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Objectives: To review prescribing practice concerning valproate, an established human teratogen, for the management of bipolar disorder in women of childbearing age., Design: The Prescribing Observatory for Mental Health conducted a baseline clinical audit in the UK, as part of a quality improvement programme., Participants: Six hundred and forty-eight clinical teams from 55 mental health Trusts submitted retrospective treatment data relating to patients with a diagnosis of bipolar disorder., Results: Of the audit sample of 6705 patients, 3854 were 50 years of age or younger. Valproate was prescribed for 24% of women and 43% men in this age group, and the mean dose of valproate was lower in women (1196 mg) than in men (1391 mg). For only half of such women was there documented evidence that information had been provided on the risks for the unborn child and the need for adequate contraception. Valproate was more often used in men to treat mania and aggression, while the most common treatment targets in women were hypomania and relapse prevention., Conclusions: Despite explicit recommendations in national treatment guidelines and published safety alerts and warnings regarding the use of valproate in women of childbearing age, current prescribing of this medication to such women in the context of the treatment of bipolar disorder falls short of best practice, particularly with regard to provision of information regarding the risks associated with exposure to valproate during pregnancy. While women younger than 50 years of age were less likely to be prescribed valproate than men in the same age group, and at a lower dosage, it is unclear to what extent this reflects clinicians' concerns about teratogenicity or is driven by perceptions of the indication for valproate, and the dosage required, for the treatment of different phases of the disorder in men and women., Competing Interests: Competing interests: In the past 3 years, TREB has received speaker fees from Janssen and been a member of scientific advisory boards for Sunovion, Otsuka/Lundbeck and Newron Pharmaceuticals. CP has undertaken consultancy work for Eli-Lilly., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aripiprazole has recently received approval for the treatment of moderate to severe manic episodes in bipolar I disorder and prevention of new manic episodes in aripiprazole-responsive patients. Aripiprazole differs from other antipsychotics in its pharmacology, and the need for prescribing guidance in the UK was recently identified. A UK multidisciplinary panel was convened in November 2007. This report describes the consensus agreed during the meeting on the optimal approach to prescribing aripiprazole: how best to approach initiation of, and switching to, treatment with aripiprazole and management strategies for side effects. A literature review of the randomised controlled clinical trials of aripiprazole in mania supports these recommendations. Aripiprazole should be initiated at 15 mg/day (range 5-20 mg/day). If necessary, adjunctive medication should be used in early treatment to manage side effects or assist in management of symptoms such as agitation. When switching to aripiprazole, the therapeutic dose of current treatment should be maintained while adding aripiprazole 15 (5-20) mg/day. Only once an effective dose of aripiprazole is reached should previous medication be reduced. Nausea, insomnia and agitation typically resolve within days. Some principles for dosing and switching are provided to assist with a successful treatment outcome with aripiprazole in mania.

The objectives of this analysis are to elucidate the clinical significance of antidepressant effects with quetiapine by evaluating number needed to treat as well as time to response and remission with quetiapine monotherapy in patients with acute bipolar depression. A post-hoc analysis was conducted of 542 patients with bipolar I or II disorder, (moderate to severe depression), randomized to 8 weeks of double-blind treatment with quetiapine 600 mg/day (n=180), quetiapine 300 mg/day (n=181), or placebo (n=181). Number needed to treat, time to response (> or =50% reduction from baseline in Montgomery-Asberg Depression Rating Scale total score) and time to remission (Montgomery-Asberg Depression Rating Scale total score < or =12) were evaluated. Response rates at week 8 were 58.2 and 57.6% for quetiapine 600 and 300 mg/day, respectively, and 36.1% for placebo (P<0.001). Remission rates were 52.9% for both quetiapine groups and 28.4% for placebo (P<0.001). The number needed to treat was five for both response and remission for quetiapine (600 and 300 mg/day) compared with placebo. Median time to response and remission were significantly shorter with quetiapine 600 and 300 mg/day than placebo. No between-group difference was found in the incidence of treatment-emergent mania or hypomania (quetiapine 600 mg/day: 2.2%, quetiapine 300 mg/day: 3.9, and placebo: 3.9%). In conclusion, quetiapine compared with placebo significantly reduces time to response and remission compared with placebo, and has a favorable number needed to treat.

