood stabilizers in the treatment of acute mania.

BACKGROUND: Typical antipsychotics are commonly used in combination with mood stabilizers for acute mania. Although typical antipsychotics are effective, they have undesirable side effects such as induction of depressive symptoms and tardive dyskinesia. Atypical antipsychotics have more favorable side effect profiles, and recent evidence shows their efficacy in treating mania. Apart from a previous small study that compared risperidone with typical neuroleptics as add-on therapy to mood stabilizers, no studies to date have directly compared atypical antipsychotics with typical antipsychotics as add-on therapy to mood stabilizers in a clinically relevant, naturalistic setting. METHOD: This study is a chart review of all patients with DSM-IV-defined bipolar disorder, current episode mania (N = 204), admitted to the University of British Columbia Hospital during a 30-month period. Patients were separated into 3 groups according to the medications used: (1) mood stabilizer and typical antipsychotic, (2) mood stabilizer and atypical antipsychotic, and (3) combination: mood stabilizer plus a typical antipsychotic, then switched to mood stabilizer plus risperidone or olanzapine within I week. The atypical group was further subdivided into risperidone and olanzapine subgroups. Outcome was measured using Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) ratings generated by review of clinical information in the chart. RESULTS: Patients treated with typical antipsychotics were more severely ill at admission and at discharge than those treated with atypical antipsychotics. Patients in the atypical (p < .005) and combination (p < .05) groups showed significantly greater clinical improvement at discharge than patients treated with typical antipsychotics. This difference was also significant in the subset of patients with psychotic features (p < .03). Risperidone and olanzapine were associated with fewer extrapyramidal side effects than were typical antipsychotics (risperidone vs. typical antipsychotics, chi2 = 8.72, p < .01; olanzapine vs. typical antipsychotics, chi2 = 16.9, p < .001). CONCLUSION: Due to their superior effectiveness and side effect profile when compared with typical antipsychotics. atypical antipsychotics are an excellent choice as add-on therapy to mood stabilizers for the treatment of patients with mania.     

Gabapentin in the acute treatment of refractory bipolar disorder

Background: Gabapentin, a new anti-epileptic agent, has been anecdotally reported to be effective in the treatment of mania. We systematically assessed the response rate in bipolar patients being treated adjunctively with gabapentin for manic symptoms, depressive symptoms, or rapid cycling not responsive to standard treatments.
Method: Twenty-eight bipolar patients experiencing manic (n=18), depressive (n=5), or rapid-cycling (n=5) symptoms inadequately responsive to at least one mood stabilizer were treated in an open fashion with adjunctive gabapentin. Illness response was assessed using the Clinical Global Impression Scale modified for bipolar disorder (CGI-BP). A 'positive response' was operationalized as a CGI response of much or very much improved.
Results: Fourteen of the 18 (78%) treated for hypomania or mania had a positive response to a dosage range of 600–3600 mg/day. Patients with hypomania responded fastest, with a positive response achieved in 12.7±7.2 days. Patients with classic mania had a mean time to positive response of 25±12 days, and in patients with mixed mania it was 31.8±20.9 days. All of the five patients treated for depression had a positive response within 21±13.9 days. Only one of five patients with rapid cycling had a positive response. Gabapentin was well tolerated by all patients, with the most common side-effect being sedation.
Conclusions: Gabapentin appears to have acute anti-manic and anti-depressant properties as an adjunctive agent for refractory bipolar illness. Prospective double-blind studies are needed to further delineate its acute efficacy when used as monotherapy and its prophylactic efficacy as monotherapy or in conjuction with other mood stabilizers.     

Role of aripiprazole in treating mood disorders

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of mood disorders. In the past few years, several atypical agents have received regulatory approval for use in mania. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers, such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Aripiprazole is a recently released antipsychotic medication that differs from other atypical antipsychotic agents by its mode of action as a dopamine D2 partial agonist. It is administered orally and has a long half-life. Randomized studies have demonstrated the efficacy of aripiprazole compared with placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, treatment of acute mania, and prevention of manic relapse in patients who responded to the drug during a manic episode. Further studies are ongoing in bipolar and unipolar depression. Aripiprazole is generally well tolerated compared with other antipsychotic medications, although commonly reported side effects include extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information regarding the comparative safety, efficacy and tolerability of aripiprazole in the treatment of affective disorders.