Joseph R. Calabrese

Antipsychotic-Induced Extrapyramidal Side Effects in Bipolar Disorder and Schizophrenia: A Systematic Review

Objectives: Newer atypical antipsychotics have been reported to cause a lower incidence of extrapyramidal side effects (EPS) than conventional agents. This review is to compare antipsychotic-induced EPS relative to placebo in bipolar disorder (BPD) and schizophrenia. Methods: English-language literature cited in Medline was searched with terms antipsychotics, placebo-controlled trial, and bipolar disorder or schizophrenia and then with antipsychotic (generic/brand name), safety, akathisia, EPS, or anticholinergic use, bipolar mania/depression, BPD, or schizophrenia, and randomized clinical trial. Randomized, double-blind, placebo-controlled, monotherapy studies with comparable doses in both BPD and schizophrenia were included. Absolute risk increase and number needed to treat to harm (NNTH) for akathisia, overall EPS, and anticholinergic use relative to placebo were estimated. Results: Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9. In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression. Conclusions: Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.

Treatment-emergent mania in unipolar and bipolar depression: focus on repetitive transcranial magnetic stimulation

This review focused on the treatment-emergent mania/hypomania (TEM) associated with repetitive transcranial magnetic stimulation (rTMS) treatment of depression. English-language literature published from 1966-2006 and indexed in Medline was searched. Ten of 53 randomized controlled trials on rTMS treatment of depression specifically addressed TEM. The pooled TEM rate is 0.84% for the active treatment group and 0.73% for the sham group. The difference is not statistically significant. Along with case reports, a total of 13 cases of TEM associated with rTMS treatment of depression have been published. Most of these patients were diagnosed with bipolar disorder and the majority of patients experiencing TEM took medication concurrent with rTMS. The parameters of rTMS used in these cases were scattered over the spectrum of major parameters explored in previous studies. Most train durations and intervals were within the published safety guidelines of the field. Reducing the frequency of sessions from two per day to one per day might be associated with a lower likelihood of TEM recurrence. The severity of manic symptoms varied significantly, but all cases responded to treatment that included a decrease or discontinuation of antidepressant and/or rTMS treatment and/or use of anti-manic medication. Current data suggests that rTMS treatment carries a slight risk of TEM that is not statistically higher than that associated with sham treatment. More systematic studies are needed to better understand TEM associated with rTMS. Special precautions and measures should be adopted to prevent, monitor, and manage TEM in research and practice.

A pilot study of topiramate as monotherapy in the treatment of acute mania.

This small-scale pilot study was performed to grossly document safety and any evidence of efficacy of topiramate in bipolar disorder. Ten patients hospitalized for acute mania were given open-label topiramate monotherapy for up to 28 days. The mean Young Mania Rating Scale (YMRS) score decreased from 32 (range, 26–40) at baseline to 22 (range, 2–40) at the end of the study. Five patients exhibited evidence of moderate to marked improvement, three subjects had at least a 50% reduction in YMRS scores, and the other two patients experienced an improvement of 25% to 49% on the YMRS. The preliminary findings of this small series suggest that topiramate may be effective in acute mania. Double-blind controlled trials are now needed to further investigate the efficacy and safety of topiramate in bipolar disorder.

Treatment-emergent mania/hypomania during antidepressant monotherapy in patients with rapid cycling bipolar disorder

