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McElroy SL, Kemp DE, Friedman ES, Reilly-Harrington NA, SylviaLG, Calabrese JR, Rabideau DJ, Ketter TA, Thase ME, Singh V,Tohen M, Bowden CL, Bernstein EE, Brody BD, Deckersbach T,Kocsis JH, Kinrys G, Bobo WV, Kamali M, McInnis MG, Leon AC,Faraone S, Nierenberg AA, Shelton RC. Obesity, but not metabolicsyndrome, negatively affects outcome in bipolar disorder.Objective: Examine the effects of obesity and metabolic syndrome onoutcome in bipolar disorder.Method: The Comparative Effectiveness of a Second GenerationAntipsychotic Mood Stabilizer and a Classic Mood Stabilizer forBipolar Disorder (Bipolar CHOICE) study randomized 482participants with bipolar disorder in a 6-month trial comparing lithium-and quetiapine-based treatment. Baseline variables were comparedbetween groups with and without obesity, with and without abdominalobesity, and with and without metabolic syndrome respectively. Theeffects of baseline obesity, abdominal obesity, and metabolic syndromeon outcomes were examined using mixed effects linear regressionmodels.Results: At baseline, 44.4% of participants had obesity, 48.0% hadabdominal obesity, and 27.3% had metabolic syndrome; neitherobesity, nor abdominal obesity, nor metabolic syndrome wereassociated with increased global severity, mood symptoms, orsuicidality, or with poorer functioning or life satisfaction. Treatmentgroups did not differ on prevalence of obesity, abdominal obesity, ormetabolic syndrome. By contrast, among the entire cohort, obesity wasassociated with less global improvement and less improvement in totalmood and depressive symptoms, suicidality, functioning, and lifesatisfaction after 6 months of treatment. Abdominal obesity wasassociated with similar findings. Metabolic syndrome had no effect onoutcome.Conclusion: Obesity and abdominal obesity, but not metabolicsyndrome, were associated with less improvement after 6 months oflithium- or quetiapine-based treatment.

Objective Our aim was to investigate the prevalence and magnitude of weight gain in-patients with bipolar disorder when treated with a second-generation antipsychotic as an add-on treatment to a mood stabilizer in routine clinical practice. Methods Data were derived from the quality register for bipolar disorder in Sweden (BipolaR). Patients with bipolar disorder who started add-on treatment with a SGA (n = 575) were compared at next yearly follow-up with age and sex matched patients who were only treated with a mood stabilizer (n = 566). The primary outcome measure was change in body weight and body mass index (BMI). We also assessed the prevalence of clinically significant weight gain defined as ≥7% gain in body weight. Results The group that received add-on treatment with antipsychotics neither gained more weight nor were at higher risk for a clinically significant weight gain than the reference group. Instead, factors associated with clinically significant weight gain were female sex, young age, low-baseline BMI, and occurrence of manic/hypomanic episodes. Conclusion We found no evidence of an overall increased risk of weight gain for patients with bipolar disorder after receiving add-on SGA to a mood stabilizer in a routine clinical setting.

OBJECTIVE: Duration of untreated illness represents a potentially modifiable component of any diagnosis-treatment pathway. In bipolar disorder (BD), this concept has rarely been systematically defined or not been applied to large clinically representative samples. METHOD: In a well-characterized sample of 501 patients with BD, we estimated the duration of untreated bipolar disorder (DUB: the interval between the first major mood episode and first treatment with a mood stabilizer). Associations between DUB and clinical onset and the temporal sequence of key clinical milestones were examined. RESULTS: The mean DUB was 9.6 years (SD 9.7; median 6). The median DUB for those with a hypomanic onset (14.5 years) exceeded that for depressive (13 years) and manic onset (8 years). Early onset BD cases have the longest DUB (P < 0.0001). An extended DUB was associated with more mood episodes (P < 0.0001), more suicidal behaviour (P = 0.0003) and a trend towards greater lifetime mood instability (e.g. rapid cycling, possible antidepressant-induced mania). CONCLUSION: Duration of untreated bipolar disorder (DUB) will only be significantly reduced by more aggressive case finding strategies. Reliable diagnosis (especially for BD-II) and/or instigation of recommended treatments is currently delayed by insufficient awareness of the early, polymorphous presentations of BD, lack of systematic screening and/or failure to follow established guidelines.

Germana C, Kempton MJ, Sarnicola A, Christodoulou T, Haldane M, Hadjulis M, Girardi P, Tatarelli R, Frangou S. The effects of lithium and anticonvulsants on brain structure in bipolar disorder. Objective: To investigate the effect of lithium, anticonvulsants and antipsychotics on brain structure in bipolar disorder (BD). Method: A cross-sectional structural brain magnetic resonance imaging study of 74 remitted patients with BD, aged 18–65, who were receiving long-term prophylactic treatment with lithium or anticonvulsants or antipsychotics. Global and regional grey matter, white matter, and cerebrospinal fluid volumes were compared between treatment groups. Results: Grey matter in the subgenual anterior cingulate gyrus on the right (extending into the hypothalamus) and in the postcentral gyrus, the hippocampus/amygdale complex and the insula on the left was greater in BD patients on lithium treatment compared to all other treatment groups. Conclusion: Lithium treatment in BD has a significant effect on brain structure particularly in limbic/paralimbic regions associated with emotional processing.

