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Background Lithium is an old proven medication, but it is infrequently used in current practice. This review examines evidence for its benefits and risks and provides clinical guidance to its use. Method Narrative review. Results Besides its benefit in bipolar illness, lithium has important underappreciated proven benefits in prevention of unipolar depression and suicide. Emerging data support neurobiological benefits for cognition and possible dementia prevention. Likely benefits also exist in low doses for mood temperaments (cyclothymia and hyperthymia). High doses (over 1.0 mmol/L) should be avoided since they increase side effects, complications associated with long-term use, and risk of toxicity. Conversely, low dosing can be legitimate, especially for suicide and dementia prevention. Nuisance side effects of lithium may affect adherence, and medically serious side-effects can occur. Managing strategies are available for side effects. Conclusion Lithium is the most effective medication in psychiatry, because it has disease-modifying, not just symptomatic, effects. It is effective not only for bipolar illness but also for prevention of suicide, episodes of unipolar depression, mood temperaments, and possibly dementia. Its many benefits need better appreciation, while lowered dosing can reduce risks.

Objective In the past decade, since the innovation of the smartphone, there has been an increase in depression, anxiety, and suicidality among teenagers and young adults. The objective of this article was to review the current evidence for these associations and to provide initial clinical guidance. Methods A narrative review of the available literature on digital technology, social media, and psychiatric outcomes in adolescents. Results Psychiatric outcomes have worsened in adolescents in the past decade, correlating with the invention of the smartphone and the rise of social media. Depressive symptoms among American teenagers rose rapidly around 2012 and now are reported in 22% of adolescents, which is at least double the rate in adults. Suicide rates have risen, especially among teenage girls in the United States, in whom there has been a doubling of completed suicide in the past decade. A causal relationship between social media use and these harmful psychiatric outcomes is supported by emerging randomized data showing reduced depressive symptoms associated with a decrease in social media use in college students. Conclusions Social media and digital technology correlate with harmful psychiatric outcomes in adolescents and young adults. Clinical recommendations should include limitations in social media use.

IntroductionAlthough classical randomized clinical trials (RCTs) are the gold standard for proof of drug efficacy, randomized discontinuation trials (RDTs), sometimes called “enriched” trials, are used increasingly, especially in psychiatric maintenance studies.MethodsA narrative review of two decades of experience with RDTs.ResultsRDTs in psychiatric maintenance trials tend to use a dependent variable as a predictor: treatment response. Treatment responders are assessed for treatment response. This tautology in the logic of RDTs renders them invalid, since the predictor and the outcome are the same variable. Although RDTs can be designed to avoid this tautologous state of affairs, like using independent predictors of outcomes, such is not the case with psychiatric maintenance studiesFurther, purported benefits of RDTs regarding feasibility were found to be questionable. Specifically, RDTs do not enhance statistical power in many settings, and, because of high dropout rates, produce results of questionable validity. Any claimed benefits come with notably reduced generalizability.ConclusionsRDTs appear to be scientifically invalid as used in psychiatric maintenance designs. Their purported feasibility benefits are not seen in actual trials for psychotropic drugs. There is warrant for changes in federal policy regarding marketing indications for maintenance efficacy using the RDT design.

Background In the last five years, the debate around the comorbidity between bipolar disorder (BD) and obsessive-compulsive disorder (OCD) has flourished within the international psychiatric community and several studies have been published on therapeutic strategies. Methods An update of our previous systematic review was conducted on clinical management of comorbid BD–OCD patients. Relevant papers published from July 1st 2013 to September 30th 2018 were identified searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. Results Fifteen studies were included. In all selected studies BD–OCD patients received mood stabilizers, alone or with second-generation antipsychotics (SGAs). Aripiprazole augmentation demonstrated to be effective as maintenance therapy and for treating obsessive-compulsive symptoms during manic episodes (40% of the studies, 6/15). Addition of antidepressants to mood stabilizers led to clinical remission of both conditions in only one case report. Limitations Almost 50% of the selected studies are case reports. Enrolment of subjects mainly from outpatient specialty units might have introduced selection bias and limited community-wide generalizability. Conclusions Mood stabilization should be the primary goal in treating BD–OCD patients. Aripiprazole augmentation to lithium carbonate seemed to be the best option in treatment-resistance comorbid patients. Addition of SRIs may be needed only in a minority of BD patients with refractory OCD.