OBJECTIVEnTo study treatment-emergent mania/hypomania (TEM) associated with second-generation antidepressant monotherapy in patients with rapid cycling bipolar disorder (RCBD).nnnMETHODSnData of patients with RCBD (n = 180) enrolled into two clinical trials were used to study the risk for TEM during second-generation antidepressant monotherapy. History of TEM was retrospectively determined at the initial assessment by asking patients whether they were exposed to second-generation antidepressants and if a hypomania/mania episode emerged during the first four weeks of treatment. Data were analyzed using t-test, chi-square, and logistic regression.nnnRESULTSnOf the 180 patients (bipolar I disorder, n = 128; bipolar II disorder, n = 52) with RCBD, 85% (n = 153) had at least one antidepressant treatment. Among these patients, 94.1% (144/153) had at least one antidepressant monotherapy treatment. Overall, 49.3% of patients had at least one TEM and 29.1% (116/399) of treatment trials were associated with TEM. In regression analysis, an inverse association between the number of mood episodes in the last 12 months and TEM was observed with an odds ratio of 0.9. However, gender, bipolar subtype, a lifetime history of comorbid anxiety disorder, substance use disorder, or psychosis, and age of mood disorder onset were not associated with TEM. For individual antidepressants, the rates of TEM varied from 42.1% for fluoxetine to 0% for fluvoxamine and mirtazapine. As a group, there was no difference between selective serotonin reuptake inhibitors and venlafaxine or bupropion in the incidence of TEM.nnnCONCLUSIONSnUse of second-generation antidepressants as monotherapy in RCBD is accompanied by clinically relevant rates of TEM. Even in patients with RCBD, differential vulnerabilities to antidepressant TEM may exist.

Treatment of bipolar affective disorder.

Bipolar affective disorder is a common condition which, among mental illnesses, ranks second only to unipolar depression as a cause of worldwide disability.1 Classically, it manifests itself as repeated periods of illness with complete recovery. However, many patients have a poor outcome: a third suffer chronic symptoms and some 13-24% develop rapid cycling disorder, where four or more episodes occur within a year. The lifetime risk of bipolar disorder is at least 1.2%, with a recognised risk of completed suicide of 15%. Young men, early in the course of their illness, are at highest risk, especially those with a history of suicide attempts or alcohol abuse and those recently discharged from hospital. Despite its shortcomings, lithium has long been the mainstay of treatment for bipolar affective disorder. Several newer drugs have emerged over the past 10 years, but evidence of their effectiveness remains disappointingly thin. n nIdeally, mood stabilisers should treat both mania and depression and prevent their recurrence. Importantly, treatment itself should not precipitate mania or depression or induce rapid cycling. Lithium has been used as a mood stabiliser in bipolar disorder for 50 years. It continues as a first line treatment in acute episodes and in prophylaxis, but doubts remain about its effectiveness in clinical practice. Some patients respond inadequately to lithium, especially those with rapid cycling disorder and those with mixed mania, where manic and depressive symptoms occur together. Its narrow therapeutic window necessitates frequent blood monitoring, limiting its use in some countries. Lithium discontinuation may precipitate recurrence, a serious problem in the poorly compliant. n nThe anticonvulsants carbamazepine and valproate are established alternative and adjunctive treatments to lithium. Valproate is the most frequently prescribed mood stabiliser in the United States and is increasingly used in Europe. The mechanism of action of anticonvulsants in bipolar disorder remains unclear. Originally they were used when lithium was poorly tolerated or ineffective; now they are increasingly used as first line monotherapy, yet the evidence for their use remains incomplete. The efficacy of valproate in treating mania was confirmed in the largest placebo controlled trial in which it was studied,2 but no randomised controlled trials have examined its effects in bipolar depression. Its use in maintenance treatment has been based on open data and one randomised controlled trial in a group of patients with heterogenous affective disorders.3 Recently, a randomised controlled trial failed to show that valproate prolonged the time to recurrence of any mood episode over 12 months, although this result is questionable because of the methodological limitations of the study.4 n nThe efficacy of carbamazepine in treating mania and bipolar depression and in prophylaxis has been shown in randomised controlled trials, but evidence for its acute efficacy in bipolar depression and overall prophylactic efficacy is not strong. Cochrane reviews on the efficacy of carbamazepine and valproate in bipolar disorder are under way. n nAll the established mood stabilisers appear to be more effective in treating and preventing mania than depression. Lithium is reported to have specific antisuicidal effects,5 but few data are available on the antisuicidal effects of carbamazepine and valproate. Although valproate and carbamazepine may be more effective than lithium for mixed states and rapid cycling disorder, much treatment resistance remains. New medications for bipolar depression, mixed states, and rapid cycling disorder are urgently needed: new anticonvulsants and atypical antipsychotics are potential candidates. n nThe anticonvulsant lamotrigine has been shown to have acute efficacy in bipolar depression in two randomised controlled trials.6,7 In the first placebo controlled trial conducted in rapid cycling disorder, lamotrigine improved the overall relapse rate.8 Two placebo controlled trials failed to replicate open label evidence of gabapentins efficacy in hypomania and mania.7,9 Cochrane reviews on both these anticonvulsants in bipolar disorder are in progress. n nAntipsychotics have long been used in bipolar disorder. Typical antipsychotics are effective in acute mania but may exacerbate postmanic depression. Little evidence supports their prophylactic use, which risks the induction of tardive dyskinesia. Placebo controlled studies of olanzapine and risperidone have shown the acute antimanic efficacy of both these atypical antipsychotics, although the effects of prolonged use are not yet clear. The prototype atypical antipsychotic, clozapine, is reserved for use in highly refractory cases of bipolar disorder.10 Intriguingly, ω-3 fatty acids showed mood stabilising effects in one small randomised placebo controlled trial; the underlying mechanism may be the inhibition of signal transduction in neuronal membranes.11 n nNew non-pharmacological treatments such as transcranial magnetic stimulation and vagal nerve stimulation are emerging. Psychological treatments such as cognitive behavioural therapy target recognition of early warning symptoms and compliance with medication and may provide strategies for coping with illness and attendant psychosocial problems.12 n nThe management of this common and often debilitating lifelong illness should be shared between primary care and general psychiatrists. Although many new acute treatments for mania have been evaluated in placebo controlled studies over the past 10 years, only a few have undergone evaluation of their prophylactic efficacy in long term randomised controlled trials. Clinicians and their patients need evidence based treatment strategies that produce complete sustained remissions and improve quality of life.

