Antidepressants worsen rapid-cycling course in bipolar depression: A STEP-BD randomized clinical trial.

BACKGROUND: The use of antidepressants in rapid-cycling bipolar disorder has been controversial. We report the first randomized clinical trial with modern antidepressants on this topic. METHODS: As part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we analyzed, as an a priori secondary outcome, rapid cycling as a predictor of response in 68 patients randomized to continue vs. discontinue antidepressant treatment, after initial response for an acute major depressive episode. Outcomes assessed were percent time well and total number of episodes. All patients received standard mood stabilizers. RESULTS: In those continued on antidepressants (AD), rapid cycling (RC) subjects experienced 268% (3.14/1.17) more total mood episodes/year, and 293% (1.29/0.44) more depressive episodes/year, compared with non-rapid cycling (NRC) subjects (mean difference in depressive episodes per year RC vs. NRC was 0.85 ± 0.37 (SE), df = 28, p = 0.03). In the AD continuation group, RC patients also had 28.8% less time in remission than NRC patients (95% confidence intervals (9.9%, 46.5%), p = 0.004). No such differences between RC and NRC subjects were seen in the AD discontinuation group (Table 1). Analyses within the rapid-cycling subgroup alone were consistent with the above comparisons between RC and NRC subjects, stratified by maintenance antidepressant treatment, though limited by sample size. CONCLUSIONS: In an a priori analysis, despite preselection for good antidepressant response and concurrent mood stabilizer treatment, antidepressant continuation in rapid-cycling was associated with worsened maintenance outcomes, especially for depressive morbidity, vs. antidepressant discontinuation.

Relationship of prior antidepressant exposure to long-term prospective outcome in bipolar I disorder outpatients.

OBJECTIVE: The long-term impact of prior antidepressant exposure on the subsequent course of bipolar illness remains controversial. METHOD: 139 outpatients (mean age, 42 years) with bipolar I disorder diagnosed by DSM-IV criteria had a detailed retrospective examination of their prior course of illness on the National Institute of Mental Health Life Chart Method. Number of prior antidepressant trials and total duration of antidepressant exposure were assessed. Prospective long-term response (for at least 6 months) to naturalistic treatment in the network from 1996 through 2002 was the primary outcome measure as it related to prior antidepressant exposure (and other illness variables) by logistic regression, with P < .05 used for statistical significance in this post hoc analysis. RESULTS: Greater number of antidepressant trials, but not duration of antidepressant exposure, was related to prospective nonresponse (P = .0051) whether or not antidepressants were covered by concurrent treatment with a mood stabilizer or atypical antipsychotic. Poor prospective response was also independently related to having had an anxiety disorder and 20 or more prior affective episodes. CONCLUSIONS: That the number of antidepressant trials, but not duration of antidepressant treatment, was associated with prospective nonresponse suggests that it is the repeated use of antidepressants to treat episodes of depression that is related to poor prospective response to naturalistic treatment. The direction of causality is unclear as to whether more antidepressant trials led to this increased treatment resistance or whether a difficult course of illness with more episodes and anxiety comorbidity engendered more attempts at antidepressant treatment.

Maintenance treatment study designs in bipolar disorder: do they demonstrate that atypical neuroleptics (antipsychotics) are mood stabilizers?

In this conceptual review we argue that by certifying some of the atypical neuroleptics (or, if one prefers, antipsychotics) as indicated for the 'maintenance' treatment of bipolar disorder, the US FDA has created confusion in the field. These maintenance indications are based on studies using a 'relapse prevention' design, a design that does not address whether the agents tested can prevent new episodes of illness, i.e. recurrence prevention or true prophylaxis. We found that the relapse prevention design fails to prove that these agents are mood stabilizers because patients are pre-selected to respond to the study drug for an acute mood episode (mania) and when they relapse, they do so into an episode of the same polarity (i.e. mania). We believe that this represents withdrawal into the same mood episode that patients experienced before the maintenance study began, rather than prevention of a new mood episode, as research into the natural history of bipolar disorder indicates that such new episodes typically are of the opposite polarity. Thus, the inability of neuroleptics to prevent depression in such maintenance studies reflects the general inability to prevent any new mood episode recurrence (which we believe should be defined as 6 months or longer after the index episode). If one defines a mood stabilizer, as we do, as a drug that prevents new episodes of mania and depression in monotherapy, then these studies do not show that atypical neuroleptics are mood stabilizers. Future maintenance research studies in bipolar disorder should use the prophylaxis design (i.e. without pre-selection of drug responders), rather than the relapse prevention design.