Objective: In a previous paper, we reported about the efficacy of the addition of lamotrigine to lithium in patients with bipolar depression. In the second phase of this study paroxetine was added to ongoing treatment in non-responders. Method: Bipolar depressed patients (n = 124) treated with lithium were randomized to addition of lamotrigine or placebo. In non-responders after 8 weeks, paroxetine 20 mg was added for another 8 weeks to ongoing treatment. Results: After 8 weeks the improvement in patients treated with lamotrigine vs. patients treated with placebo was significant. After addition of paroxetine this difference disappeared as a result of greater further improvement in the non-responders to placebo. Conclusion: Addition of lamotrigine to lithium was found effective in bipolar depressed patients. Further addition of paroxetine in non-responders to lithium plus lamotrigine did not appear to provide additional benefit, while it appeared to do so in non-responders to lithium plus placebo.

Objective: Schizoaffective disorder is a common diagnosis in mental health services. The aim of the present article was to review treatment studies for schizoaffective disorder and draw conclusions for clinical decision making. Method: We searched MEDLINE and Cochrane Library for relevant clinical trials and review articles up to the year 2008. Results: Thirty-three studies using standardized diagnostic criteria, 14 of which were randomized controlled trials, could be identified. The comparability of studies is limited by the use of different diagnostic criteria. The studies reviewed do not permit consistent recommendations as to whether schizoaffective disorder should be treated primarily with antipsychotics, mood stabilizers or combinations of these drugs. The relevance of diverse subtypes of schizoaffective disorder for treatment recommendations is unclear. Conclusion: The pertinent empirical database is small and heterogeneous. The lack of conclusive recommendations is related to issues of nosological status, plurality of diagnostic criteria and validity of the concept of schizoaffective disorder.

Tondo L, Vazquez G, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Objective: To review available data pertaining to risk of mania–hypomania among bipolar (BPD) and major depressive disorder (MDD) patients with vs. without exposure to antidepressant drugs (ADs) and consider effects of mood stabilizers. Method: Computerized searching yielded 73 reports (109 trials, 114 521 adult patients); 35 were suitable for random effects meta-analysis, and multivariate-regression modeling included all available trials to test for effects of trial design, AD type, and mood-stabilizer use. Results: The overall risk of mania with/without ADs averaged 12.5%/7.5%. The AD-associated mania was more frequent in BPD than MDD patients, but increased more in MDD cases. Tricyclic antidepressants were riskier than serotonin-reuptake inhibitors (SRIs); data for other types of ADs were inconclusive. Mood stabilizers had minor effects probably confounded by their preferential use in mania-prone patients. Conclusion: Use of ADs in adults with BPD or MDD was highly prevalent and moderately increased the risk of mania overall, with little protection by mood stabilizers.

Objective: The purpose of this study was to evaluate the efficacy of adding folic acid to sodium valproate in the acute phase of mania. Method: Following a double-blind randomized controlled trial, 88 clinically manic patients with diagnosis of type I bipolar disorder (BID) were divided randomly into two groups (case and control). The case group was treated with folic acid and sodium valproate and the control group with sodium valproate and placebo. The severity of mania was assessed using the Young Mania Rating Scale (YMRS) at the beginning and end of the first, second and third weeks of the study. Results: The case group’s mean manic YMRS measurements (SD) before the initiation of therapy and in the first, second and third weeks of treatment were 34.0 ± 7.7, 26.7 ± 2.1, 18.1 ± 2.1 and 7.1 ± 0.9 respectively. The control group’s measurements were 34.7 ± 3.8, 27.3 ± 2.3, 20.7 ± 2.5 and 10.1 ± 1.1. There was a statistically significant difference in YMRS scaling results between the case and control groups after 3 weeks of treatment (7.1 ± 0.9 vs. 10.1 ± 1.1, P = 0.005). Conclusion: Based on our findings, folic acid seems to be an effective adjuvant to sodium valproate in the treatment of the acute phase of mania in patients with bipolar disorder.

Objective: To assess the relationship between depressive relapse and change in thyroid function in an exploratory post hoc analysis from a controlled maintenance evaluation of bipolar I disorder. Method: Mean thyroid-stimulating hormone (TSH) and outcome data were pooled from two 18-month, double-blind, placebo-controlled, maintenance studies of lamotrigine and lithium monotherapy. A post hoc analysis of 109 subjects (n = 55 lamotrigine, n = 32 lithium, n = 22 placebo) with serum TSH values at screening and either week 52 (±14 days) or study drop-out was conducted. Results: Lithium-treated subjects who required an intervention for a depressive episode had a significantly higher adjusted mean TSH level (4.4 μIU/ml) compared with lithium-treated subjects who did not require intervention for a depressive episode (2.4 μIU/ml). Conclusion: Lithium-related changes in thyroid function are clinically relevant and should be carefully monitored in the maintenance phase of bipolar disorder to maximize mood stability and minimize the risk of subsyndromal or syndromal depressive relapse.