Background Apparent comorbidity between bipolar disorder (BD) and obsessive-compulsive disorder (OCD) is a common condition in psychiatry, but treatment of BD-OCD remains a clinical challenge. Although serotonin reuptake inhibitors (SRIs) are the first line treatment for OCD, they can induce mood instability in BD. An optimal treatment approach remains to be defined. Methods A systematic review was conducted on aripiprazole augmentation in treating comorbid BD-OCD patients. Relevant papers published through August 31st 2018 were identified searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. Results Aripiprazole augmentation to mood stabilizers (lithium carbonate, valproate), even at low doses (10–15 mg/day), helped to achieve significant remission in affective and obsessive-compulsive symptoms. Aripiprazole was generally safe and well tolerated. Limitations Most studies are case reports. Enrolment of subjects mainly from outpatient specialty units might have introduced selection bias and limited community-wide generalizability. Conclusions Keeping in mind scantiness and heterogeneity of the available literature, the best interpretation of the available evidence appears to be that aripiprazole augmentation to mood stabilizers, even at low doses, is effective in BD-OCD patients.

Introduction:Many clinicians are reluctant to use traditional mood-stabilizing agents, especially lithium, in children and adolescents. This review examined the evidence for lithium’s safety and efficacy in this population.Methods:A systematic review was conducted on the use of lithium in children and adolescents with bipolar disorder (BD). Relevant papers published through June 30th 2018 were identified searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library.Results:30 articles met inclusion criteria, including 12 randomized controlled trials (RCTs). Findings from RCTs demonstrate efficacy for acute mania in up to 50% of patients, and evidence of long-term maintenance efficacy. Lithium was generally safe, at least in the short term, with most common side effects being gastrointestinal, polyuria, or headache. Only a minority of patients experienced hypothyroidism. No cases of acute kidney injury or chronic kidney disease were reported.Conclusions:Though the available literature is mostly short-term, there is evidence that lithium monotherapy is reasonably safe and effective in children and adolescents, specifically for acute mania and for prevention of mood episodes.

Background We sought to test the hypothesis that antidepressants (ADs) may show preferential efficacy and safety among patients with type II bipolar disorder (BD, BD-II) more than patients with type I BD (BD-I). Methods Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BD-I (n = 21) and BD-II (n = 49) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then randomized openly to continue or discontinue ADs for up to 3 years. Outcomes were episode recurrences and changes in standardized symptom ratings. Results In follow-up averaging 1.64 years, both subgroups showed improvement in depressive episode frequency with AD continuation, but contrary to the hypothesis, more improvement was seen in BD-I than in BD-II (for type II, mean [standard deviation] decrease in depressive episodes per year, 0.21 [0.26]; for type I, mean (SD) decrease, 0.35 [0.15]). Subjects with BD-II who continued on ADs had slightly more depressive, but fewer manic/hypomanic, episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission. Conclusions The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I, except somewhat lower risk of manic/hypomanic episodes.

Psychiatric comorbidity is extremely common. One of the most common and difficult to manage comorbid conditions is the co-occurrence of bipolar disorder (BD) and obsessive compulsive disorder (OCD). We updated our recent systematic review searching the electronic databases MEDLINE, Embase, and PsycINFO to investigate course of illness in BD-OCD patients. We identified a total of 13 relevant papers which found that the majority of comorbid OCD cases appeared to be related to mood episodes. OC symptoms in comorbid patients appeared more often during depressive episodes, and comorbid BD and OCD cycled together, with OC symptoms often remitting during manic/hypomanic episodes.

Objective To examine the empirical literature on diagnostic validators in borderline personality and bipolar illness. Method Using principles of evidence-based medicine, the highest levels of evidence were emphasized in interpretation of similarities or differences between bipolar illness and borderline personality on the five standard diagnostic validators in psychiatric nosology: symptoms, course, genetics, treatment response, and neurobiology. Results Bipolar illness and borderline personality were found to be similar in the nosological validator of symptoms of mood lability and impulsivity, but differed notably on all other diagnostic validators, especially the course validator of past sexual abuse and the genetic validator of a bipolar family history. They also differ notably in the symptom validator of parasuicidal self-harm. Treatment response and neurobiological differences were also present and consistent. Conclusion This review of the literature indicates that these two conditions, bipolar illness and borderline personality, are different and can be distinguished. The much stronger biological and genetic evidence for bipolar illness in particular suggests that the two conditions can be reasonably seen as different kinds of clinical entities, namely a biological disease versus a psychosocially caused clinical picture. If this interpretation is correct, similarities between the two conditions, such as mood lability and impulsivity, are superficial, while differences are profound. Further, true comorbidity may be much less common than often presumed.