This paper reviews the evidence for the efficacy of anticonvulsants in the continuation and maintenance phases of treatment of bipolar disorder, when there has been an episode of mania (Bipolar-I disorder). The evidence to be considered is primarily that arising from randomized controlled trials. A literature search was performed to identify all randomized controlled trials of anticonvulsants used as maintenance treatment for bipolar-I disorder. Placebo-controlled studies were preferred, however there have been relatively few of these and clinical practice must therefore be guided by evidence carrying a lower level of conviction. Valproate monotherapy lacks a convincing evidence base. The view that valproate is more effective than lithium in rapid cycling has not been borne out. Lamotrigine is effective in preventing depression after an episode of mania. As monotherapy, lithium appears superior to carbamazepine in bipolar patients not previously treated with either drug. The combination of lithium and carbamazepine may be superior to either drug alone, in certain treatment-resistant patients, but is associated with increased side effects. Other anticonvulsants lack evidence supporting their use in bipolar disorder except in treating co-morbid alcohol dependence, anxiety and bulimic symptoms. Valproate continues to be recommended by most current guidelines despite the lack of evidence.

This review describes the clinical spectrum of bipolar disorder and its classification in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and the International Classification of Diseases (IACD)-10. The development of new diagnostic trends and their clinical implications are discussed.

Background: Lamotrigine has demonstrated efficacy for the acute treatment of depression in bipolar I patients in a placebo-controlled, monotherapy study. We describe the results of a 52-week, open-label continuation of that trial., Method: Patients meeting DSM-IV criteria for bipolar I disorder with a current major depressive episode who completed a 7-week, double-blind study of bipolar depression were offered 1 year of open-label lamotrigine therapy (flexible doses of 100-500 mg/day) in a continuation study. To maintain the acute study blind, the first 3 weeks of the continuation study remained blinded while patients previously randomly assigned to placebo were titrated to a lamotrigine dose of 50 mg/day. Patients who had been randomly assigned to lamotrigine continued at their fixed doses. Beginning at week 4, all patients received open-label lamotrigine for up to 49 additional weeks. Concomitant psychotropic medications were permitted during the open-label phase. Effectiveness (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement scale) and safety assessments were administered at weeks 4, 12, 24, 36, and 52. The study was conducted from June 1996 to December 1998., Results: Of 135 patients completing the acute study, 124 (92%) entered the continuation study: 77 had received lamotrigine and 47 had received placebo in the acute study. The mean duration of lamotrigine exposure was 10.4 months, with a mean modal dose of 187 mg/day. Sixty-nine patients (56%) completed 1 year of treatment. Significant and sustained improvement from baseline was seen in mean observed MADRS scores (p <.05). The proportion of patients achieving remission (MADRS score < or = 11) by week 4 of the study was 81.4%, and episodes of mania/hypomania occurred less frequently than in the preceding year. Headache was the most common drug-related adverse event., Conclusion: During 1 year of open-label therapy with lamotrigine as adjunctive therapy or monotherapy, bipolar I patients experienced sustained improvement in depressive symptoms without evidence of mood destabilization.

Background: Studies highlighting the difficulties associated with lithium suggest that the role of antipsychotic drugs and mood stabilizers in bipolar disorder should be reconsidered., Aims: To review the efficacy and mode of action of antipsychotic drugs in mania, and to consider the differences between official guidelines and routine clinical practice in the use of these agents for mania., Method: Review of research, guideline- and practice-based literature., Results: Guidelines recommend lithium or valproate as first-line treatments for mania, and antipsychotic agents only as 'adjuncts' for agitation, dangerous behaviour or psychosis. However, in routine practice, antipsychotic drugs are often prescribed. The effectiveness of these agents in mania has been established by several studies; newer atypical compounds demonstrate antimanic efficacy with a reduced incidence of neurological side-effects., Conclusion: Antipsychotic drugs are important in the treatment of bipolar disorder and mania. Future studies should evaluate the long-term efficacy and safety of newer atypical antipsychotic agents, and the place of anticonvulsants in combination with antipsychotics in bipolar disorder.