Objective: The study aimed to increase the knowledge about the detailed course differences between different forms of bipolar disorder. Method: Using the prospective life-chart-clinician version, we compared the fine-grain analysis of mood swings and treatment modalities of 18 bipolar II with 31 bipolar I patients. Results: During an observational period of a mean of 26 months we observed an increase of euthymic days, and a decrease of (sub)depressive and (hypo)manic days. Days in a (sub)depressed state were more frequent than days of (hypo)mania as well as days of subdepression or hypomania in comparison to days of full-blown depression or mania. Bipolar II patients showed an increase in hypomanic days receiving more frequently antidepressants. Bipolar I patients, with a decrease of manic days, were significantly taking more often mood stabilizers. Conclusion: Treatment in a specialized bipolar clinic improves the overall outcome, but bipolar II disorder seems to be still treated sub-optimally with a possible iatrogenic increase of hypomanic days.

Objective: To provide clinically relevant evidence-based recommendations for the management of bipolar disorder in adults that are informative, easy to assimilate and facilitate clinical decision-making. Method: A comprehensive literature review of over 500 articles was undertaken using electronic database search engines (e.g. MEDLINE, PsychINFO and Cochrane reviews). In addition articles, book chapters and other literature known to the authors were reviewed. The findings were then formulated into a set of recommendations that were developed by a multidisciplinary team of clinicians who routinely deal with mood disorders. These preliminary recommendations underwent extensive consultative review by a broader advisory panel that included experts in the field, clinical staff and patient representatives. Results: The clinical practice recommendations for bipolar disorder (bipolar CPR) summarise evidence-based treatments and provide a synopsis of recommendations relating to each phase of the illness. They are designed for clinical use and have therefore been presented succinctly in an innovative and engaging manner that is clear and informative. Conclusion: These up-to-date recommendations provide an evidence-based framework that incorporates clinical wisdom and consideration of individual factors in the management of bipolar disorder. Further, the novel style and practical approach should promote their uptake and implementation.

Objective: To review the literature on the efficacy and safety of depot formulations of first- and second-generation antipsychotic medications (FGAs and SGAs) in patients with bipolar disorder. Method: We conducted a computer-aided MEDLINE search using the search terms ‘depot antipsychotic’, ‘bipolar disorder’ and ‘compliance.’ Results: We identified eight published reports in bipolar patients regarding the use of depot FGAs, and six preliminary reports on the use of depot SGAs. These studies suggest that depots FGAs are efficacious in preventing manic episodes during the maintenance treatment of bipolar disorder. Several studies, however, indicate that depot FGAs may be associated with increased time with depressive symptoms, particularly in patients with a predominantly depressive course of illness. Preliminary data on the role of depot formulations of SGAs suggest that they reduce the frequency of both manic and depressive episodes during maintenance treatment, and are well tolerated by patients. Conclusion: After a careful risk–benefit analysis, depot antipsychotics may be considered for the long-term control of mood episodes in bipolar patients who have relapsed due to medication non-adherence or who have failed to respond to standard therapies. Depot FGAs should be avoided in patients with a high burden of illness from depressive symptoms and particularly in those judged to be at high risk of suicide. The available data on depot formulations of SGAs indicate that they are efficacious in the maintenance treatment of bipolar illness without increasing the burden of the depressive pole of the illness, but further systematic studies are required to definitively assess this.

Objective: To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants.Method: Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study.Results: Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02).Conclusions: There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded.

Objective To detail the disconnect between the quantified efficacy of the mood stabilizer lamotrigine in its registration controlled trials and its later judged clinical effectiveness and consider some determinants of disconnects between some efficacy trial findings and ‘real-world’ clinical effectiveness judgments. Method Published articles considering lamotrigine as a treatment for the bipolar I or II disorders were selected for review. While randomized controlled trials were weighted, we also consider open trials and effectiveness observations from clinician researchers and demonstrate that lamotrigine has been quite variably judged over time. Results We suggest that the early trials evaluating lamotrigine for acute bipolar disorder depression focused on a suboptimal clinical target, and in so doing, ensured less lamotrigine efficacy compared with trials of bipolar disorder preventative treatment. Moreover, a number of additional methodological limitations compromised analyses. We also detail variable reporting of actual study results. The initial sharp disconnect (between efficacy and effectiveness judgments) has narrowed as lamotrigine has been evaluated and progressively taken up as a maintenance mood stabilizer. Conclusion The lamotrigine disconnect story provides a number of salutary lessons that are salient to evaluating the effectiveness and ecological niche of any psychotropic medication. The lamotrigine story presented here argues strongly for the wisdom of encouraging an iterative process between efficacy studies and clinical observation.

Objective: To review the pharmacological basis of antidepressant potentiation in combination therapy and the clinical evidence for its efficacy. Method: Literature searches were undertaken and the results reviewed. Results: Treatment-resistant depression is common (15–30%). Various strategies exist for dealing with resistant depression, including pharmacological potentiation, i.e. adding a treatment that itself does not have antidepressant actions but that enhances the efficacy of the original treatment. Lithium, triiodothyronine (T3) and buspirone are the best studied potentiating drugs, although other options include pindolol, dopaminergic agents, second-generation antipsychotics, psychostimulants, hormones and anticonvulsants. Conclusion: Several pharmacological potentiation strategies exist. Whilst good evidence exists for lithium combined with antidepressants, although good results have also been reported with augmentation strategies involving T3 or buspirone.

