Bipolar Disorder: Sachs GS

Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. · Partners Bipolar Treatment Center, Massachusetts General Hospital, USA. · Postgrad Med. · Pubmed #10895797 No free full text.

Abstract: OBJECTIVES: New treatments for bipolar disorder have been reported since we first published survey-based expert consensus guidelines in 1996. The evidence for these treatments varies widely; data are especially limited regarding comparisons between treatments and how to sequence them. We therefore undertook a new survey of expert opinion in order to bridge gaps between the research evidence and key clinical decisions. METHOD: Based on a literature review, a written survey was prepared which asked about 1,276 options for psychopharmacologic interventions in 48 specific clinical situations. Most options were scored using a modified version of the RAND Corporation 9-point scale for rating appropriateness of medical decisions. We contacted 65 national experts, 58 of whom (89%) completed the survey. Consensus on each option was defined as a non-random distribution of scores by chi-square test. We assigned a categorical rank (first-line/preferred choice, second-line/alternate choice, third-line/usually inappropriate) to each option based on the confidence interval of its mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. RESULTS: The expert panel reached consensus on many key strategies, including acute and preventive treatment for mania (euphoric, mixed, and dysphoric subtypes), depression, and rapid cycling, and approaches to managing the complications of treatment resistance and comorbidity. Use of a mood stabilizer is recommended in all phases of treatment. Divalproex (especially for mixed or dysphoric subtypes) and lithium are the cornerstone choices among this class for both acute and preventive treatment of mania. Regardless of which is selected first, if monotherapy fails, the next recommended intervention is to use these agents in combination. The combination can then serve as the foundation on which other medications are added, if needed. Carbamazepine is the leading alternative mood stabilizer for mania. Expert opinion regards other new anticonvulsants as second-line options (e.g., if the previously mentioned mood stabilizers 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, a standard antidepressant should be combined with lithium or divalproex. Bupropion, selective serotonin reuptake inhibitors (SSRIs), and venlafaxine are preferred antidepressants, and should be tapered 2 to 6 months after remission. Divalproex monotherapy is recommended for initial treatment of either depression or mania with rapid cycling. Antipsychotics are recommended for use with the above regimens for mania or depression with psychosis, and as potential adjuncts in non-psychotic episodes. Atypical antipsychotics, especially olanzapine and risperidone, were generally preferred over conventional antipsychotics. Recommendations are also given concerning the use of electroconvulsive therapy (ECT), clozapine, thyroid hormone, stimulants, and various novel agents for patients with treatment-refractory illness. CONCLUSIONS: 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 reserve strongest support for initial strategies and individual medications for which there are high-quality research data, or for which there are longstanding patterns of clinical usage. 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 in a manner that can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions.

Sachs GS, Gaughan S. · No affiliation provided · J Clin Psychiatry. · Pubmed #10074871 No free full text.

This publication has no abstract.

Sachs GS, Gardner-Schuster EE. · Harvard Medical School, Boston, MA 02114, USA. · Acta Psychiatr Scand Suppl. · Pubmed #17688460 No free full text.

Abstract: OBJECTIVE: To provide an overview of the available high quality evidence-base of studies of adjunctive pharmacologic treatment for acute mania. METHOD: Double-blind controlled trials with adequate samples (n > 100) were identified through search of PubMed/MEDLINE and computerized abstracts from 2004-2006 meetings of the American Psychiatric Association, International Conference on Bipolar Disorder, and Collegium Internationale Neuro-Psychopharmacolium using key words mania, adjunct, and combination. RESULTS: Placebo-controlled studies with positive results support the adjunctive use of five agents including valproate, olanzapine, risperidone, quetiapine, and haloperidol. Agents with only negative or failed placebo-controlled studies included carbamazepine, gabapentin, lamotrigine, topiramate, oxcarbazepine, and ziprasidone. We found no placebo-controlled study of many commonly used agents including lithium, aripiprazole, and clozapine. No studies explicitly excluded subjects, based on prior treatment with the monotherapy being offered and several studies limited randomization to patients with documented inadequate response to the monotherapy arm. CONCLUSION: The available placebo-controlled randomized clinical trials support adjunctive therapy combining lithium or valproate with olanzapine, risperidone, haloperidol or quetiapine. The additional increment of antimanic efficacy of these combinations over monotherapy was similar in magnitude to that seen for the same agents as monotherapy in comparison with placebo. These additive benefits enhanced the tolerability of adverse effects sufficiently to allow a higher proportion of subjects receiving combination therapies to complete the studies than monotherapy treated patients. The available data has several shortcomings and the available studies are inadequate to conclusively determine whether combination treatment is more efficacious than monotherapy when used by subjects naive to both treatments. Nevertheless, adjunctive treatment, which combines agents with proven antimanic efficacy, offers an attractive option for patients with acute mania.