Background: Despite availability of validated screening tests for mood disorders, busy general practitioners (GPs) often lack the time to use them routinely. This study aimed to develop a simplified clinical predictive score to help screen for presence of current mood disorder in low-income primary care settings. Methods: In a cross-sectional study, 197 patients seen at 10 primary care centers in Santiago, Chile completed self-administered screening tools for mood disorders: the Patient Health questionnaire (PHQ-9) and the Mood Disorder Questionnaire (MDQ). To determine participants’ current-point mood disorder status, trained clinicians applied a gold-standard diagnostic interview (SCID-I). A simplified clinical predictive model (CM) was developed based on clinical features and selected questions from the screening tools. Using CM, a clinical predictive score (PS) was developed. Full PHQ-9 and GP assessment were compared with PS. Results: Using multivariate logistic regression, clinical and demographic variables predictive of current mood disorder were identified for a simplified 8-point predictive score (PS). PS had better discrimination than GP assessment (auROC-statistic ¼0.80 [95% CI 0.72, 0.85] vs. 0.58 [95% CI 0.52, 0.62] p-value o0.0001), but not as good as the full PHQ-9 (0.89 [95% CI 0.85, 0.93], p-value¼0.03). Compared with GP assessment, PS increased sensitivity by 50% at a fixed specificity of 90%. Administered in a typical primary care clinical population, it correctly predicted almost 80% of cases. Limitations: Further research must verify external validity of the PS. Conclusion: An easily administered clinical predictive score determined, with reasonable accuracy, the current risk of mood disorders in low-income primary care settings.

Objective The differential diagnosis of bipolar illness vs. borderline personality is controversial. Both conditions manifest impulsive behavior, unstable interpersonal relationships, and mood symptoms. This study examines whether and which mood clinical features can differentiate between both conditions. Method A total of 260 patients (mean ± standard deviation age 41 ± 13 years, 68% female) attending to a mood clinic were examined for diagnosis of bipolar illness and borderline personality disorder using SCID-I, SCID-II, and clinical mood criteria extracted from Mood Disorder Questionnaire (MDQ). They were analyzed using diagnoses as dependent variables. Predictors of bipolar and borderline diagnoses were identified by multivariable logistic regressions, and predictive validity of models was assessed using ROC curve analysis. Results Bipolar illness was strongly predicted by elevated mood (OR = 4.02, 95% CI: 1.80–9.15), increased goal-directed activities (OR = 3.90, 95% CI: 1.73–8.96), and episodicity of mood symptoms (OR = 3.48, 95% CI 1.49–8.39). This triad model predicted bipolar illness with 88.7% sensitivity, 81.4% specificity, and obtained an auROC of 0.91 (95% CI: 0.76–0.96) and a positive predictive value of 85.1%. For borderline personality disorder, only female gender was a statistically significant predictor (OR = 3.41, 95% CI: 1.29–13.7), and the predictive model obtained an auROC of 0.67 (95% CI: 0.53–0.74). Conclusion In a mood disorder clinic setting, manic criteria and episodic mood course distinguished bipolar illness from borderline personality disorder.

Phelps J, Ghaemi SN. The mistaken claim of bipolar ‘overdiagnosis’: solving the false positives problem for DSM-5/ICD-11. Objective: For psychiatric diagnoses, solving the problem of false positives is thought to be a matter of tightening diagnostic criteria. But low prevalence illnesses by their nature have high false positive rates. A recent study of bipolar disorder found the predictive value of bipolar diagnoses to be 50% requires diagnostic specificity of >95%. Holding specificity at a level already achieved clinically (86%), increasing prior probability yields predictive values as high as 83%. Conclusion: Systematic assessment of clinical factors that increase the prior probability of illness, before applying DSM/ICD criteria, could raise PPV substantially compared with targeting greater specificity via more stringent diagnostic criteria.

Malhi GS, Chengappa KNR, Gershon S, Ghaemi SN. Atypical mood stabilizers: a new role for neuroleptics? Bipolar Disord 2011: 13: 583–586. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S.

All observations ― whether those of one clinician on one patient, or one clinician on a thousand patients over decades, or entire nations ― are inherently wrong, or, at least probably wrong, in some way. Even if huge databases are used, and the fanciest statistical regression models employed, observations are still observations, limited by the context in which they are made.