Objective: To review the clinical trials literature on the use of antiepileptic drugs (AED) as mood stabilizers and to suggest an evidence-based approach when utilizing these agents in bipolar disorder. Method: The literature is reviewed and subdivided into the following sections: carbamazepine and oxcarbazepine, valproate, lamotrigine, gabapentin and other AED, and discussion. Results: Data exist to support the use of carbamazepine and valproate – and to a lesser extent, oxcarbazepine – in the management of acute manic episodes associated with bipolar I disorder. Lamotrigine, gabapentin, and other AED have not demonstrated consistent anti-manic effects. Clinical trials data favor lamotrigine over all other AED in the treatment of acute bipolar I depression and in rapid cycling bipolar disorder (particularly type II), although the absence of an active comparator in these lamotrigine trials must be noted. Lamotrigine, carbamazepine, and valproate all have evidence supporting their roles as potential long-term mood stabilizers to prevent bipolar relapse, with lamotrigine having a stronger effect in the prevention of depression. Conclusion: The AED are a heterogeneous group of medications with differential spectrum of efficacy in the treatment of bipolar disorder.

Objective: To assess the potential role of atypical antipsychotics as mood stabilizers. Method: A MedLine, PsychLIT, PubMed, and EMBASE literature search of papers published up to December 2004 was conducted using the names of atypical antipsychotics and a number of key terms relevant to bipolar disorder. Additional articles were retrieved by scrutinizing the bibliographies of review papers and literature known to the authors. Data pertinent to the objective was reviewed according to the various phases of bipolar disorder. Results: The data is most substantive for the use of atypical antipsychotics in mania, to the extent that an argument for a class effect of significant efficacy can be made. This does not extend to bipolar depression, however, good data is now emerging for some agents and will need to be considered for each individual agent as it accumulates. As regards mixed states and rapid cycling the evidence is thus far sparse and too few maintenance studies have been conducted to make any firm assertions. However, with respect to long-term therapy the atypical antipsychotics do have clinically significant side-effects of which clinicians need to be aware. Conclusion: Based on the evidence thus far it is perhaps premature to describe the atypical antipsychotics as mood stabilizers. Individual agents may eventually be able to claim this label, however, much further research is needed especially with respect to maintenance and relapse prevention. Copyright © Blackwell Munksgaard 2005.

A subcommittee under the Danish Psychiatric Association and the Child and Adolescent Psychiatric Association in Denmark have recently developed national guidelines for the psychopharmacological treatment with lithium and antiepileptic drugs, and the present translation aims at contributing to the international discussion on the development of proper guidelines for the treatment of bipolar disorder. Among the antiepileptic drugs, the report deals with valproate, carbamazepine and lamotrigine and to a lesser extent with oxcarbazepine, gabapentin and topiramate. The various drugs will be reviewed, outlining the scientific evidence for mood-stabilizing properties and discussing major side effects, the most important interactions with other drugs and practical use. Special considerations during pregnancy and lactation, during treatment of children and adolescents and during treatment of the elderly will also be presented. Antidepressants and antipsychotics are beyond the scope of the report, but due to the mood-stabilizing properties of at least some of the atypical antipsychotics, these agents will be brought into some focus in connection with the overall treatment guidelines for the different phases of bipolar disorder given at the end of this report.

Objective: To compare responses to long-term treatment of rapid-cycling (RC) vs. non-RC bipolar disorder patients and assess relative effectiveness of specific agents in RC patients. Method: Studies identified by literature searching were analyzed for effects of RC status and treatment-type on clinical outcome (recurrence or non-improvement per exposure-time), using random-effects methods to estimate pooled rates and their 95% CI for quantitative meta-analytic modeling. Results: Data were obtained from 16 reports with 25 trial-arms involving 1856 (905 RC and 951 non-RC) patients treated with carbamazepine, lamotrigine, lithium, topiramate, or valproate, alone or with other agents over an average of 47.5 months (7347 total patient-years). Estimated RC prevalence was 15.4%. Crude rates (%/month) of recurrence (2.31/1.20) and clinical non-improvement (1.93/0.49) averaged 2.9-fold greater in RC vs. non-RC subjects. The pooled RC/non-RC risk ratio (RR) for inferior treatment-response (in 13 direct comparisons) was 1.40 (CI 1.26—1.56; P

Objective: This study investigated the impact of latency (the time between illness onset and initiation of prophylactic treatment) on the outcome of prophylaxis in bipolar disorders. Method: The effect of prophylaxis delay (latency) on the course of illness was assessed in 147 patients. Dependent variables were: reduction of days spent in the hospital (prior to vs. during prophylaxis), time to first recurrence, and Morbidity-Index during prophylaxis (lithium or carbamazepine). Latency and other independent variables were tested using a multivariate approach. Results: Latency (9.3 years on average) had no significant effect on the subsequent response. Illness severity prior to prophylaxis, however, did predict the relative response. The course of illness during treatment could not be predicted by any one factor. Conclusion: The delay in initiating prophylaxis appears to have no influence on prophylaxis outcome. Instead, those whose illness was more severe were treated earlier and these patients subsequently showed a relatively greater response. If severity is not controlled for as part of the analysis, latency may be mistaken as an important predictor for response.