Reilly-Harrington N, Sachs GS. · Bipolar Clinic and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, USA. · J Clin Psychiatry. · Pubmed #17107229 No free full text.

Abstract: Half of patients with bipolar disorder may exhibit poor medication compliance, and relapse often occurs even when patients take their medication as prescribed. Psychosocial strategies can help patients to recognize the need for treatment and, therefore, improve medication adherence. Another benefit of psychosocial strategies is that they aid patients in controlling their moods. Cognitive-behavioral therapy teaches patients to modify dysfunctional thinking and behavior. Treatment contracting allows patients to develop a plan for identifying and coping with symptoms before they become severe. Daily mood charting assists patients in quickly identifying and intervening when changes occur. Creating and following a weekly activity schedule ensures that patients will participate in enough positive activities and avoid destructive activities. Using a variety of psychosocial strategies, patients can train themselves and a support team to effectively deal with bipolar disorder.

Nierenberg AA, Ostacher MJ, Borrelli DJ, Iosifescu DV, Perlis RH, Desrosiers A, Armistead MS, Calkins AW, Sachs GS. · Bipolar Clinic and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · J Clin Psychiatry. · Pubmed #17029489 No free full text.

Abstract: Patients with bipolar disorder are among the most challenging to treat. These patients frequently present with complex mood and other symptoms that change over time, complex psychiatric and medical comorbid conditions, and multiple medications. Clinicians rarely systematically assess or measure all of these factors and instead rely on memory and general impressions. It is imperative that clinicians systematically track and monitor these relevant variables to ensure treatment decisions are based on precise clinical data. By integrating measurement and management, clinicians and patients can collaborate to assess the effectiveness of treatments and to make joint decisions about critical points at which to adjust treatment. This method was shown to be successful in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

Sachs GS. · Department of Psychiatry, Harvard-Massachusetts General Hospital, Cambridge, USA. · J Clin Psychiatry. · Pubmed #16965190 No free full text.

Abstract: Agitation has been poorly addressed as a unique entity in many psychiatric disorders. Recent medical literature and a range of instruments have measured agitation in various clinical settings. Agitation is a common problem in many patients with schizophrenia, bipolar mania, or dementia. Moreover, agitation adversely impacts many facets of the healing process, including direct patient care, caregiver burden, and community resources. Frontal lobe dysfunction and mutations in the catechol O-methyltransferase (COMT) gene involved in dopamine metabolism and catecholamine inactivation have been linked to agitation in patients with schizophrenia and bipolar disorder. Cerebral impairment and deficits in cognitive function predispose patients with dementia to agitation. In patients with Alzheimer's dementia, both frontal and temporal lobe pathology may be associated with agitation. Addressing agitation as a symptom of psychiatric illness would represent a great opportunity for therapeutic intervention and the alleviation of patient suffering, family burden, and societal costs.

Mansour HA, Talkowski ME, Wood J, Pless L, Bamne M, Chowdari KV, Allen M, Bowden CL, Calabrese J, El-Mallakh RS, Fagiolini A, Faraone SV, Fossey MD, Friedman ES, Gyulai L, Hauser P, Ketter TA, Loftis JM, Marangell LB, Miklowitz DJ, Nierenberg AA, Patel J, Sachs GS, Sklar P, Smoller JW, Thase ME, Frank E, Kupfer DJ, Nimgaonkar VL. · Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213, U S A. · Ann Med. · Pubmed #16338761 No free full text.