> “There is a type of interaction between human beings which proceeds not from knowledge, or even lack of knowledge, but from failure to know what isn’t known.” John Kenneth Galbraith1 The medical literature meets Galbraith’s description. Some things we know, and know that we know. Other things we do not know, and know that we do not know. But perhaps the largest class involves those things we do not know, and do not realise that we do not know. This latter state of affairs is exemplified by the problem of negative studies. It has become increasingly clear that the medical literature is biased toward positive studies; negative studies are less frequently published.2 Sometimes this may reflect loss of passion, as disappointed researchers file away their negative results. Sometimes it may be systematic, as pharmaceutical sponsors may actively suppress negative data which would adversely impact their marketplace sales. And journals may also systematically reject negative studies—which will generate fewer readers, fewer citations and lower impact factors for the journal—more frequently than positive ones. Negative studies may provide important information. “Negative” does not mean unimportant, and proving something ineffective is as important, perhaps more so, than proving it effective. To be a good physician, knowing when not to use which medications, as Pinel famously said, is even more important than knowing when and how to use them.3 Drugs that are ineffective might be somewhat harmful; almost all drugs are harmful in some way; thus the risk–benefit calculation is always hurtful for an ineffective drug. Furthermore, drugs which are effective are often not used, since the ineffective drugs are seen as effective, and thus the truly effective drugs, which sometimes have more side effects, are pushed aside. It is as if the princess at a ball, hidden in servant clothes, …

More than half of patients with bipolar disorder (BD) have anadditional diagnosis, one of the most difficult to manage beingobsessive–compulsive disorder (OCD). French psychiatristB!en !edict Augustin Morel first described patients with BD-OCD arising questions around the nosological and clinicalmeaning of this condition. In a standard 1969 psychiatrytextbook, Mayer-Gross and colleagues, mostly consideringcourse of illness, included patients with BD-OCD in themanic-depressive disorders (1). Although recent studies haveinvestigated the co-occurrence of anxiety and bipolar disor-ders, the topic is insufficiently studied and the relationshipbetween BD and OCD remains unclear. However, given theavailable scientific evidence, some observations can be made.i) Apparent BD-OCD comorbidity is a common conditionin psychiatry. In our recent meta-analysis, the pooledprevalence of OCD in BD was 17.0% (95% CI 12.7–22.4%), which was comparable to the results reported bythe pooled prevalence of BD in OCD (18.35%, 95% CI13.2–24.8%) (2). Although limited by retrospective studydesign, small sample size, different thresholds for BDdiagnosis (i.e. categorical vs. dimensional approach) anda different accuracy in diagnosing OCD (i.e. discrimina-tion between true ego-dystonic obsessions and depressiveruminations), these results confirm the relevance ofcomorbid BD-OCD.ii) As reported by recent studies, OC symptoms in childhoodand adolescence increase the risk of a later BD diagnosis(3). These results would be suggestive of partially sharedaetiopathogenetic mechanisms between these severe men-tal disorders.iii) In our previous systematic review, considering course ofillness as a key diagnostic validator, especially amongpatients with a primary diagnosis of BD, the majority ofcomorbid OCD cases appeared to be related to mood epi-sodes (1). OC symptoms in comorbid patients appearedmore often – and sometimes exclusively – during depres-sive episodes, and comorbid BD and OCD cycledtogether, with OC symptoms often remitting duringmanic/hypomanic episodes.iv) Results from our meta-analysis showed higher comorbid-ity rates in youths (24.2%, 95% CI = 10.36–41.60,n = 345, z = !9.5) compared to adults (13.56%, 95%CI = 10.4–16.25, n = 4,539) (2). In other words, OCsymptoms would initially coexist with BD symptoms andthey would gradually tend to decrease in the adulthood.v) From a neurobiological perspective, BD mostly showedhypoactivity in orbitofrontal cortex (OFC) (i.e. decisionmaking, impulse control) and in dorsolateral prefrontalcortex (DLPFC) (i.e. planning, attentional set shifting)with grey matter volume reduction associated to manicepisodes, while OCD mainly presented hyperactivity ofOFC with deficit in emotional processing (4). The overlapof similar cortical–subcortical circuits may partiallyexplain clinical features of comorbid patients with BD-OCD during the course of illness.vi) The clinical features of comorbid patients with BD-OCD would explain why OCD and BD symptomsrespond to adequate mood stabilizer treatment (5).Only in a minority of comorbid patients with persis-tent OCD, despite improvement in mood episodes,addition of low doses of antidepressants could be con-sidered while strictly monitoring emerging symptomsof mania or mixed states.To conclude, according to the available literature, we specu-late that OC symptoms in childhood and adolescence may beexpression of vulnerability to BD increasing the risk of a laterBD diagnosis. OC symptoms would initially coexist with BDsymptoms even cycling together, and they would graduallytend to decrease in the adulthood.Considering the important nosological, clinical and thera-peutic implications, further original studies are needed to clar-ify BD-OCD comorbidity. In particular, studies addressingneurobiological substrates are essential to illuminate patho-genetic mechanisms that underlie comorbid BD-OCD.