An automated Internet application to help patients with bipolar disorder track social rhythm stabilization.

This column describes a pilot study of a fully automated, Internet-based program that provides a key element of interpersonal and social rhythm therapy, a form of psychotherapy shown to be effective in the treatment of bipolar disorder when combined with mood-stabilizing medication. Participants (N=64) recorded the time they completed activities of daily living and their mood at the time of each entry. After 90 days they demonstrated a 31% increase in social rhythm stability and a small, though statistically significant, decrease in symptoms of abnormal mood. Internet-based programs can enhance access to a best practice in the management of bipolar disorder.

Suicidality and risk of suicide--definition, drug safety concerns, and a necessary target for drug development: a consensus statement.

OBJECTIVE: To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009. PARTICIPANTS: This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies of major depression, bipolar disorder, schizophrenia, substance abuse/dependence, and other psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest. EVIDENCE: Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted. CONSENSUS PROCESS: Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this scholarly article, which has been developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement have been noted. CONCLUSIONS: The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's effort to promote standard definitions and definable expectations for investigators and industry sponsors by endorsing the terminology in the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to build upon its new authority to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk within informative large health care-related databases in the United States and abroad. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the current Agency requirement that all CNS clinical drug trials must include a C-CASA-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed, and they need to be included to enable premarket assessments of the risks and benefits of medications related to suicidal ideation, suicidal behavior, and suicide in such patients.

Suicidality and risk of suicide--definition, drug safety concerns, and a necessary target for drug development: a brief report.

OBJECTIVE: To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009. PARTICIPANTS: This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies in studies of psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest. EVIDENCE: Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted. CONSENSUS PROCESS: Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this brief report and the accompanying full article from which it is distilled. The full article was developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement at the conference have been noted in the text. CONCLUSIONS: The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's encouragement of standard definitions and definable expectations for investigators and industry sponsors. Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the requirement that all central nervous system clinical drug trials must include a Columbia Classification Algorithm of Suicide Assessment (C-CASA)-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed.

The role of gender in single vs married individuals with bipolar disorder.

BACKGROUND: Despite the importance of marriage as a source of social support, it has been largely neglected in studies of bipolar disorder; and differential effects on men and women have not been explored. METHODS: Data on episodes of depression, mania, and mixed states were collected for the previous 2 years from a sample of 282 bipolar individuals using the National Institute of Mental Health Life Chart Methodology. RESULTS: Effects unique to women included the following: Bipolar women were significantly more likely to be married. Married women had fewer episodes of depression during the past 2 years than never-married women, and the cumulative severity of depression was lower. There were no differences in diagnostic subtype or age of onset between married and never-married women. Among men, never-married men were more likely to have bipolar I disorder and had an earlier age of onset compared with married men. There were no differences between married and never-married men in frequency, duration, or severity of mood episodes. CONCLUSIONS: Partner selection processes as they relate to bipolar disorder may be different for men and women. The bipolar I diagnostic subtype and early age of onset were associated with a lower likelihood of being married for men, but not for women. Marriage was associated with less depression in women during a 2-year period; but marital status was not associated with disease course differences in men, suggesting that women may be more sensitive to the positive effects of social support available within a stable marital relationship.

Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety.

OBJECTIVE: To assess long-term effectiveness and safety of randomized antidepressant discontinuation after acute recovery from bipolar depression. METHOD: In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, conducted between 2000 and 2007, 70 patients with DSM-IV-diagnosed bipolar disorder (72.5% non-rapid cycling, 70% type I) with acute major depression, initially responding to treatment with antidepressants plus mood stabilizers, and euthymic for 2 months, were openly randomly assigned to antidepressant continuation versus discontinuation for 1-3 years. Mood stabilizers were continued in both groups. RESULTS: The primary outcome was mean change on the depressive subscale of the STEP-BD Clinical Monitoring Form. Antidepressant continuation trended toward less severe depressive symptoms (mean difference in DSM-IV depression criteria = -1.84 [95% CI, -0.08 to 3.77]) and mildly delayed depressive episode relapse (HR = 2.13 [1.00-4.56]), without increased manic symptoms (mean difference in DSM-IV mania criteria = +0.23 [-0.73 to 1.20]). No benefits in prevalence or severity of new depressive or manic episodes, or overall time in remission, occurred. Type II bipolar disorder did not predict enhanced antidepressant response, but rapid-cycling course predicted 3 times more depressive episodes with antidepressant continuation (rapid cycling = 1.29 vs non-rapid cycling = 0.42 episodes/year, P = .04). CONCLUSIONS: This first randomized discontinuation study with modern antidepressants showed no statistically significant symptomatic benefit with those agents in the long-term treatment of bipolar disorder, along with neither robust depressive episode prevention benefit nor enhanced remission rates. Trends toward mild benefits, however, were found in subjects who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with modern antidepressant continuation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00012558.