Objective: New mood stabilizers are needed that possess efficacy for all phases of bipolar disorder. This study was designed to provide preliminary evidence for the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients with bipolar disorder who had been inadequately responsive to or intolerant of prior pharmacotherapy., Method: A 48-week, open-label, prospective trial was conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was used as adjunctive therapy (N = 60) or monotherapy (N = 15) in patients presenting in depressed, hypomanic, manic, or mixed states., Results: Of the 40 depressed patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in 17-item Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a 42% decrease in Hamilton depression scale scores, and the patients presenting with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, nausea, and rash. Rash was the most common adverse event resulting in drug discontinuation (9% of patients); one patient developed a serious rash and required hospitalization., Conclusions: These open-label data provide preliminary evidence that lamotrigine may be an effective treatment option for patients with refractory bipolar disorder; however, potential benefits must be weighed against potential side effects, including rash.

Background: Patients with bipolar disorder (BD) who have rapid cycling features are often treatment refractory. Clear and conclusive evidence regarding effective treatments for this group is not available., Methods: Patients with diagnoses of refractory bipolar disorder who were currently experiencing manic, mixed, depressive, or hypomanic episodes were treated with lamotrigine as add-on therapy (60 patients) or monotherapy (15 patients). We compared the efficacy of lamotrigine in the 41 rapid cycling and 34 non-rapid cycling patients with BD., Results: Improvement from baseline to last visit was significant among both rapid cycling and non-rapid cycling patients for both depressive and manic symptomatology. For patients entering the study in a depressive episode, improvement in depressive symptomatology was equivalent in the two groups. Among patients entering the study in a manic, mixed, or hypomanic episode, those with rapid cycling improved less in manic symptomatology than did non-rapid cycling patients. Among rapid cycling patients with initial mild-to-moderate manic symptom severity, improvement was comparable to that in non-rapid cycling subjects; however, the subset of rapid cycling patients with severe initial manic symptomatology had little improvement in mania. Rapid cycling patients had earlier onset and more lifetime episodes of mania, depression, and mixed mania., Conclusions: Lamotrigine was generally effective and well tolerated in this group of previously non-responsive, rapid cycling bipolar patients.

Background: The efficacy of depot antipsychotic drugs in the prophylaxis of bipolar affective disorder was investigated., Method: Life charts were constructed for 18 outpatients with bipolar disorder receiving prophylactic treatment with depot medication. The durations of affective episodes were compared during periods on or off medication., Results: The subjects suffered fewer relapses and spent significantly less time in hospital (P = 0.001) for treatment of manic, depressive and mixed affective illness during treatment with depot antipsychotics., Conclusions: Depot antipsychotic medication may be a useful prophylactic treatment for certain patients with bipolar affective disorder.

A 12-month double-blind trial of carbamazepine vs lithium, given as sole treatment for the prophylaxis of bipolar affective disorder, was carried out in 31 patients. All were previously stable on lithium; 15 were switched over to carbamazepine and 16 remained on lithium. Although the overall relapse rate was similar in the 2 groups (6 on carbamazepine, 8 on lithium), nearly all the relapses in carbamazepine occurred in the first month, probably precipitated by lithium withdrawal. Two patients on carbamazepine developed a rash and were withdrawn. More side effects were noted during the early stages on carbamazepine. Patients on lithium tended to gain weight (+4 kg) compared with carbamazepine (-3.1 kg). It is concluded that carbamazepine is as effective as lithium in the prophylaxis of bipolar affective disorder; changeover from lithium to carbamazepine should be done slowly.