Background : Although some authors have recently investigated the co-occurrence of anxiety and bipolar disorders, the topic remains insufficiently studied. Defining the prevalence and predictors of BD–OCD comorbidity has important nosological, clinical and therapeutic implications. Methods : A systematic review and meta-analysis was conducted on the prevalence and predictors of comorbid BD–OCD. Relevant papers published through March 30th, 2015 were identified searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. Results : 46 articles met inclusion criteria. The pooled prevalence of OCD in BD was 17.0% (95% CI 12.7–22.4%), which was comparable to the results reported by the pooled prevalence of BD in OCD (18.35%, 95% CI 13.2–24.8%). With regard to OCD–BD predictors, a higher mean age predicted a lower prevalence of OCD in BD patients. Sub group meta-analyses reported higher OCD prevalence rates in BD children and adolescents (24.2%, compared to 13.5% in adults), in BD-I patients (24.6%, compared to 13.6% in mixed BD patients), and among population-based studies (22.2%, compared to 13.2% in hospital-based studies). Limitations : Most studies use retrospective assessment scales with low sensitivity in discriminating true ego-dystonic obsessions from depressive ruminations that may bias results towards an overestimation of obsessive symptom prevalence. Conclusions : This first systematic review and meta-analysis of the prevalence and predictors of comorbid BD–OCD confirms that BD–OCD comorbidity is a common condition in psychiatry with children and adolescents and BD-I patients as the most affected subgroups.

Objective: At least 50% of bipolar disorder (BD) patients have an additional diagnosis, one of the most difficult to manage being obsessive-compulsive disorder (OCD). Defining the nosology of BD-OCD comorbidity has important clinical implications, given that treatments for OCD can worsen BD outcomes. Method: A systematic review was conducted on: i) BD-OCD comorbidity lifetime prevalence and ii) on standard diagnostic validators: phenomenology, course of illness, heredity, biological markers, and treatment response. Relevant papers published through March 30th 2013 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library. Results: Sixty-four articles met inclusion criteria. Lifetime comorbidity prevalence was 11-21% in BD patients and 6-10% in OCD patients. Compared to non-comorbid subjects, BD-OCD has a more episodic course of OC symptoms (up to 75% vs. 3%), typically with worsening during depression (78%) and improvement during mania/hypomania (64%), as well as a higher total mean number of depressive episodes (8.9 ± 4.2 vs. 4.1 ± 2.7) and perhaps more antidepressant-induced mania/hypomania (39% vs. 9%). Conclusion: In this first systematic review of BD-OCD comorbidity, it appears that OC symptoms are usually secondary to BD, rather than representing a separate disease. © 2014 John Wiley & Sons A/S.

Background More than 20% of patients with bipolar disorder (BD) show lifetime comorbidity for obsessive–compulsive disorder (OCD), but treatment of BD–OCD is a clinical challenge. Although serotonin reuptake inhibitors (SRIs) are the first line treatment for OCD, they can induce mood instability in BD. An optimal treatment approach remains to be defined. Methods We systematically reviewed MEDLINE, Embase, PsychINFO and the Cochrane Library and retrieved data on clinical management of comorbid BD–OCD patients. Pharmacologic, psychotherapeutic and others alternative approaches were included. Results Fourteen studies were selected. In all selected studies BD–OCD patients received mood stabilizers. In the largest study, 42.1% of comorbid patients required a combination of multiple mood stabilizers and 10.5% a combination of mood stabilizers with atypical antipsychotics. Addition of antidepressants to mood stabilizers led to clinical remission of both conditions in only one study. Some BD–OCD patients on mood stabilizer therapy benefitted from adjunctive psychotherapy. Limitations Most studies are case reports or cross-sectional studies based on retrospective assessments. Enrollment of subjects mainly from outpatient specialty units might have introduced selection bias and limited community-wide generalizability. Conclusions Keeping in mind scantiness and heterogeneity of the available literature, the best interpretation of the available evidence appears to be that mood stabilization should be the primary goal in treating BD–OCD patients. Addition of SRI agents seems unnecessary in most cases, although it may be needed in a minority of BD patients with refractory OCD.