A randomized comparison of online and paper mood charts for people with bipolar disorder.

BACKGROUND: Longitudinal mood instability is the essential feature of bipolar disorder, however most rating scales are cross sectional in nature, and focus on acute symptoms. By contrast, the NIMH Life Chart Methodology (LCM) characterizes in detail the severity, duration, and frequency of mood episodes. Adherence to daily rating, however, tends to be low. In this study an online version of the LCM, designed to enhance adherence, was compared to the standard paper version. METHODS: Patients from a mood disorders specialty clinic were randomized to the standard LCM or an online, open-source adaptation. The online version used hypertext links embedded in a daily email as the primary rating interface. Participants rated for 90 days. The total number of days rated and the number of days with complete data were compared for the two groups. RESULTS: Forty-eight patients participated in the study. The online group rated approximately twice as many days compared to the standard group (44.3 versus 20.4, p=.029). The online group also entered complete data for a larger portion of days (55.2% versus 27.7%, p=.039). LIMITATIONS: This was a small, short-term study. The implications for longer-term rating are unclear. CONCLUSIONS: Despite the advantages of documenting mood fluctuation on a daily basis, the LCM is not commonly used, in part because ensuring adequate adherence can be resource intensive. An easily accessible online adaptation that utilizes email checking behavior can make this tool available to a wider range of patients.

Mood stabilization and destabilization during acute and continuation phase treatment for bipolar I disorder with lamotrigine or placebo.

BACKGROUND: During post-acute phase pharmacotherapy for bipolar disorder, there has been little empirical study to establish when emerging mania symptoms (1) are of clinical significance and (2) reflect iatrogenic events versus the natural course of illness. METHOD: Secondary analyses were conducted in a previously studied group of bipolar I disorder (DSM-IV) outpatients randomly assigned to lamotrigine monotherapy (n=171) or placebo (n=121), and a larger prerandomization group (N=966) during open-label titration of lamotrigine, following an index depressive episode. Time until the emergence of mania symptoms, at varying severity thresholds, was examined over 6 months for lamotrigine versus placebo, while controlling for potential confounding factors in Cox proportional hazard models. Subject enrollment occurred between July 1997 and August 2001. RESULTS: Rates of mood elevation during both acute open-label and randomized continuation phases of lamotrigine treatment were comparable to those seen with placebo during the randomized phase. The hazard ratio for the emergence of mania symptoms with lamotrigine was not significantly different from placebo (hazard ratio=0.79; 95% CI, 0.53 to 1.16), with an upper bound that suggests no meaningful increase in susceptibility toward mania with lamotrigine. By contrast, clinically meaningful rises in mania symptom severity were predicted by baseline residual manic symptoms prerandomization and by the number of manic, hypomanic, or mixed episodes in the past year. CONCLUSIONS: Based on a composite definition of mood destabilization involving a range of severity thresholds for emerging signs of mania, lamotrigine confers no meaningful elevated risk relative to placebo for mood destabilization in bipolar I disorder. Rather, illness burden related to residual or lifetime mania features may hold greater importance for explaining mania relapses or breakthrough manic features during lamotrigine continuation pharmacotherapy.

The history and current state of antidepressant clinical trial design: a call to action for proof-of-concept studies.

