Psychopharmacologic strategies for the prevention of suicidal behavior in bipolar patients

Current pharmacological strategies for the prevention of the suicide behavior in bipolar patients are reviewed. Additionally, these studies are discussed in the context of a stress–diathesis model, to explore whether this model explains the empirical fact that some drugs appear to have antisuicidal properties while others do not. A review of the relevant literature suggests that lithium and serotonin enhancing antidepressants reduce suicidal behavior in bipolar patients. A stress–diathesis model explains the differential effect of such medications compared to other antidepressants or mood stabilizers by proposing additional effects of these medications on the diathesis for suicidal behavior. This effect may be mediated by augmentation of serotonergic function, which is linked to suicidal behavior. Serotonergic enhancing drugs therefore can potentially reduce suicidal behavior.     

Pharmacologic treatment of hospitalized patients with schizoaffective disorder.

This study examined changes in the pharmacologic treatment of 70 patients who were hospitalized with a diagnosis of schizoaffective disorder at some time during a six-year period. An increasing use of divalproex sodium and atypical antipsychotics instead of lithium and conventional antipsychotics was observed. The use of a combination of an antipsychotic and a thymoleptic medication was more common than monotherapy, and physicians tended to continue antidepressants if patients had a history of depression. Patients with a new diagnosis of schizoaffective disorder were stabilized less quickly than those with a previous diagnosis. The use of divalproex sodium and newer antipsychotics did not reduce the time to stabilization in routine clinical practice.     

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment

Suicidal behavior is strongly associated with depression, especially if accompanied by behavioral activation, dysphoria, or agitation. It may respond to some treatments, but the design of scientifically sound, ethical trials to test for therapeutic effects on suicidal behavior is highly challenging. In bipolar disorder, and possibly also unipolar major depression, an underprescribed medical intervention with substantial evidence of preventive effects on suicidal behavior is long-term treatment with lithium. It is unclear whether this effect is specifically antisuicidal or reflects beneficial effects of lithium on depression, mood instability, and perhaps aggression and impulsivity. Antisuicidal effects of anticonvulsant mood stabilizers (carbamazepine, lamotrigine, valproate) appear to be less than with lithium. Further evaluation is needed for potential antisuicidal effects of atypical antipsychotics with growing evidence of efficacy in depression, particularly acute bipolar depression, while generally lacking risk of inducing agitation, mania, or mood instability. Short-term and long-term value and safety of antidepressants are relatively secure for unipolar depression but uncertain and poorly tested for bipolar depression; their effects on suicidal risk in unipolar depression may be age-dependent. Sedative anxiolytics are virtually unstudied as regards suicidal risks. Adequate management of suicidal risks in mood disorder patients requires comprehensive, clinically skillful monitoring and timely interventions.     

Medication treatment of bipolar disorder 2000: a summary of the expert consensus guidelines

The original Expert Consensus Guidelines on the Treatment of Bipolar Disorder were published in 1996. Since that time, a variety of new treatments for bipolar disorder have been reported; however, evidence for these treatments varies widely, with data especially limited regarding comparisons between treatments and how to sequence them. For this reason, a new survey of expert opinion was undertaken to bridge gaps between the research evidence and key clinical decisions. The results of this new survey, which was completed by 58 experts, are presented in The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000, which was published in April 2000 as a Postgraduate Medicine Special Report. In this article, the authors describe the methodology used in the survey and summarize the clinical recommendations given in the resulting guidelines. The expert panel reached consensus on many key strategies, including acute and preventive treatment of mania (euphoric, mixed, and dysphoric subtypes), depression, rapid cycling, and approaches to managing treatment resistance and comorbid psychiatric conditions. Use of a mood stabilizer is recommended in all phases of treatment. Divalproex (especially for mixed or dysphoric subtypes) and lithium are the primary mood stabilizers for both acute and preventive treatment of mania. If monotherapy with these agents fails, the next recommended intervention is to combine them. This combination of lithium and divalproex can then serve as the foundation to which other medications are added if needed. Carbamazepine is the leading alternative mood stabilizer for mania. The experts rated the other new anticonvulsants as second-line options (i.e., their use is recommended if lithium, divalproex, and carbamazepine fail or are contraindicated). For milder depression, a mood stabilizer, especially lithium, may be used as monotherapy. Divalproex and lamotrigine are other first-line choices. For more severe depression, the experts recommend combining a standard antidepressant with lithium or divalproex. Bupropion, selective serotonin reuptake inhibitors (SSRIs), and venlafaxine are preferred antidepressants. The antidepressants should usually be tapered 2-6 months after remission. Monotherapy with divalproex is recommended for the initial treatment of either depression or mania in rapid-cycling bipolar disorder. Antipsychotics are recommended for use in combination with the above regimens for mania or depression with psychosis, and as potential adjuncts in nonpsychotic episodes. Atypical antipsychotics, especially olanzapine and risperidone, were generally preferred over conventional antipsychotics. The guidelines also include recommendations concerning the use of electroconvulsive therapy (ECT), clozapine, thyroid hormone, stimulants, and various novel agents for patients with treatment-refractory bipolar illness. The experts reached high levels of consensus on key steps in treating bipolar disorder despite obvious gaps in high-quality data. To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data; however, their recommendations are generally conservative. Experts give their strongest support to initial strategies and medications for which high-quality research data or longstanding patterns of clinical usage exist. Within the limits of expert opinion and with the understanding that new research data may take precedence, these guidelines provide clear pathways for addressing common clinical questions and can be used to inform clinicians and educate patients about the relative merits of a variety of interventions.     