Whereas much progress has been made in the diagnosis and treatment of schizophrenia and depression in recent years, bipolar disorder continues to be frequently misunderstood, leading to its inconsistent diagnosis and treatment. In this article, we seek to identify the causes of this problem and suggest possible solutions, based on a critical review of studies concerning the nosology of bipolar disorder and the effects of antidepressant agents. Bipolar disorder appears to be underdiagnosed as well as frequently misdiagnosed as unipolar major depressive disorder. Underdiagnosis can stem from patients' impaired insight into mania and failure to involve family members in the diagnostic process and also from clinicians' inadequate understanding of manic symptoms. Underdiagnosis may also reflect disagreement about the breadth of the bipolar spectrum. We therefore propose a heuristic definition of "bipolar spectrum disorder," a diagnosis that gives greater weight to family history and antidepressant-induced manic symptoms. This diagnosis would include all forms of bipolar illness that are not type I or II . The evidence also suggests that antidepressants are probably overused and mood stabilizers underused. We consequently recommend aggressive use of mood stabilizers and less emphasis on antidepressants. In summary, the state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to the criteria for mania is necessary. In addition, the current pattern of antidepressant use in bipolar disorder does not appear to be evidence-based.

Objective: We sought to review research on use of antidepressants for long-term treatment of bipolar depression. Method: We conducted a computerized literature search of the MEDLINE, HealthStar, Current Contents, Psychlnfo, and National Library of Medicine databases to identify studies involving antidepressant, anticonvulsant, or lithium use in bipolar disorder or manic-depressive illness published from 1966 through 2000. Results: Only 7 blinded, controlled trials of long-term antidepressant treatment in bipolar disorders were found. The available information is not adequate to support the safety or effectiveness of long-term antidepressant treatment for bipolar depression, with or without mood-stabilizing cotherapy. Conclusion: Antidepressant treatment of bipolar depression is extraordinarily understudied. Controlled trials comparing specific antidepressants, particularly to compare mood-stabilizing agents given alone and combined with an antidepressant, are needed.

Background: Our purpose was to evaluate the overall efficacy and tolerability of novel antipsychotic medications for patients with bipolar disorder type I. Method: A retrospective study of the Massachusetts General Hospital Bipolar Clinic database was carried out to identify 50 consecutive treatment trials in patients with DSM-IV bipolar disorder type I who had received adjunctive treatment with risperidone, olanzapine, or clozapine, along with standard mood stabilizers. The treatment charts of those patients (N = 42) were reviewed for details of adverse effects, tolerability, and efficacy of medication. Results: Overall results indicated equivalent efficacy in novel antipsychotic treatments according to change in Clinical Global Impressions scale score. Levels of extrapyramidal symptoms were similar in all groups and occurred in 12/42 patients (28.6%). Prolactin-related side effects were not observed in any patients. There were no cases of affective switch or worsening of mania. Substantial weight gain of more than 10 1b (4.5 kg) was significantly greater in patients treated with olanzapine. Conclusion: These results suggest that the efficacy and tolerability of risperidone, olanzapine, and clozapine are similar in patients with bipolar disorder. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. This may, in part, also be related to the need to use mood-stabilizing agents, like lithium or divalproex sodium, which may potentiate the weight-gain effect of novel antipsychotics.

Accumulating evidence suggests that at least some novel anticonvulsants may have mood-stabilizing properties. This paper reviews the literature for empirical studies of this topic. Lamotrigine has the most evidence in favor of its efficacy, with two double-blind studies in which it was more efficacious than placebo in the treatment of bipolar depression. However, it is associated with a 1/1000 risk of potentially fatal Stevens-Johnson syndrome. Gabapentin, although safe and well-tolerated, has been found in two double-blind studies not to be efficacious in treatment-refractory mania or refractory bipolar depression. Topiramate is currently supported only by naturalistic evidence of mild to moderate mood-stabilizing efficacy, but it has the advantage of often producing weight loss. Based on these data, lamotrigine may be effective, in monotherapy or as an adjunct, for treating depression in type I bipolar disorder, but suggestions regarding gabapentin and topiramate await further efficacy data. Most of the current findings derive from small, non-double-blind studies, and further research is required before clinicians can consider any of these agents to be mood stabilizers.

INTRODUCTION The present study is aimed at investigating possible predictors of response to ziprasidone in a sample of patients with mixed depressive state. METHODS 72 patients were randomized to either ziprasidone or placebo and treated prospectively for 6 weeks. The clinical response and remission were defined with various clinical variables including Montgomery Asberg Depression Rating Scale. Further outcome measures included predictors of remission and other clinical variables over time. RESULTS None of the variables under investigation were significantly associated with response or remission at 6 weeks (all p-values>0.003, respectively). CONCLUSIONS Further investigations are warranted due to clear limitations, mostly small sample size and use of concomitant medications.