Objective: The treatment of bipolar depression is a significant clinical problem that remains understudied. The role for antidepressant (AD) agents vs. mood stabilizers has been particularly problematic to ascertain. Method: Detailed life charting data from 42 patients with 67 depressive episodes were reviewed. Response rates and rates of switch into mania were compared based on the preceding mood state and on whether an AD or mood stabilizing (MS) agent was added following onset of depression. Results: Patients who became depressed following a period of euthymia were more likely to respond to treatment (62.5%) than patients who became depressed following a period of mania or hypomania (27.9%). The ratio of response to switch for previously euthymic patients was particularly favorable. Conclusion: Mood state prior to onset of depression in bipolar disorder appears to be an important clinical variable that may guide both choice of treatment administered and expectation of outcome to treatment.

Objective: The aim of this paper is to review the prevalence, predictors and methods for improving medication adherence in unipolar and bipolar affective disorders. Method: Studies were identified through Medline and PsycLit searches of English language publications between 1976 and 2001. This was supplemented by a hand search and the inclusion of selected descriptive articles on good clinical practice. Results: Estimates of medication non-adherence for unipolar and bipolar disorders range from 10 to 60% (median 40%). This prevalence has not changed significantly with the introduction of new medications. There is evidence that attitudes and beliefs are at least as important as side-effects in predicting adherence. The limited number of empirical studies of how to reduce non-adherence offer encouraging evidence that, if recognized, the problem can be overcome. Conclusion: Only 1–2% of all publications on the treatment of affective disorders explore factors associated with medication non-adherence. This is disappointing as research and clinical data highlight the importance of extended courses of medication in improving the long-term prognosis of affective disorders.

Objective: A number of studies have suggested that lithium may be particularly effective in reducing suicide risks among patients with major affective disorders. The design of many of these studies left them open to biases associated with treatment compliance, however. Method: Subjects were drawn from a naturalistic, long-term follow-up of patients with major affective disorders. Fifteen who committed suicide while receiving somatotherapy where matched to non-suicidal patients who were similarly receiving somatotherapy at the same point in follow-up. The same procedure was followed for 41 patients who made a serious suicide attempt during follow-up. Results: Six (40.0%) of the patients who committed suicide, and eight (53.3%) of their controls, were thought to have been taking lithium in the preceding week. Among attempters and their controls, nine (22.0%) and eight (19.5%), respectively, were taking lithium. Conclusion: These results do not support previous suggestions that lithium has uniquely antisuicidal properties. Other existing datasets should be explored with this design to establish whether lithium does, or does not, offer special protection against suicide.

Objective: To compare suicide rates with vs. without long-term lithium treatment in major affective disorders. Method: Broad searching yielded 22 studies providing suicide rates during lithium maintenance; 13 also provide rates without such treatment. Study quality was scored, between-study variance tested, and suicide rates on vs. off lithium examined by meta-analyses using random-effects regression methods to model risk ratios. Results: Among 5647 patients (33 473 patient-years of risk) in 22 studies, suicide was 82% less frequent during lithium-treatment (0.159 vs. 0.875 deaths/100 patient-years). The computed risk-ratio in studies with rates on/off lithium was 8.85 (95% CI, 4.12–19.1; P

Objective: Typical antipsychotics have their indication in the ultra-short (first week) treatment of severe episodes of mania. In this setting the Bech–Rafaelsen Mania Scale (MAS) was psychometrically compared with the Clinical Global Impression scale (CGI) to assess its ability to measure response. Method: Ratings on patients with marked to severe mania (n=80) who participated in the clinical trials to evaluate the ultra-short antimanic effect of zuclopenthixol acetate were assessed. The MAS was analysed for internal validity (total score a sufficient statistic) and for external validity. Results: The MAS was shown to have a high internal validity showing onset of action already after days of treatment. After 6 days of treatment 53% of the patients responded according to the MAS but only 30% according to the CGI. The difference was statistically significant. Conclusion: The MAS has been found to be a valid scale to measure early onset of action and response in the ultra-short antimanic treatment with typical antipsychotics.

Objective: Bipolar disorder starts typically in early age and late-onset cases are rare. Late-onset cases are more likely to have comorbid medical illnesses responsible for them. This case report highlights late-onset bipolar disorder due to hyperthyroidism. Method: A 65-year-old patient of bipolar disorder has been described. Result: Physical examination and laboratory investigations detected presence of hyperthyroidism and the patient was treated with antithyroid and anxiolytics. Conclusion: A thorough examination and investigation are required in late-onset cases of bipolar disorder to rule out secondary causes. Definitive antimanic agents or mood stabilizers may not be required in such cases.