Abstract: The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n = 182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.

Sachs GS. · Partners Bipolar Treatment Center, Massachusetts General Hospital, Boston, Mass., USA. · J Clin Psychiatry. · Pubmed #12892540 No free full text.

Abstract: Clinicians managing patients with bipolar disorder confront a myriad of complex treatment decisions. This complexity limits the practicality of treatment guidelines, which attempt to be comprehensive. A user-friendly guide can, however, be constructed by considering only the most common early critical decision points likely to be encountered in the management of bipolar patients: new onset of an acute manic or mixed episode, interepisode treatment entry, and initial treatment for acute bipolar depression. Three general treatment principles, i.e., use proven treatments first, use a mood stabilizer in every phase of the illness, and use a multiphase treatment strategy to link current assessment with an appropriate treatment plan, can be applied to guide decision making at critical decision points that follow entry into clinical care. To guide the selection of appropriate therapeutic agents, a simple grading system can be used to evaluate the weight of evidence supporting use of various options. Multiple high-quality studies with positive results support the use of lithium, divalproex, carbamazepine, olanzapine, and haloperidol as initial intervention for acute mania; other agents with positive results in one double-blind mania trial are reasonable first-line alternatives. In the absence of high-quality evidence to guide treatment selection for nonacutely ill bipolar patients, guidelines recommend maintenance mood-stabilizer treatment. Standard antidepressant medications do not appear to add statistically significant benefit beyond that of mood stabilizers alone; lithium and lamotrigine have shown some benefit, and promising preliminary data have been presented on the antidepressant benefit of divalproex and topiramate as well.

Sachs GS. · Harvard Bipolar Research Program, Massachusetts General Hospital, Boston, 02114, USA. · J Clin Psychopharmacol. · Pubmed #12832943 No free full text.

Abstract: Bipolar disorder is a complex, chronic condition associated with considerable morbidity and mortality, including a high rate of suicide. Currently available treatment options for bipolar disorder fail to adequately address many of the important needs of bipolar patients. Long-term maintenance therapy with lithium has been shown to prevent further episodes of mania and depression and to decrease the likelihood of suicide. However, many patients stop lithium treatment after only a few weeks, because of either untoward side effects or other factors, such as the belief that they no longer require medication. Even when lithium is taken regularly and at adequate doses, many patients continue to exhibit severe functional disability and also fail to achieve remission. Bipolar depression is also poorly understood and difficult to treat. A number of adjunctive medications are used in combination with lithium, but residual symptoms and recurring episodes of mania and depression remain common. Recently, atypical antipsychotics, such as olanzapine, risperidone, and quetiapine, have been evaluated for the treatment of bipolar disorder. Although considerable research is still needed, preliminary findings suggest that some of these agents may act as mood stabilizers, improving the acute symptoms of mania without inducing depression or rapid cycling. The role of atypical antipsychotics in maintenance therapy for bipolar disorder is currently being evaluated in a number of large clinical trials.

Sachs GS, Thase ME, Otto MW, Bauer M, Miklowitz D, Wisniewski SR, Lavori P, Lebowitz B, Rudorfer M, Frank E, Nierenberg AA, Fava M, Bowden C, Ketter T, Marangell L, Calabrese J, Kupfer D, Rosenbaum JF. · Partners Bipolar Treatment Center, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. · Biol Psychiatry. · Pubmed #12788248 No free full text.

Abstract: The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age >/= 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, the treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention.

Thase ME, Bhargava M, Sachs GS. · Department of Psychiatry, University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213-2593, USA. · Psychiatr Clin North Am. · Pubmed #12778844 No free full text.

Abstract: Even though at least 10% (if not 20%) of those who experience a first lifetime episode of depression will subsequently develop bipolar disorder, the alliance of academic and industry research agendas that leads to developing and testing new antidepressants has failed to produce a sufficient knowledge base. It is therefore impossible to apply a truly empirical approach to guide the treatment of people with bipolar depression. Consequently, there are holes in contemporary evidenced-based practice guidelines large enough to drive a truck through; furthermore, there are some recommendations that have no factual basis other than expert opinion. However, with new research emerging on lamotrigine and olanzapine, in addition to the pending results of larger studies supported by the National Institute of Mental Health and the Stanley Foundation, there is evidence that some progress is being made.