Background We sought to examine correlations between clinical validators and temperaments in clinical practice. Methods We provided the self-report TEMPS-A (50 item long) to 123 consecutive patients seen in the Mood Disorders Program of Tufts Medical Center. Temperament was assessed as cyclothymia, dysthymia, irritable or hyperthymia. Cut-offs were tested using (50%) and (75%) thresholds of affirmative responses, as well as highest percent for dominant temperament. We reported no dominant temperament at 75% cut-off . Multivariate regression modeling was conducted to assess confounding bias. Results Using clinical and demographic validators, cyclothymia was the most strongly validated temperament, followed by dysthymia and hyperthymia. Irritable temperament did not appear to be valid in this sample. A 75% item endorsement cut-off appeared to identify clinically important temperaments in slightly less than half of this sample. Those without any temperament at 75% cut-off had better prognostic features. 50% cut-off was highly nonspecific, and poorly correlated with diagnostic validators. Conclusions Affective temperaments correlate with clinical validators, most robustly for cyclothymia. 75% cut-off on the TEMPS may provide a useful categorical definition of abnormal affective temperaments in mood disorders. With that definition, slightly less than one-half of patients with mood disorders have affective temperaments. Those without abnormal affective temperaments have better prognostic features.

Long-term antidepressant (AD) treatment for depression in bipolar disorder (BPD) patients is highly prevalent, but its benefits and risks remain uncertain, encouraging this meta-analysis of available research.We reviewed randomized controlled trials for BPD involvingor=6 months of treatment with AD +/- mood stabilizer (MS) vs. placebo +/- MS, using meta-analyses to compare reported risks of new depression vs. mania.In seven trials (350 BPD patients) involving 12 contrasts, long-term treatments that included ADs yielded 27% lower risk of new depression vs. MS-only or no treatment [pooled relative risk, RR = 0.73; 95% CI 0.55-0.97; number-needed-to-treat (NNT) = 11], but 72% greater risk for new mania [RR = 1.72; 95% CI 1.23-2.41; number-needed-to-harm (NNH) = 7]. Compared with giving an MS-alone, adding an AD yielded neither major protection from depression (RR = 0.84; 95% CI 0.56-1.27; NNT = 16) nor substantial increase in risk of mania (RR = 1.37; 95% CI 0.81-2.33; NNH = 16).Long-term adjunctive AD treatment was not superior to MS-alone in BPD, further encouraging reliance on MSs as the cornerstone of prophylaxis.

Objective: To assess frequencies of types of publications about bipolar disorder (BD) and evaluate methodological quality of treatment studies. Method: We classified 100 randomly selected articles (1998–2002) from five psychiatric journals with highest impact ratings, by topic areas, and assessed methods employed in treatment studies. Results: Topics ranked: treatment (41%; 37% on pharmacotherapy) > biology (31%) > psychopathology (14%) = miscellaneous (14%). Of treatment studies, only 19% of original articles were randomized, 15% were relatively large (n ≥ 50) but non-randomized, 65% were small non-randomized, case-series or -reports, and 53% relied on baseline-to-endpoint contrasts without a control group. Patient dropout rates were ≥40% in 43% of prospective studies. Only two reports provided confidence intervals; one included a power analysis, and 53% included no references on study design or statistical methods. Conclusion: Even in highly respected journals, the typical methodological quality of recent reports on therapeutics for BD was unexpectedly limited, and psychopathology and psychotherapies were little studied.

The objective of this paper was to determine if topiramate is effective as treatment for bipolar spectrum disorders in a naturalistic setting. All charts of outpatients treated with topiramate (n = 76) were reviewed, and clinical response was assessed retrospectively using the Clinical Global Impressions Scale for Improvement. Mild improvement was seen in 47% (n = 36) and moderate-to-marked improvement in 13% (n = 10). Responders received a higher mean dose (180 mg/day) than did nonresponders (83.2 mg/day, p = 0.002). Topiramate dose was also higher in those who lost weight (138.3 mg/day) than in those who did not (70 mg/day, p = 0.007). Weight loss was experienced by 50% of the sample, with a mean loss of 14.2 lbs. Side effects were reported by 82% (n = 62) of the population, including cognitive effects, sedation, parasthesias, nausea, insomnia, headache, and dizziness. Adverse effects led 36% (n = 27) of the total sample to discontinue treatment with topiramate. Topiramate led to significant weight loss in about half of this bipolar population, while also improving mood symptoms at least mildly in most patients. Topiramate response and weight loss were both dose-related, with efficacy, in particular, associated with higher doses (mean = 180 mg/day) than frequently used in current clinical practice.