Objective: Bipolar disorder in children and adolescents is less well studied than bipolar disorder in adults. This review addresses issues related to its underdiagnosis, precursors of bipolarity, comorbidity, natural course and treatment. Method: Literature from Medline and other searches, and earlier relevant articles including references from recent review articles on juvenile bipolarity were reviewed. Results: Bipolar disorder in juveniles is underdiagnosed and misdiagnosed on various counts. Few recent studies have reported high rates of comorbid attention deficit and disruptive disorders, prompting some researchers to consider them as probable developmental precursors of juvenile bipolarity. There is also evidence to suggest that some juvenile depression could be pre-bipolar, and that certain temperamental predispositions are probable precursors to bipolarity. Limited data on the natural course and outcome suggest that juvenile bipolar disorder is a highly recurring illness as in adults, and that it is associated with significant functional impairment. The psychopharmacological treatment of juvenile bipolar disorder is remarkably understudied, and treatment is often based on studies of adults. Conclusion: There is a need for epidemiological studies of juvenile bipolar disorder. Similarly, there is an urgent need for the methodologically rigorous studies to establish the efficacy of various antimanic drugs. Finally, issues related to comorbidity and temperamental predispositions to juvenile bipolarity need greater clarity, as they may have important treatment and research implications.

While lithium is generally considered to be a first-line treatment for mania, the position of the anticonvulsants and the antipsychotics in the treatment of this disorder is currently under debate. For that reason, this paper reviews the original literature, in particular addressing the randomized controlled trials (RCTs) on lithium, anticonvulsants and antipsychotics, and the methodological limitations therein. As the treatment of mania needs to anticipate the future course of the illness, the data on prophylaxis will also be reviewed, albeit briefly. It is concluded that antipsychotics are powerful antimanics, which are particularly beneficial for some clinical presentations of severe mania. However, in general their use should not be prolonged into the maintenance phase. Lithium is still to be considered the mood-stabilizing drug par excellence, although it may be insufficient in mixed states and severe mania. The evidence for antimanic efficacy of valproate, in particular for mixed states, seems more convincing than that for carbamazepine, while the evidence for a prophylactic action of carbamazepine still exceeds that for valproate. Adjunctive treatment with benzodiazepines is often useful. Small sample sizes, highly selected study populations and high drop-out rates seem to be the most important limitations of the RCTs on mania. Quasi-experimental, naturalistic studies on unselected populations are needed to investigate how the various treatments work in clinical practice. Based on the available evidence, summary guidelines for treatment are proposed.

This paper focuses on the importance of data collected not only from controlled clinical trials, but also from naturalistic treatment experience. In particular we examine the use of divalproex sodium either as monotherapy or as part of combined therapy on an in-patient ward for adolescents aged 13-18 years. All admissions in which divalproex sodium use was attempted (n=36) were analysed over a 1-year period. The most common use was in patients with a mixed-presentation bipolar disorder (n=16), followed by patients with major depression (n=7), mania (n=4) or psychoses not otherwise specified (n=4). Divalproex sodium use was evaluated in the control of mania, psychosis, agitation, mood swings, aggression and/or anxiety. Overall, the use of divalproex sodium was associated with a marked improvement along all psychopathological variables in the vast majority of patients. Few side-effects or medical complications were noted. We believe that divalproex sodium is a potentially useful drug in adolescent patients with varying forms of psychopathology.

Objective: Psychiatric manifestations of systemic lupus erythematosus (SLE) are well recognized but usually occur in the later stages of the illness, with organic syndromes being the most common. This case highlights the fact that SLE can present with mania. Method: Single case report. Results: A 32-year-old woman was admitted to hospital with her first manic illness. Physical examination and investigations revealed her to be suffering from SLE although this had not been previously diagnosed. Her physical and psychiatric symptoms settled rapidly following treatment with prednisolone and chlorpromazine. Conclusion: The case emphasizes the polymorphous manifestations of SLE and the importance of considering physical disorders in patients with a first episode of psychosis.

Objective: To describe and integrate observations from bipolar patients responsive to lithium stabilization and their children. Method: Selected findings are described from the clinical and biological investigations of adults meeting research criteria for bipolar disorder and for responsiveness to lithium stabilization; and from prospective studies of the children of lithium responders and non-responders. Results: Response to prophylactic lithium identifies a valid subtype of bipolar disorder, however the search for biological markers of lithium response, while promising, has so far remained inconclusive. Adult responders to lithium stabilization exhibit definable clinical features which are also observable in their affected children. In prospective studies the children of bipolar parents develop symptoms earlier than reported previously, with marked differences between the offspring of lithium responders and non-responders. The illness evolves in predictable clinical stages, first from non-specific sleep and anxiety disorders to mood symptoms and then, often starting in adolescence, major depressive and later activated episodes. Conclusion: Investigating and comparing unequivocal responders and non-responders to long-term lithium treatment and their offspring is a fertile research strategy for addressing a multitude of clinical and research questions.