Sachs GS, Rush AJ. · Harvard Bipolar Research Program, Massachusetts General Hospital, Boston 02114, USA. · J Clin Psychiatry. · Pubmed #12720476 No free full text.

Abstract: Bipolar disorder presents particular challenges with regard to assessing response to therapy. Criteria for determining remission and recovery have been suggested for mood disorders, but the clinical usefulness of these terms in bipolar disorder is elusive. Formal psychological rating scales may be impractical in a routine medical practice setting. As an alternative, clinicians might probe for information about particular "signal events," such as sleep disturbances, that may herald mood fluctuations. The ultimate goal of bipolar management should be complete and sustained remission, whenever possible, although most patients will not achieve this status for any significant length of time. Furthermore, overaggressive management might entail pushing medication doses to intolerable levels. Individual treatment goals should always take into account patient acceptance of side effect burden, allowing for trade-offs between treatment effect and quality of life. Noncompliance with therapy, notoriously common among patients suffering from bipolar disorder, can stem from drug side effects, treatment ineffectiveness, or even treatment success if the patient misses the manic symptoms. Despite effective treatment, relapse is common. Realistic treatment goals should strive for sustained symptom abatement while maximizing patient quality of life from visit to visit.

Ghaemi N, Sachs GS, Goodwin FK. · Harvard Bipolar Research Program, Massachusetts General Hospital, Consolidated Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA. · World J Biol Psychiatry. · Pubmed #12607202 No free full text.

Abstract: BACKGROUND: In recent years, much progress has been made in the diagnosis and treatment of schizophrenia and depression. Bipolar disorder, however, remains frequently misunderstood, leading to inconsistent diagnosis and treatment. Why is the case? What is to be done about it? METHODS: We critically review studies in the nosology of bipolar disorder and the effects of antidepressant agents. RESULTS: Bipolar disorder is underdiagnosed and frequently misdiagnosed as unipolar major depressive disorder. Antidepressants are probably overused and mood stabilisers underused. Reasons for underdiagnosis include patients' impaired insight into mania, failure to involve family members in the diagnostic process, and inadequate understanding by clinicians of manic symptoms. We propose using a mnemonic to aid in diagnosis, obtaining family report, and utilising careful clinical interviewing techniques given the limitations of patients' self-report. We recommend aggressive use of mood stabilisers, and less emphasis on antidepressants. CONCLUSIONS: The state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to manic criteria is necessary and the current pattern of use of antidepressant use in bipolar disorder needs to change.

Otto MW, Reilly-Harrington N, Sachs GS. · Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. · J Affect Disord. · Pubmed #12507750 No free full text.

Abstract: Despite advances in the pharmacologic treatment of bipolar disorder, it is clear that additional strategies are needed to provide patients with longer-term mood stability. Recent years have witnessed the development of a number of psychosocial strategies for bipolar disorder that are design as adjuncts to ongoing pharmacotherapy. In this article we describe psychoeducational and cognitive-behavioral approaches to the management of bipolar disorder, with emphasis on broader treatment packages that can be offered by cognitive-behavior therapists working in specialty bipolar clinics, as well as specific strategies that can be integrated into standard pharmacotherapy for the disorder. A growing body of evidence documents the potential value of these interventions, and large-scale studies are underway, including the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), which will provide outcome on these interventions from the perspective of large, multicenter trials.

Calabrese JR, Sullivan JR, Bowden CL, Suppes T, Goldberg JF, Sachs GS, Shelton MD, Goodwin FK, Frye MA, Kusumakar V. · Department of Psychiatry, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, Ohio, USA. · J Clin Psychiatry. · Pubmed #12444815 No free full text.