BACKGROUND: The development of new antidepressant drugs has reached a plateau. There is an unmet need for faster, better, and safer medications, but as placebo-response rates rise, effect sizes shrink, and more studies fail or are negative, pharmaceutical companies are increasingly reluctant to invest in new drug development because of the risk of failure. In the absence of an identifiable human pathophysiology that can be modeled in preclinical studies, the principal point of leverage to move beyond the present dilemma may be improving the information gleaned from well-designed proof-of-concept (POC) studies of new antidepressant drugs with novel central nervous system effects. With this in mind, a group of experts was convened under the auspices of the University of Arizona Department of Psychiatry and Best Practice Project Management, Inc. PARTICIPANTS: Forty-five experts in the study of antidepressant drugs from academia, government (U.S. Food and Drug Administration and National Institute of Mental Health), and industry participated. EVIDENCE/CONSENSUS PROCESS: In order to define the state of clinical trials methodology in the antidepressant area, and to chart a way forward, a 2-day consensus conference was held June 21-22, 2007, in Bethesda, Md., at which careful reviews of the literature were presented for discussion. Following the presentations, participants were divided into 3 workgroups and asked to address a series of separate questions related to methodology in POC studies. The goals were to review the history of antidepressant drug trials, discuss ways to improve study design and data analysis, and plan more informative POC studies. CONCLUSIONS: The participants concluded that the federal government, academic centers, and the pharmaceutical industry need to collaborate on establishing a network of sites at which small, POC studies can be conducted and resulting data can be shared. New technologies to analyze and measure the major affective, cognitive, and behavioral components of depression in relationship to potential biomarkers of response should be incorporated. Standard assessment instruments should be employed across studies to allow for future meta-analyses, but new instruments should be developed to differentiate subtypes and symptom clusters within the disorder that might respond differently to treatment. Better early-stage POC studies are needed and should be able to amplify the signal strength of drug efficacy and enhance the quality of information in clinical trials of new medications with novel pharmacologic profiles.

The ethics of clinical innovation in psychopharmacology: Challenging traditional bioethics.

OBJECTIVE: To assess the scientific and ethical basis for clinical innovation in psychopharmacology. METHODS: We conducted a literature review, utilizing MEDLINE search and bibliographic cross-referencing, and historical evidence regarding the discovery and development of new medications in psychiatry. Clinical innovation was defined as use of treatments in a clinical setting which have not been well-proven in a research setting. RESULTS: Empirical data regarding the impact of clinical innovation in psychopharmacology are lacking. A conceptual and historical assessment of this topic highlights the ethical and scientific importance of clinical innovation. Ethically, it touches a borderline that, in our judgment, is not adequately framed in contemporary mainstream bioethics. Currently, research is viewed as not at all benefiting the patients who participate in it, while clinical care is viewed as being solely for the benefit of patients. Clinical innovation straddles these two worlds, uncomfortably at times. While many argue that clinical innovation should either be avoided or folded into research projects, we argue that clinical innovation is necessary for progress in psychopharmacology research, and that it can prosper best when guided by the following ethical principles: 1.) The treatment should be based on a viable hypothesis. 2.) Whenever possible, one's clinical observations should be reported so they can be evaluated by the scientific community. 3.) One should be willing to report unexpected observations of drug effects. 4.) A high standard of informed consent should be maintained. Again, this proposal goes against the standard view among bioethicists that research and clinical care are categorically opposed activities, as made clear by the either-or dichotomy of the Belmont Report on bioethics. This approach has so polarized our profession into clinicians versus researchers, that many clinicians will not apply new knowledge produced by clinical research until it eventually gets incorporated into formal treatment guidelines, while researchers have little to guide them as to what kind of new knowledge it is most important to provide. SUMMARY: Clinical innovation brings out the ambiguities in our current ethical conceptions of research versus clinical care. Yet, historically, clinical innovation has been an important contributor to progress in psychopharmacology. We argue that clinical innovation should not be discouraged, but rather it should occur under certain ethical conditions."Almost everyone can and should do research...because almost everyone has a unique observational opportunity at some time in his life which he has an obligation to record.... If one considers the fundamental operations or methods of research, one immediately realizes that most people do research at some time or another, except that they do not call their activity by that name. There are seven operations.... In simple language they are counting, sorting, measuring, comparing, nature-study, guess testing, and reappraisal.... Guess testing is of course what most people think of when the word research is mentioned; except that it is bad manners to call a guess a guess. It should be called an hypothesis. Let us make one plea. Guessing becomes merely a game unless it is done in the context of a plan for action. It is a waste of time elaborating untestable hypotheses 1." John Cade.

Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review.