Objective: To summarize the conceptual and operational definitions of treatment-resistant bipolar depression and to review the evidence-based therapeutic options. Method: Structured searches of PubMed, Index Medicus, Excerpta Medica and Psyclit conducted in December 2008. Results: Criteria for treatment resistance in bipolar depression are commonly based on concepts stemming from treatment resistance as defined for unipolar depression, an approach that proved to be inadequate. In fact, the addition of an ad hoc criterion based on lithium and other mood stabilizer unresponsiveness after reaching adequate plasma levels appears to be a patch that attempts to take into account the uniqueness of bipolar depression but fails to become operational. Recent data from randomized clinical trials of new anticonvulsants and second-generation antipsychotics should lead to the development of a modern definition of treatment-resistant bipolar depression, and specific therapeutic algorithms. Conclusion: We suggest a redefinition of resistant bipolar I and II depression. We propose different degrees of severity within bipolar depression in a stepwise manner.

Amsterdam JD, Wang G, Shults J. Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy. Objective: We examine the safety and efficacy of venlafaxine monotherapy in bipolar type II (BP II) patients with major depressive episode (MDE) who were unresponsive to prior lithium monotherapy. We hypothesized that venlafaxine would be superior to lithium with a low hypomanic conversion rate. Method: Seventeen patients who were unresponsive to prior lithium monotherapy were crossed to venlafaxine monotherapy for 12 weeks. The primary outcome was within-subject change in total Hamilton Depression Rating (HAM-D) score over time. Secondary outcomes included the change in Young Mania Rating (YMRS) and clinical global impressions severity (CGI/S) and change (CGI/C) scores. Results: Venlafaxine produced significantly greater reductions in HAM-D (P

Usher J, Menzel P, Schneider-Axmann T, Kemmer C, Reith W, Falkai P, Gruber O, Scherk H. Increased right amygdala volume in lithium-treated patients with bipolar I disorder. Objective: The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. Method: We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. Results: Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. Conclusion: Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.

One of the predictive factors of treatment-resistant depression is the syndrome of relative insulin resistance, i.e. adipositas, mild hypertension and a family history of type-2 diabetes. Such a case is here reported with a good outcome to anti-stress medication, including ketoconazole and lithium.

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: The aim of this paper was to review the association of most commonly used psychopharmacological drugs with weight gain in bipolar disorder. Method: Information was retrieved from a PubMed/Medline literature search reviewing weight gain in pharmacological studies in bipolar disorder. Results: Obesity and overweight in bipolar disorder are partly related to prescribed drugs with a strong effect of clozapine and olanzapine. Lesser but still relevant weight gain is caused by quetiapine, risperidone, lithium, valproate, gabapentin and by some antidepressants. Ziprasidone, aripiprazole, carbamazepine and lamotrigine do not seem to cause significant overweight. Conclusion: Careful monitoring of weight changes in patients before and after drug prescription should be implemented in the clinical routine and drugs which potentially cause weight gain should be avoided in overweight patients with bipolar disorder. Furthermore, eating habits and daily activities should be targeted as they may also have a significant impact on overall health and weight-related issues.

Objective: Lithium-neuroleptics induced encephalopathy is a rare drug interaction. Here I am reporting a patient who developed reversible encepatholopathy with lithium-risperidone combination. Method: A single case report. Result: A patient of bipolar disorder, who presented with manic symptoms with psychotic feature, started with a combination of lithium and risperidone. Within few days, the patient developed encepatholopathy, which reversed upon discontinuation of lithium and risperidone. Conclusion: Combining lithium and neuroleptic is useful in treatment of bipolar disorder. However, encepatholapthy can be anticipated to result when lithium is used with high potency anti-psychotic such as haloperidol and risperidone and there are baseline EEG abnormalities.

Introduction:? The aim of this meta-analysis was to systematically review the effectiveness of co-therapy compared with monotherapy for people with bipolar mania. Method:? MEDLINE, Embase, Psychinfo, The Cochrane Library and reference lists of retrieved studies were searched without language restrictions for randomized controlled trials evaluating co-therapy compared with monotherapy for acute bipolar mania. Each trial was assessed for susceptibility to bias. Data on mania outcomes, withdrawals, extrapyramidal symptoms and weight were extracted and pooled effect estimates summarized as relative risks (RR) or differences in mean values (MD) where appropriate. Results:? Eight eligible studies were included (1124 participants). Significant reductions in mania (Young Mania Rating Scale, YMRS) scores were shown for haloperidol, olanzapine, risperidone and quetiapine as co-therapy compared with monotherapy with a mood stabilizer. For atypical antipsychotics combined, the pooled difference in mean scores was 4.41 (95% CI: 2.74, 6.07). Significantly more participants on co-therapy met the response criterion (at least 50% reduction in YMRS score), RR 1.53 (1.31, 1.80). With some drugs, co-therapy decreased tolerability compared with monotherapy, and resulted in greater weight gain. There were insufficient data to compare one co-therapy regimen with another. Conclusion:? The addition of antipsychotic treatment to established mood-stabilizer treatment is more effective than mood-stabilizer treatment alone.

Non-compliance is the most frequent cause of recurrence during prophylactic lithium treatment and is associated with poor response and high levels of suicidality. Non-compliance is a complex phenomenon and may have a number of causes. When manic-depressive patients fare badly under the conditions of so-called 'naturalistic' trials, this usually indicates that such conditions are inadequate for long-term maintenance treatment. Prophylactic lithium treatment must be accompanied by measures to sustain compliance and counteract drop-out, and these measures build on three cornerstones, namely information, support and supervision.