Abstract: BACKGROUND: The rate of lamotrigine-associated rash in patients with mood disorders has not been well characterized. The objective of this report was to determine rash rates in clinical trials of lamotrigine in DSM-IV unipolar depression or bipolar disorder. METHOD: A retrospective analysis was conducted of rates of lamotrigine-related rash in 12 multicenter studies, including 1 open study, 7 randomized controlled acute trials, and 4 randomized controlled maintenance trials from 1996 to 2001. RESULTS: A total of 1955 patients were treated with lamotrigine in open-label settings (open-label phases preceding or following randomization and 1 stand-alone open-label study); 1198 patients received lamotrigine in controlled settings, and 1056 patients received placebo. In controlled settings, rates of benign rash were 8.3% and 6.4% in lamotrigine- and placebo-treated patients, respectively. Rates of serious rash were 0% with lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the open-label setting, the overall rate of rash for lamotrigine was 13.1% (N = 257) and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not requiring hospitalization occurred in a patient treated with lamotrigine. There were no cases of toxic epidermal necrolysis in any setting. CONCLUSION: Serious drug eruptions associated with lamotrigine were rare. Although rash is a potentially life-threatening reaction, the risk of serious rash due to lamotrigine should be weighed against more common risks associated with untreated or undertreated bipolar depression.

Suppes T, Dennehy EB, Swann AC, Bowden CL, Calabrese JR, Hirschfeld RM, Keck PE, Sachs GS, Crismon ML, Toprac MG, Shon SP, Anonymous00056. · Department of Psychiatry The University of Texas Southwestern Medical Center Dallas, 75390-9070, USA. · J Clin Psychiatry. · Pubmed #12004801 No free full text.

Abstract: BACKGROUND: The process and outcome of a consensus conference to develop revised algorithms for treatment of bipolar disorder to be implemented in the public mental health system of Texas are described. These medication algorithms for bipolar disorder are an update of those developed for the Texas Medication Algorithm Project, a research study that tested the clinical and economic impact of treatment guidelines for major psychiatric illnesses treated in the Texas public mental health system (Texas Department of Mental Health and Mental Retardation [TDMHMR]). METHOD: Academic clinicians and researchers, practicing clinicians in the TDMHMR system, administrators, advocates, and consumers participated in a consensus conference in August 2000. Participants attended presentations reviewing new evidence in the pharmacologic treatment of bipolar disorder and discussed the needs of consumers in the TDMHMR system. Principles were enumerated, including balancing of evidence for efficacy, tolerability, and safety in medication choices. A set of 7 distinct algorithms was drafted. In the following months, a subcommittee condensed this product into 2 primary algorithms. RESULTS: The panel agreed to 2 primary algorithms: treatment of mania/hypomania, including 3 pathways for treatment of euphoric symptoms, mixed or dysphoric symptoms, and psychotic symptoms; and treatment of depressive symptoms. General principles to guide algorithm implementation were discussed and drafted. CONCLUSION: The revised algorithms are currently being disseminated and implemented within the Texas public mental health system. The goals of the Texas initiative include increasing the consistency of appropriate treatment of bipolar disorder, encouraging systematic and optimal use of available pharmacotherapies, and improving the outcomes of patients with bipolar disorder.

Charney DS, Nemeroff CB, Lewis L, Laden SK, Gorman JM, Laska EM, Borenstein M, Bowden CL, Caplan A, Emslie GJ, Evans DL, Geller B, Grabowski LE, Herson J, Kalin NH, Keck PE, Kirsch I, Krishnan KR, Kupfer DJ, Makuch RW, Miller FG, Pardes H, Post R, Reynolds MM, Roberts L, Rosenbaum JF, Rosenstein DL, Rubinow DR, Rush AJ, Ryan ND, Sachs GS, Schatzberg AF, Solomon S, Anonymous00188. · Division of Intramural Research Programs, National Institute of Mental Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. · Arch Gen Psychiatry. · Pubmed #11879164 No free full text.