OBJECTIVES: To update and extend comparisons of rates of suicides and suicide attempts among patients with major affective disorders with versus without long-term lithium treatment. METHODS: Broad searching yielded 45 studies providing rates of suicidal acts during lithium treatment, including 34 also providing rates without lithium treatment. We scored study quality, tested between-study variance, and examined suicidal rates on versus off lithium by meta-analytic methods to determine risk ratios (RRs) and 95% confidence intervals (CI). RESULTS: In 31 studies suitable for meta-analysis, involving a total of 85,229 person-years of risk-exposure, the overall risk of suicides and attempts was five times less among lithium-treated subjects than among those not treated with lithium (RR = 4.91, 95% CI 3.82-6.31, p < 0.0001). Similar effects were found with other meta-analytic methods, as well as for completed versus attempted suicide, and for bipolar versus major mood disorder patients. Studies with higher quality ratings, including randomized, controlled trials, involved shorter exposures with somewhat lesser lithium superiority. Omitting one very large study or those involving lithium-discontinuation had little effect on the results. The incidence-ratio of attempts-to-suicides increased 2.5 times with lithium-treatment, indicating reduced lethality of suicidal acts. There was no indication of bias toward reporting positive findings, nor were outcomes significantly influenced by publication-year or study size. CONCLUSIONS: Risks of completed and attempted suicide were consistently lower, by approximately 80%, during treatment of bipolar and other major affective disorder patients with lithium for an average of 18 months. These benefits were sustained in randomized as well as open clinical trials.

Substance use disorder and other predictors of antidepressant-induced mania: a retrospective chart review.

OBJECTIVE: To determine if substance use disorder (SUD) is a predictor of antidepressant-induced mania (ADM) in bipolar disorder, correcting for confounding factors in a regression model. METHOD: 335 antidepressant trials were identified in 98 patients treated in an academic bipolar specialty clinic from 2000 to 2004. Patient charts were reviewed, and histories of SUD and ADM (primary outcome; defined as a hypomanic or manic episode within 12 weeks of beginning an antidepressant trial) were identified. Mood disorder diagnoses were made using the Structured Clinical Interview for DSM-IV mood module, and SUD diagnoses were defined using DSM-IV criteria. Potential confounding variables were also examined and included in a multivariable regression model. Concomitant mood stabilizer, antimanic, and antidepressant use was adjusted for in the regression model. RESULTS: In univariate analyses, there was no evidence of an association between ADM and past SUD. However, after adjustment for confounding variables in a multivariable regression model, there was a strong relationship (OR = 5.06, 95% CI = 1.31 to 19.64, p < .05). Other statistically significant predictors of ADM in the regression model were type II subtype of bipolar illness, female gender, and tricyclic antidepressant (TCA) use (vs. bupropion). CONCLUSIONS: Along with other factors, a history of SUD was a strong predictor of ADM. Possible underestimation of ADM in randomized clinical trials may occur due to the exclusion of subjects with SUD. Type II illness, female gender, and TCA use also appeared to be predictors of ADM, while bupropion use appeared to predict lower likelihood of ADM.

Long-term lamotrigine plus lithium for bipolar disorder: One year outcome.

OBJECTIVE: To obtain pilot data in an observational setting on the use of lamotrigine plus lithium in the long-term treatment of patients with bipolar disorder, 87% of whom had failed to respond to at least one previous mood stabilizer. METHODS: Charts of 21 patients (11 females, 10 males, mean age 43.2 years) treated with the combination of lithium and lamotrigine were reviewed retrospectively for treatment response using the Clinical Global Impression-Bipolar Disorder-Improvement scale, divided into benefit for acute depressive symptoms, acute manic symptoms, and overall illness (including prophylaxis of mood episodes). Of the 21 patients, 76% were diagnosed with bipolar I disorder, and depressive symptoms were the most common acute indication for treatment (52%). Mean doses of lithium and lamotrigine were 963 mg/day and 179 mg/day, respectively, used for a mean of 55.7 weeks. RESULTS: Acute antidepressant benefit was observed in 48% of patients, acute anti-manic benefit in 14%, and overall prophylactic benefit in 29%. Side effects were observed in 38%, with cognitive problems most common (29%). 48% discontinued combination therapy, mainly due to lack of efficacy (19%) or activation of manic-like symptoms (19%). CONCLUSIONS: Among a group of largely treatment-resistant bipolar patients, the combination of lithium and lamotrigine appeared effective for acute depressive symptoms in about half of the patients, but acute anti-manic and long-term prophylactic efficacy appeared less robust.

Extrapyramidal side effects with atypical neuroleptics in bipolar disorder.