Patterns of concomitant psychotropic medication use during a 2-year study comparing clozapine and olanzapine for the prevention of suicidal behavior

BACKGROUND: Results from the International Suicide Prevention Trial (InterSePT) indicate that clozapine is more effective than olanzapine in reducing suicidal behavior in schizophrenic and schizoaffective patients. However, because InterSePT allowed the uncontrolled use of concomitant psychotropic medications (CPMs), it is possible that the antisuicidal effect of clozapine may have been influenced by greater use of such agents. This article describes the use patterns of CPMs during InterSePT and examines whether CPM use may have affected study outcome. METHOD: In this study, 479 patients received clozapine and 477 patients received olanzapine. Concomitant psychotropic medications were grouped into 4 classes: antipsychotics, antidepressants, sedatives/anxiolytics, and mood stabilizers. The doses of each CPM were converted into dosage equivalents of standard reference drugs. An analysis of covariance was performed to compare mean daily doses of CPMs between the 2 groups over the 2-year treatment period. The duration of treatment for each patient was 2 years, with the first patient entering the study in March 1998 and the last patient completing treatment in February 2001. RESULTS: Approximately 90% of patients in both treatment groups received at least 1 CPM. The mean +/- SD number of CPMs per patient was 3.8 +/- 2.90 in the clozapine group and 4.2 +/- 3.16 in the olanzapine group. For each CPM class, the mean daily dose was statistically significantly lower in the clozapine group (antipsychotics, p <.001; antidepressants, p <.01; sedatives/anxiolytics, p <.001; mood stabilizers, p <.05). Analyses of CPM use by study intervals, suicide attempters versus nonattempters, study completers versus noncompleters, and geographic region resulted in similar findings. CONCLUSION: The results support the conclusion that the effects of clozapine in reducing the risk of suicidal behavior derive from its intrinsic pharmacology and not from the influence of concomitant psychotropic medications.     

Augmentation of antidepressants with atypical antipsychotics in non-delusional unipolar depressed patients with non-response to antidepressant-monotherapy

Objective Augmentation of antidepressants with atypical antipsychotics is used in depressive patients with non-response to antidepressants. We investigated the utility of this strategy.Methods Systematic computer-based search in the online library Pubmed for randomized placebo-controlled double-blind trials (RCT) from the years 1990 to 2011.Results We found 14 RCT about augmentation of antidepressants with atypical antipsychotics in depressive patients with non-response to antidepressants. Trials examined olanzapine, risperidone, quetiapine and aripiprazole.Conclusions Augmentation of antidepressants with atypical antipsychotics is an alternative to the augmentation with lithium in unipolar depressive patients with non-response to antidepressants. But treatment with atypical antipsychotics as opposed to placebo increases the risk of non-compliance due to side-effects of medication. Augmentation of antidepressants with atypical antipsychotics in unipolar depression is an off-label therapy in Germany except for the augmentation with extended-release quetiapine. Knowledge about treatment strategies regarding augmentation of antidepressants with atypical antipsychotics can increase the chance of a successful treatment, but interactions and side-effects should be considered.     

Atypical antipsychotics and suicide in mood and anxiety disorders

Abstract:  Globally, a million people commit suicide every year, and 10–20 million attempt it. Mood disorders, especially major depressive disorder (MDD) and bipolar disorder, are the most common psychiatric conditions associated with suicide. Primary (psychiatric and physical illness), secondary (psychosocial), and tertiary (demographic) risk factors for suicide have been identified. Comorbid psychiatric illness, particularly anxiety symptoms or disorders, significantly increase the risk of suicidal behavior. Current standard risk assessments and precautions may be of limited value, while assessing the severity of anxiety and agitation may be more effective in identifying patients at risk. Lithium is the medication that has most consistently demonstrated an antisuicidal effect. The effects of antidepressants and conventional antipsychotics on suicide risk are uncertain, but atypical antipsychotics appear promising. Atypical antipsychotics have beneficial effects on depressed mood both in patients with MDD and in patients with bipolar disorder. In addition, data in patients with schizophrenia have demonstrated a significant improvement in the incidence of suicidal behavior with clozapine compared with olanzapine. Electroconvulsive therapy appears to have an acute benefit on suicidality.     

Tardive dyskinesia: eliminated, forgotten, or overshadowed?