Objective: Bipolar disorders are prevalent in women. Women with bipolar disorder often present with different clinical features than men. Reproductive events and hormonal treatments may impact the course of bipolar disorder. Our main objectives are to i) assess the impact of reproductive events on the course of the disorder, and ii) to discuss the relationships between reproductive events and psychiatric treatments. Method: A literature search was conducted of MEDLINE journals from 1965 to present. Manual literature searches were also conducted. We review the presentation, clinical course, and treatment considerations of bipolar disorder in women, with emphasis on treatment considerations in the context of reproductive events. Treatment-related issues such as teratogenicity, breastfeeding, polycystic ovarian syndrome, weight gain and obesity, and medication interactions with oral contraceptives are reviewed. Results: Women with bipolar disorder may be more vulnerable to mood episodes in the context of reproductive events, particularly postpartum. In women of reproductive age, mood stabilizers must be selected with teratogenic risks in mind, with the highest reported risks in pregnancy with valproate, and the greatest concern during breastfeeding with lithium use. In the areas of the perimenopause and polycycstic ovarian syndrome, more data are needed to advise treatment decisions. Conclusion: We urgently need further study in these areas to deliver care that is appropriate to women with bipolar disorder.

Objective: To review the available literature on psychoeducation and cognitive-behavioral therapy (CBT) in bipolar disorder (BD) and to give an integral view of these therapies. Method: Studies were identified through Medline searches in English language publications between 1971 and 2003. This was supplemented by a hand search and the inclusion of selected descriptive articles on good clinical practice. Results: A number of studies demonstrate that psychoeducation enhances adherence to treatment, and one finds that it improves outcome in BD. Other studies find that CBT diminishes depressive symptoms and improves quality of life in BD. Occasionally some adverse effects may occur with psychotherapy and, although they are sporadic, should not be overlooked. Conclusion: When combined with pharmacological treatment, psychoeducation helps to improve adherence. Training in the identification of early manic symptoms helps to improve outcomes and decreases the number of manic relapses in BD.

Objective To determine by meta-analysis the efficacy of mood stabilizers in preventing recurrence of bipolar or unipolar mood disorders and to consider the evidence for a lithium withdrawal-induced relapse syndrome. Method Controlled studies of lithium, valproate and carbamazepine in preventing future episodes of affective disorders were classified according to methodological rigour, and meta-analyses were performed overall and on each type. Results A total of 19 blinded, randomized, controlled trials of prophylaxis in 865 patients found lithium highly effective (74% recurrence on placebo vs. 29% on lithium). In the mirror-image studies, whose substantial lithium vs. prior treatment difference cannot be explained by withdrawal relapse, lithium reduced relapse by 50% (bipolar) and 58% (unipolar). Conclusion Maintenance lithium produces a highly significant reduction in relapses. The mirror-image studies had not been systematically analysed previously, and they support the effectiveness of lithium. We also failed to find sufficient evidence to prove that the lithium-withdrawal relapse phenomenon exists.

The purpose of the study was to examine the outcome of long-term lithium treatment in consecutively admitted affective disorder patients assigned to high and low serum lithium levels. A total of 91 patients were diagnosed according to DSM-III criteria and randomly allocated to two open treatment groups in which prophylactic lithium was administered in high (serum lithium 0.8-1.0 mmol L-1) and low (serum lithium 0.5-0.8 mmol L-1) doses, respectively. The patients were followed for 2 years or until discontinuation of lithium treatment or readmission to hospital for recurrence of affective illness. The main outcome of the treatment groups was compared with Kaplan-Meier survival curves and by Cox regression analysis. A total of 31 patients (34%) completed 24 months of prophylactic lithium treatment without recurrence and readmission to hospital. In total, 18 patients (20%) suffered a recurrence on lithium, and 42 patients (46%) discontinued lithium or were lost to follow-up. No effect of treatment group was seen, either for the total patient group or for the large subgroup of bipolar patients when analysed separately. A number of patients did not maintain their original assignment to the high serum lithium levels group. The results were analysed both according to assignment and according to actual serum lithium levels. Abuse of alcohol or medication was associated with a poor outcome. Only one third of the patients completed 2 years of lithium prophylaxis successfully. No difference in the protection against recurrences was observed between patients maintained on high and low serum lithium levels.

Objective: To provide evidence that some borderline patients with poor prognosis can obtain complete remission. Method: Case of a violent rapist with borderline personality disorder in remission is reported. An attempt was made to reveal the mechanism of recovery in this forensic patient who initially was assessed as psychotherapeutically untreatable. Results: Psychotherapeutic effects and favourable psychosocial factors such as successful college graduation, increased social–emotional capacities and valuable new relationships did also play a very important role in this remission process. Conclusion: Controlled studies are necessary to elucidate the mechanism of recovery among criminal patients with borderline personality disorder in order to provide adequate treatment programmes and to construct more reliable prediction methods for prognosis and reoffending.