Rapid-cycling bipolar disorder

EARLY OBSERVATIONS Emil Kraepelin first described the phenomenon of frequent cycling in manic depressive insanity in 1913 in his landmark textbook (Kraepelin 1913). Although he never used the term rapid cycling to describe the course of patients who cycled frequently, he meticulously documented that a significant subgroup of patients with bipolar disorder exhibited episode frequencies in excess of four per year. Through what might be the earliest use of the method of retrospective and prospective life charting, Kraepelin documented episode frequency and duration, but not amplitude (see Figure 1). In his survey of the general course of manic depressive insanity he described the colouring and frequency of attacks in 899 patients with manic depressive insanity. Unfortunately, he never reported on the prevalence of rapid cycling in this cohort. These early observations led Kraepelin to conclude that bipolar disorder was accompanied by periodic cycling separated by symptom-free well intervals early in the course of the illness, whereas schizophrenia was more a stable disease marked by few if any remissions as well as a degenerative course. More recently, Dunner and Fieve (1974) first coined the term rapid cycling in a landmark paper which summarized longitudinal data designed to evaluate clinical factors associated with lithium prophylaxis failure. Koukopoulos (1980) replicated and extended the findings of Dunner and Fieve in a longitudinal study of the course of 434 patients with bipolar disorder. Both of these early reports suggested for the first time that patients with rapid cycling do not do well on lithium. A. Marneros and J. Angst (eds), Bipolar Disorders: 100 years after manic-depressive insanity, 89–109.

Treatment of bipolar depression

OBJECTIVESnThe treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management.nnnMETHODSnA literature search was conducted using keywords bipolar disorder, depression, drug therapy, antidepressants, lithium, and anticonvulsants.nnnRESULTSnIf effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate.nnnCONCLUSIONSnDoctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.