Abstract: A consensus conference on the use of placebo in mood disorder studies consisted of expert presentations on bioethics, biostatistics, unipolar depression, and bipolar disorder. Work groups considered evidence and presented statements to the group. Although it was not possible to write a document for which there was complete agreement on all issues, the final document incorporated input from all authors. There was consensus that placebo has a definite role in mood disorder studies. Findings of equivalence between a new drug and standard treatment in active control studies is not evidence of efficacy unless the new drug is also significantly more effective than placebo. Add-on studies in which patients are randomized to standard therapy plus the investigational drug or standard therapy plus placebo are especially indicated for high-risk patients. Mood disorders in elderly and pediatric patients are understudied, and properly designed trials are urgently needed. Research is needed on the ethical conduct of studies to limit risks of medication-free intervals and facilitate poststudy treatment. Patients must fully understand the risks and lack of individualized treatment involved in research.

Sachs GS, Yan LJ, Swann AC, Allen MH. · Partners Bipolar Treatment Center, Massachusetts General Hospital, Boston 02114, USA. · J Clin Psychiatry. · Pubmed #11765093 No free full text.

Abstract: Suicide prevention is a critical objective in the treatment of bipolar disorder. This article describes practical mechanisms by which monitoring and management of suicide risk can be integrated into the routine care of patients with bipolar disorder. Suicide risk is assessed in terms of inclination (the drive to commit a self-destructive act) and opportunity (access to lethal means). Intervention strategies are adapted to the needs of bipolar patients across 3 phases of treatment: the acute episode; the continuation phase, when symptom reduction has occurred but adaptive recovery has not; and the maintenance phase, in which optimization of adaptive function and vigilance against impending relapse are paramount. Integration of suicide prevention into the outpatient management plan begins with a routine discussion of suicide risk at the initiation of a treatment relationship, even in the absence of other known risk factors. This discussion paves the way for ongoing assessment of suicidality. Just as the recommended routine monitoring of every euthymic bipolar patient includes at least some minimal assessment for prodromal symptoms of acute mania or depression, every clinical visit can include sufficient probes to determine the need for new interventions specific to suicide prevention. Ongoing assessment of risk and protective factors can be linked to a range of individualized interventions designed to meet the varying needs of patients over time. The intensity of monitoring and interventions reflects the clinician's knowledge of risk factors and may be life saving, but it is also important that patients and others involved in their care understand that monitoring cannot guarantee safety.

Sachs GS, Koslow CL, Ghaemi SN. · Massachusetts General Hospital, Consolidated Department of Psychiatry, Harvard Medical School, Boston 02114, USA. · Bipolar Disord. · Pubmed #11249803 No free full text.

Abstract: OBJECTIVES: The 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. METHODS: A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'. RESULTS: If 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. CONCLUSIONS: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.

Sachs GS, Thase ME. · Department of Psychiatry, Harvard Medical School, Boston, MA, USA. · Biol Psychiatry. · Pubmed #11018228 No free full text.

Abstract: Although most of the care received by bipolar patients occurs during the maintenance phase, relatively little empirical data is available to guide long-term treatment decisions. We review literature pertaining to key questions related to use of pharmacotherapy in the maintenance phase of bipolar disorder. The few double-blind trials with a reasonable sample size are restricted to bipolar I patients and address a modest range of questions mostly related to use of lithium. One rigorous multicenter trial found valproate to have prophylactic benefit. Other studies with valproate alone and in combination suggest efficacy equivalent to lithium and perhaps greater than carbamazepine. Data available for combination treatment are sparse but moderately encouraging. Maintenance treatment with standard antidepressant medications appears destabilizing for some bipolar patients, particularly following a mixed episode. Although some bipolar patients may benefit from combined treatment with a mood stabilizer and a standard antidepressant medication, current knowledge does not allow confident selection of the bipolar patients who might benefit. Clozapine and perhaps other atypical antipsychotics are promising options for maintenance treatment but have not been evaluated in double-blind trials. The numerous other agents used in maintenance treatment are primarily adjuncts to lithium, valproate, or carbamazepine, and information about them is largely anecdotal and uncontrolled. Study design for maintenance trials remains an imperfect art. Conclusions must be drawn cautiously, given the limited generalizability of study designs that accession samples enriched with presumed treatment responders, randomize patients after brief periods of partial remission, abruptly taper prior treatment, make no attempt to distinguish relapse from recurrence, use no formal outcome assessments, or report hospitalization as the only outcome criterion.