Until 1980, manic depressive illness (MDI) was defined as follows: the presence of recurrent severe depressive or manic episodes alternating with periods of normal mood or markedly decreased mood symptoms.[1][1] In that year, the DSM-III rejected this definition of MDI and replaced it with two

Mood-stabilizing agents are ideally conceptualized as possessing antimanic and antidepressant properties. While research on olanzapine's antimanic effects is growing, data on its possible antidepressant properties are limited. We sought to determine if olanzapine is effective in the add-on treatment of major affective disorders, particularly depressive symptoms, in a naturalistic setting.All charts of patients meeting DSM-IV criteria for bipolar disorder or unipolar major depressive disorder treated with olanzapine in a private psychiatric practice were reviewed and clinical response was assessed retrospectively using the Clinical Global Impression Scale for Improvement (CGI-I).Olanzapine was moderately effective in 6/10 (60%) patients. Side-effects were present in 8/10 (80%), most commonly weight gain.Olanzapine appears to be moderately effective in open add-on treatment in patients with mainly depressive symptoms. Accumulating evidence suggests that olanzapine, and atypical antipsychotics in general, possess mild to moderate adjunctive antidepressant properties.

To assess cholesterol levels in patients with mood disorders.All consecutively admitted patients meeting inclusion criteria (n = 50) who were hospitalized in an affective disorders unit received assessments of cholesterol levels. Correlations were made with diagnosis using DSM-IV criteria, current mood states, and other clinical and demographic features of illness. Exclusion criteria included current alcohol abuse, medical illnesses that could influence cholesterol levels, eating disorders, and age greater than 70 years.Cholesterol levels did not differ based on diagnostic status of unipolar depression or bipolar disorder. In the total sample, cholesterol levels were lower in patients with current manic (170.2 +/- 38.9, p = 0.05) and depressive (182.0 +/- 42.0) than in mixed (226.4 +/- 43.3) episodes (p = 0.05). In subgroups of patients with bipolar disorder, manic episodes (169.9 +/- 38.8, n = 9) were associated with lower cholesterol levels than depressive (201.0 +/- 49.4) or mixed (226.4 +/- 44.4) episodes (p = 0.02 for comparison of manic and mixed episodes). Body mass index (BMI), age, alcohol use, and gender did not account for these findings.Cholesterol levels were lower in manic and depressive than in mixed episodes. No differences were found between diagnoses of unipolar or bipolar mood disorders. Cholesterol may be a state rather than a trait function, and may be influenced by the acute mood state.

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.A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'.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.Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.

With the availability of newer, safer antidepressants in the past decade, initiation of definitive treatment for depression in the emergency setting has become an accepted practice. However, the use of newer antidepressants and atypical antipsychotics in depression complicated by psychosis or agitation has not yet been well studied. This article will review relevant data and make recommendations for the emergency management of psychotic and agitated depressive syndromes.

Atypical neuroleptic agents are an excellent, safer, and more effective alternative to the widespread practice of maintenance adjunctive treatment with traditional neuroleptic agents in patients with bipolar disorder. Currently, a number of prospective studies are available with clozapine, risperidone, olanzapine, and quetiapine in the treatment of bipolar disorder. Most are short-term studies, although longer-term data are becoming available. Four double-blind studies of acute mania have been conducted with risperidone and olanzapine, leading to recent Food and Drug Administration approval for olanzapine in the indication of acute mania. Given the limited longer-term data, and the evidence for mostly adjunctive benefits with these agents, it seems unlikely that these agents will prove to be primary mood stabilizers in their own right. Nonetheless, they serve an important role as adjunctive treatments along with standard mood stabilizers in the rational polypharmacy of bipolar disorder. To date, differences in efficacy have not been established. However, differences in the side effect of weight gain may be even more relevant in bipolar disorder than in schizophrenia due to the need to use standard mood stabilizers that often potentiate such weight gain.

To assess the effectiveness and safety of pramipexole as an adjunctive medication in refractory bipolar and unipolar depression in a naturalistic setting.Retrospective chart review by psychiatrists on staff at a university hospital identified all patients who had received pramipexole. Response was based on moderate to marked improvement in the Clinical Global Impression-Improvement (CGI-I) scale.Pramipexole (mean dose 0.70 mg/d, mean duration 24.4 weeks) was effective in 6/12 (50.0%) of patients with bipolar depression, and 8/20 (40%) of patients with unipolar depression, mean duration of follow-up of 24.4 weeks. One case of transient hypomania was noted. Eight patients discontinued pramipexole due to lack of response and four due to side effects.Pramipexole, used as an adjunct to antidepressants or mood stabilizers, appeared to be effective and safe in the treatment of unipolar and bipolar depression. These uncontrolled, retrospective, naturalistic pilot data require confirmation by controlled research before conclusions can be made.