Pimozide (PMZ), a relatively specific dopamine (DA) receptor blocking drug, was compared to chlorpromazine (CPZ) in a double-blind, between-patient clinical trial in mania. The trial lasted 14 days. Twenty-three patients who fulfilled Feighner's criteria for mania entered the trial (one patient entering on two separate occasions). Both drugs led to clinical improvement, with a significant effect being noted within 24 hours. According to one of the two rating scales used, initial improvement was greater with chlorpromazine, probably due to its greater sedative effect. By 7 days both drugs were equally effective. Sedative side effects were more frequent in patients on CPZ; extrapyramidal side effects were more frequent with PMZ. The finding that the relatively specific DA receptor blocking drug PMZ was as effective as CPZ in the treatment of mania is consistent with the view that hyperactivity of central DA pathways is involved in the pathogenesis of this condition.

In a double-blind, between-patient clinical trial carbamazepine (CBZ) (n = 8) was compared to haloperidol (HP) (n = 9) in patients presenting with mania (DSM III). Seven patients on HP and 2 on CBZ failed to complete 4 weeks treatment. In 4 of the HP group this was because of extrapyramidal side-effects (EPS). Two patients on CBZ and 2 on HP were withdrawn because of lack of efficacy. Statistically significant clinical improvement was seen in both groups within the first 2 weeks of treatment with HP acting more quickly. In addition to EPS which occurred in HP patients, drowsiness was experienced in 4 on CBZ and 3 on HP, and gastrointestinal symptoms in 3 on CBZ. No serious haematological changes, nor abnormalities in clinical chemistry occurred in either group. We conclude that CBZ appears to be a potentially useful drug in the treatment of acute mania.

Six bipolar patients in a manic episode were treated with the calcium antagonist verapamil. A decrease in the level of psychopathology was noted in 5 of the 6, though there was a tendency for patients to relapse in the third week of treatment. Cortisol levels decreased steadily with clinical improvement while growth hormone levels tended to rise. In contrast to traditional antipsychotics verapamil did not alter prolactin levels. Its neuroendocrine profile suggests its therapeutic effects are not mediated by dopamine receptor blockade.

Twelve manic patients were treated for 2 weeks with oral haloperidol; in 6 patients treatment commenced with intravenous haloperidol, and intravenous 'test' doses were given after 1, 3-5 and 14 days of oral medication. From 24 hours to 14 days baseline serum prolactin levels rose towards a plateau, as did the improvement in clinical ratings. After the first intravenous test doses of haloperidol, prolactin levels peaked at 1 hour; however, they fell to a low point at 24 hours, and no response to further test doses was seen for 3-5 days. The response tended to return at 14 days. The mechanisms underlying the changes in prolactin levels, and in clinical state, are discussed.

Bipolar manic-depressive disorder may present as mania, depression, or mixed states, and there is increasing knowledge of its responsiveness to drugs as therapeutic agents. In addition a number of drugs may act as aggravating factors for the disorder.

Plasma cortisol levels were elevated in a large proportion of samples from manic patients. Although a correlation was found between clinical ratings of the severity of mania and the degree of elevation of daytime cortisol levels, some patients with low clinical ratings had elevated cortisol levels. During treatment with haloperidol, cortisol levels returned to normal earlier that the clinical state. The underlying mechanisms are discussed.

During two weeks' treatment of 11 manic patients with pimozide there was close correspondence between the timecourse of improvement in clinical ratings and the rise in plasma prolactin between the second and fourteenth day. There were no significant differences in growth hormone levels during the manic episodes compared to recovery. These findings are discussed in relation to the role of dopamine in the release of prolactin and growth hormone, and in the pathogenesis of mania.

The paper reviews the endocrine findings in manic patients and the effects of treatment, as well as the association between endocrine conditions or hormonal treatments and abnormal states of elation resembling mania. The findings are discussed in relation to hypotheses about the neurochemical basis of mania, particularly the mesolimbic dopamine hypothesis.