OBJECTIVE: To examine, in a real-world clinical setting, the risk of extrapyramidal symptoms (EPS) with atypical neuroleptics in bipolar patients. METHODS: The authors assessed 51 individual patient trials of atypical neuroleptic agents (17 risperidone, 13 olanzapine, 11 quetiapine, 8 ziprasidone, and 2 aripiprazole) in 37 bipolar patients (type I or type II). Risk of EPS was assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and the Simpson-Angus Scale. Mean duration of treatment was 25.5 weeks (range 3-107 weeks) and 60.8% of patients were female. RESULTS: 62.7% of trials resulted in moderate to severe EPS. EPS and discontinuation frequencies were similar between specific neuroleptic agents or between high potency (risperidone/ziprasidone/aripiprazole; 52.9%, 27/51 trials) and low potency (quetiapine/olanzapine; 47.1%, 24/51 trials) agents. In a multiple regression model adjusted for confounders, akathisia was less common with low potency agents. Younger age was associated with more akathisia. 31.4% (11/35) of trials discontinued due to side effects. 7.8% (4/51) of trials led to mild de novo tardive dyskinesia. CONCLUSIONS: Over one-half of bipolar patients experienced EPS in this real world clinical setting. This rate is much higher than the 5-15% range reported in clinical trials, suggesting potential problems with clinical trial generalizability.

ACNP Task Force report on SSRIs and suicidal behavior in youth.

This Task Force report by the American College of Neuropsychopharmacology evaluates the safety and efficacy of selective serotonin reuptake inhibitor (SSRIs) antidepressants for depressed youth under 18 years. The report was undertaken after regulatory agencies in the United States and United Kingdom raised concerns in 2003 about the possibility that treatment of depression in children and adolescents with SSRIs may increase the risk of suicidal thinking or suicide attempts.

Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder.

BACKGROUND: This analysis describes the effects of bipolar I disorder on self-reported neurocognitive measures and remediation of these deficits with lamotrigine therapy. METHOD: Data were derived from 2 clinical trials designed to assess the efficacy of lamotrigine as maintenance therapy for recently manic (N = 349) or depressed (N = 966) patients (DSM-IV criteria). During the 8- to 16-week open stabilization phase, patients received lamotrigine as monotherapy or as adjunctive therapy (target dose = 200 mg/day, minimum dose = 100 mg/day) while other psychotropic drugs were discontinued. The Medical Outcomes Study Cognitive Scale (MOS-Cog) and the AB-Neurological Assessment Scale (AB-NAS) were used to measure cognitive functioning at baseline and at the end of the open-label phase. To examine the relationship between depressive and manic symptomatology, initiation of lamotrigine, and cognitive functioning, correlational analyses and analyses of covariance were conducted. RESULTS: Bipolar patients in both trials had significant cognitive impairment; however, it was much greater in index episode depressed bipolar patients compared with index episode manic patients. In both studies, substitution of lamotrigine for other psychotropic medications significantly improved the mean scores from baseline to the end of the open-label phase on the MOS-Cog and the AB-NAS (p < .0001). Among patients who took lamotrigine as monotherapy, the mean MOS-Cog score also improved significantly versus baseline (+32.2, or 81%, for depressed patients, p < .0001; and +19.9, or 35%, for manic patients, p < .0001). Mean AB-NAS scores (-19.7, or -55%, for depressed patients, p < .0001; and -7.2, or -32%, for manic patients, p = .0062) showed similar improvement. Cognitive impairment was significantly correlated with depression symptom severity based on Hamilton Rating Scale for Depression scores (p < .0001). After controlling for change in mood, age, gender, baseline score, duration of illness, and duration of use of other psychotropics, a significant improvement in cognition was observed during the open-label phase when lamotrigine was used as monotherapy/adjunctive therapy. CONCLUSION: Treatment with lamotrigine as monotherapy and as adjunctive therapy was associated with improved cognitive functioning and reduced neurocognitive side effects, regardless of index mood polarity.

Separate and concomitant use of lamotrigine, lithium, and divalproex in bipolar disorders.

Expert consensus emphasizes the need for better recognition and accurate diagnosis of bipolar disorder. Current research on lithium, divalproex, and lamotrigine provides new insight into the effective management of this illness. Advances in identifying the mechanism of action of mood stabilization has focused on signaling pathways within the cell that are associated with neurotrophic effects. Clinical research has led to confirmatory evidence of the efficacy of lithium in all phases of bipolar disorder, with the greatest effects seen in the treatment and prevention of mania. Compared to divalproex, lithium also has been found to have greater efficacy in the prevention of suicide. Lamotrigine has emerged as a first line treatment for bipolar depression, which is an area of weakness for other mood stabilizers. Oral loading of divalproex leads to rapid stabilization of mania without imposing a greater adverse effect burden than conventional dosing. Because no agent is universally effective in all phases of the illness, combination therapy with two or more agents often is the best option.