PURPOSE OF REVIEW: The present review focuses on atypical antipsychotics and tardive dyskinesia. RECENT FINDINGS: We have known for many years that clozapine has a diminished risk of tardive dyskinesia compared with typical antipsychotics. The last decade has seen the introduction of a number of other atypical antipsychotics, allowing us to begin evaluating whether they too share this attribute. In addition, the opportunity to use these drugs as first-line treatment permits a more precise means of establishing risk. While longer-term data are required, the limited evidence available clearly indicates that the atypical antipsychotics have a decreased liability of tardive dyskinesia, approximately 1% compared with 5% for typical agents annually. Like clozapine, the other atypical antipsychotics also demonstrate antidyskinetic properties in individuals with preexisting tardive dyskinesia. The underlying mechanisms remain unclear, and without such information it is not possible to say what clinical conditions, if any, might diminish or even eliminate these advantages. SUMMARY: An update is provided regarding the atypical antipsychotics and tardive dyskinesia. This information is critical in our decision-making regarding choice of antipsychotic and optimal use in the clinical setting.     

Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part I: a review

OBJECTIVES: To review the evidence for the safety and efficacy of nonpharmacological and pharmacological treatments for aggression in children and adolescents. METHOD: and searches (1990-present) were conducted for double-blind, placebo-controlled studies of atypical antipsychotics for aggression and for literature on the use of other pharmacological agents and psychosocial interventions for aggression. Case reports and adult literature regarding the safety of atypical antipsychotics were used where controlled data for youth were lacking. RESULTS: Controlled data on the treatment of aggression in youth is scarce. Psychosocial interventions may be effective alone or in combination with pharmacological treatments. Psychotropic agents (e.g., stimulants, mood stabilizers, beta-blockers) have also been shown to have limited efficacy in reducing aggression. Antipsychotics, particularly the atypical antipsychotics, show substantial efficacy in the treatment of aggression in selected pediatric populations. Atypical antipsychotics are generally associated with fewer extrapyramidal symptoms than are typical antipsychotics. CONCLUSIONS: Psychosocial interventions and atypical antipsychotics are promising treatments for aggression in youth. Double-blind studies should examine the safety and efficacy of atypical antipsychotics compared to each other and to medications from other classes, the efficacy of specific medications for different subtypes of aggression, combining various psychotropic medications, optimal dosages, and long-term safety.     

Acute treatment of patients with bipolar mixed episodes

Managing bipolar mixed states should start by establishing a diagnosis, assessing for comorbidities, and clarifying targets for therapy. Differentiating between unipolar and bipolar disorder is important because these conditions have dissimilar efficacious pharmacotherapeutic options. To treat mixed states, atypical antipsychotics or divalproex have been shown to be effective, and antidepressants should generally be avoided. Because of the complexity of mixed episodes, monotherapy may be insufficient and patients may require combination treatment. As more medications become available in the treatment of bipolar disorder, algorithms can help clinicians make the appropriate treatment choices by offering recommendations for sequencing agents.     

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.     

Bipolar disorder and comorbid alcoholism: prevalence rate and treatment considerations

Classic Kraepelian observations and contemporary epidemiological studies have noted a high prevalence rate between bipolar disorder and alcoholism. The extent to which these two illnesses are comorbid (i.e., two distinct disease processes each with an independent course of illness), genetically linked, or different phenotypic expressions of bipolar illness itself continues to be investigated. It is increasingly clear that co-occurring alcohol abuse or dependence in bipolar disorder phenomenologically changes the illness presentation with higher rates of mixed or dysphoric mania, rapid cycling, increased symptom severity, and higher levels of novelty seeking, suicidality, aggressivity, and impulsivity. It is very encouraging that interest and efforts at evaluating pharmacotherapeutic compounds has substantially increased over the past few years in this difficult-to-treat patient population. This article will review the clinical studies that have evaluated the effectiveness of conventional mood stabilizers (lithium, carbamazepine, divalproex, and atypical antipsychotics) in the treatment of alcohol withdrawal and relapse prevention in patients with alcoholism and in the treatment of bipolar disorder with comorbid alcoholism. A number of add-on, adjunctive medications, such as naltrexone, acamprosate, topiramate, and the atypical antipsychotics quetiapine and clozapine, may be candidates for further testing.     

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.     

In the Aftermath of CATIE: How Should Administrators Value Atypical Antipsychotic Medications?

The wide scale use of expensive atypical antipsychotic medications has led to a dramatic increase in the proportion of direct costs schizophrenia being allocated for medications. Although there is evidence that the atypical antipsychotic, clozapine, may lead to cost savings in patients with refractory schizophrenia the cost-effectiveness of the other atypical antipsychotics remains in question. We therefore reviewed the published, long-term randomized, prospective cost-effectiveness treatment studies that compared an atypical to a typical antipsychotic. There were serious methodological problems with all. In general, those that were based on efficacy trials showed an advantage for atypicals while those based on effectiveness studies found the opposite. It appears that to the extent that studies mimic “real world” conditions they fail to support the cost-effectiveness of the atypical antipsychotics.     

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.