Thase ME, Sachs GS. · Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pennsylvania 15213, USA. · Biol Psychiatry. · Pubmed #11018227 No free full text.

Abstract: The depressed phase of bipolar affective disorder is a significant cause of suffering, disability, and mortality and represents a major challenge to treating clinicians. This article first briefly reviews the phenomenology and clinical correlates of bipolar depression and then focuses on the major pharmacological treatment options. We strongly recommend use of mood stabilizers as the first-line treatment for the type I form of bipolar depression, largely because longer-term preventative therapy with these agents almost certainly will be indicated. Depressive episodes that do not respond to lithium, divalproex, or another mood stabilizer, or episodes that "breakthrough" despite preventive treatment, often warrant treatment with an antidepressant or electroconvulsive therapy. The necessity of mood stabilizers in the type II form of bipolar depression is less certain, aside from the rapid cycling presentation. Both experts and practicing clinicians recommend bupropion and the selective serotonin reuptake inhibitors as coequal initial choices, with venlafaxine and monoamine oxidase inhibitors, such as tranylcypromine, preferred for more resistant cases. The risk of antidepressant-induced hypomania or mania with concomitant mood stabilizer therapy is low, on the order of 5% to 10% during acute phase therapy. Additional therapeutic options and optimal durations of therapy also are discussed.

Perlis RH, Smoller JW, Ferreira MA, McQuillin A, Bass N, Lawrence J, Sachs GS, Nimgaonkar V, Scolnick EM, Gurling H, Sklar P, Purcell S. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. · Am J Psychiatry. · Pubmed #19448189 No free full text.

Abstract: OBJECTIVE: Lithium remains a first-line treatment for bipolar disorder, but the mechanisms by which it prevents the recurrence of mood episodes are not known. The authors utilized data from a genomewide association study to examine associations between single nucleotide polymorphisms (SNPs) and the outcome of lithium treatment in two cohorts of patients with bipolar I disorder or bipolar II disorder. METHOD: The hazard for mood episode recurrence was examined among 1,177 patients with bipolar I disorder or bipolar II disorder, including 458 individuals treated with lithium carbonate or citrate, who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort. SNPs showing the greatest evidence of association in Cox regression models were then examined for association with positive lithium response among 359 bipolar I or II disorder patients treated with lithium carbonate or citrate in a second cohort from the University College London. RESULTS: The strongest association in the STEP-BD cohort (minimum p=5.5 x 10(-7)) was identified for a region on chromosome 10p15 (rs10795189). Of the regions showing suggestive evidence (p<5 x 10(-4)) of association with lithium response, five were further associated with positive lithium response in the University College London cohort, including SNPs in a region on chromosome 4q32 spanning a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2. CONCLUSIONS: Multiple novel loci merit further examination for association with lithium response in bipolar disorder patients, including one region that spans the GRIA2 gene, for which expression has been shown to be regulated by lithium treatment.

Joffe H, Cohen LS, Suppes T, McLaughlin WL, Lavori P, Adams JM, Hwang CH, Hall JE, Sachs GS. · Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. · Biol Psychiatry. · Pubmed #16448626 No free full text.

Abstract: BACKGROUND: Preliminary evidence suggests that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of PCOS features after initiation of valproate was therefore examined in women with bipolar disorder using a standardized definition of PCOS. METHODS: Three hundred women 18 to 45 years old with bipolar disorder were evaluated for PCOS at 16 Systematic Treatment Enhancement for Bipolar Disorder sites. A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, elevated androgens) with oligoamenorrhea that developed while taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained, and hyperandrogenism was assessed. RESULTS: Among 230 women who could be evaluated, oligoamenorrhea with hyperandrogenism developed in 9 (10.5%) of 86 women on valproate and in 2 (1.4%) of 144 women on a nonvalproate anticonvulsant or lithium (relative risk 7.5, 95% confidence interval [CI] 1.7-34.1, p = .002). Oligoamenorrhea always began within 12 months of valproate use. CONCLUSIONS: Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism. Monitoring for reproductive-endocrine abnormalities is important when starting and using valproate in reproductive-aged women. Prospective studies are needed to elucidate risk factors for development of PCOS on valproate.

Henin A, Biederman J, Mick E, Sachs GS, Hirshfeld-Becker DR, Siegel RS, McMurrich S, Grandin L, Nierenberg AA. · Pediatric Psychopharmacology Unit and Harvard Bipolar Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02138, USA. · Biol Psychiatry. · Pubmed #16112654 No free full text.

Abstract: BACKGROUND: To examine the risk for psychopathology in offspring at risk for bipolar disorder and the course of psychiatric disorders in these youth. METHODS: Using structured diagnostic interviews (Structured Clinical Interview for DSM-IV [SCID] and Kiddie Schedule for Affective Disorders and Schizophrenia [K-SADS]), psychiatric diagnoses of 117 nonreferred offspring of parents with diagnosed bipolar disorder were compared with those of 171 age- and gender-matched offspring of parents without bipolar disorder or major depression. RESULTS: Compared with offspring of parents without mood disorders, high-risk youth had elevated rates of major depression and bipolar disorder, anxiety, and disruptive behavior disorders. High-risk offspring also had significantly more impaired Global Assessment of Functioning (GAF) scores, higher rates of psychiatric treatment, and higher rates of placement in special education classes. Disruptive behavior disorders, separation anxiety disorder, generalized anxiety disorder (GAD), social phobia, and depression tended to have their onset in early or middle childhood, whereas bipolar disorder, obsessive-compulsive disorder (OCD), panic disorder, and substance use disorder had onset most frequently in adolescence. CONCLUSIONS: These findings support the hypothesis that offspring of parents with bipolar disorder are at significantly increased risk for developing a wide range of severe psychiatric disorders and accompanying dysfunction. Early disruptive behavior and anxiety disorders, as well as early-onset depression, may be useful markers of risk for subsequent bipolar disorder in high-risk samples.

Tohen M, Greil W, Calabrese JR, Sachs GS, Yatham LN, Oerlinghausen BM, Koukopoulos A, Cassano GB, Grunze H, Licht RW, Dell'Osso L, Evans AR, Risser R, Baker RW, Crane H, Dossenbach MR, Bowden CL. · Lilly Research Laboratories, Indianapolis, IN 46285, USA. · Am J Psychiatry. · Pubmed #15994710 links to  free full text

Abstract: OBJECTIVE: The authors compared the efficacy of olanzapine and lithium in the prevention of mood episode relapse/recurrence. METHOD: Patients with a diagnosis of bipolar disorder (manic/mixed), a history of two or more manic or mixed episodes within 6 years, and a Young Mania Rating Scale total score > or =20 entered the study and received open-label co-treatment with olanzapine and lithium for 6-12 weeks. Those meeting symptomatic remission criteria (Young Mania Rating Scale score < or =12; 21-item Hamilton depression scale score < or =8) were randomly assigned to 52 weeks of double-blind monotherapy with olanzapine, 5-20 mg/day (N=217), or lithium (target blood level: 0.6-1.2 meq/liter) (N=214). RESULTS: Symptomatic relapse/recurrence (score > or =15 on either the Young Mania Rating Scale or Hamilton depression scale) occurred in 30.0% of olanzapine-treated and 38.8% of lithium-treated patients. The noninferiority of olanzapine relative to lithium (primary objective) in preventing relapse/recurrence was met, since the lower limit of the 95% confidence interval on the 8.8% risk difference (-0.1% to 17.8%) exceeded the predefined noninferiority margin (-7.3%). Secondary results showed that compared with lithium, olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence. Depression relapse/recurrence occurred in 15.7% of olanzapine-treated and 10.7% of lithium-treated patients. Mean weight gain during open-label co-treatment was 2.7 kg; during double-blind monotherapy, weight gain was significantly greater with olanzapine (1.8 kg) than with lithium (-1.4 kg). CONCLUSIONS: These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment. Both agents were comparable in preventing depression relapse/recurrence.