Divalproex Depakote has recently obtained the authorization to market in France and may be prescribed for manic states or hypomanic states that do not tolerate lithium therapy or for which lithium therapy is contraindicated. A number of other anticonvulsants lamotrigine, gabapentin and topiramate are currently being tested.
Because of the side effects of the conventional antipsychotic agents, atypical antipsychotic agents are currently on trial and appear to be of interest in the treatment of bipolar disorders. Currently, a number of prospective studies are available with clozapine, risperidone and olanzapine in the treatment of bipolar disorder. Most are short-term studies. Recent randomised, double-blind, placebo-controlled studies have shown clozapine, risperidone and olanzapine to be effective with antimanic and antidepressive effects, both as monotherapy and as add-on maintenance therapy with lithium or valproate.
They also have a favorable side effect profile and a positive effect on overall functioning. Similarly, valproate combined with antipsychotics provides greater improvement in mania than antipsychotic medication alone and results in lower dosage of the antipsychotic medication.
There is currently no double-blind study regarding the use of clozapine for bipolar disorders. However, based on the results of a number of open-label studies, clozapine appears to be effective in relation to schizo-affective and bipolar patients including those with rapid cycling or those who respond inadequately to mood stabilizers, carbamazepine, valproate or conventional antipsychotics.
Clozapine seems to be more appropriate for bipolar and schizo-affective patients than schizophrenics. In particular, studies show that patients with manic and mixed-psychotic state of illness are better responders than patients with major depressive syndromes. Four open studies suggest the efficacy of clozapine in the maintenance treatment of bipolar disorder and three prospective, open-label studies show the efficacy of clozapine in the manic state of the illness. However, the number of patients in the studies was not important and these studies are not controlled.
Clozapine has also adverse side affects, one of which consisting of a major risk of agranulocytosis and, potentially, death.
Our study has several limitations. First, the confidence in evidence of the first NMA was often low or very low. In the primary outcome, confidence levels were deemed to be low or very low in Second, we did not perform the inconsistency test for dry mouth and prolactin-related adverse events for the first NMA and all outcomes for second NMA.
Third, the range of study durations included in our meta-analysis was Thus, the long-term efficacy and safety of drugs still need to be verified. Fourth, we did not cover important clinical issues that might inform treatment decision-making in routine clinical practice e. Fifth, a cost-effectiveness analysis should be performed and included in the decision-making process.
In conclusion, our study represents the most comprehensive evidence currently available to guide the initial choice of pharmacological treatment for adult patients with BD in the maintenance phase. Clinicians and patients should consider the maintenance phase when selecting the treatment for the acute phase of BD.
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A double-blind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. The authors were able to control for a number of confounding factors, though unable to allow for the effects of manic or depressive episodes. The main adverse events noted with second generation antipsychotics include metabolic effects including weight gain, effects on glucose metabolism, cholesterol and prolactin , sedation, sexual dysfunction, as well as extrapyramidal symptoms though to a lesser degree than FGAs Young et al.
When considering adverse events, it should be noted that effects are heterogenous between compounds Leucht et al. This limits interpretation of results, given that natural history of illness may require prolonged treatment with prophylactic medication before beneficial effects may be seen. As above, most trials of antipsychotics adopt an enriched design, where participants are stabilized on the antipsychotic before randomisation, i.
Observational studies are notoriously difficult to interpret, given the effects of confounding factors, and selection bias. It may therefore be helpful to examine aetiological mechanisms and the biology of treatment response. From the above evidence it is clear that response to treatment is heterogenous and that lithium, and to a lesser extent, quetiapine, appear most likely to have efficacy in preventing relapse to depression.
Lithium also appears to have anti-suicidal effects. An understanding of the pharmacology and neurobiology of treatment response enables one to unpick the difference between lithium and specific antipsychotics in maintenance therapy.
Various hypotheses exist for lithium response and can be grouped into those regulating cell membrane properties, cell membrane transport and ion distribution, neurotransmitter regulation, and intracellular signalling, linked at various levels. Similarly, effects on the dopamine system occur downstream of dopamine D 2 receptors Ashok et al. They generally have less affinity for the D 2 receptor than first generation antipsychotics, such as haloperidol, and more affinity for receptor sites such as the 5HT 2A receptor an exception being amisulpride , though there is little evidence of an association between this and effectiveness.
When examining the antipsychotics, it is worth considering the Neuroscience-based nomenclature NbN which classifies psychotropic medication on the basis of their pharmacological profiles Zohar et al. For those antipsychotics approved for maintenance treatment in BD this is as follows; aripiprazole receptor partial agonist D 2 , 5HT 1A , receptor antagonist 5HT 2A , olanzapine receptor antagonist D 2, 5HT 2 , quetiapine immediate-release receptor antagonist D 2 , 5HT 2 , reuptake inhibitor norepinephrine transporter , ziprasidone receptor antagonist D 2 , 5HT 2.
Given their effects in acute bipolar depression it is also worth noting the properties of asenapine receptor antagonist 5HT 2 , D 2 , norepinephrine, alpha 2 and lurasidone receptor antagonist D 2 , 5HT 2. This nomenclature, with a focus on receptor affinity and selectivity give some clue as to the pharmacological mode of action necessary for preventing mania- and to a lesser extent, depression. In terms of neurobiological research, in mania, there is a paucity of in vivo studies, with one Positron Emission Tomography PET study suggesting no elevation in dopamine synthesis capacity in mania, compared to controls Yatham et al.
Other possible mechanisms include effects on the NMDA system explaining benefits of ketamine in bipolar depression Bauer et al. Most National guidelines continue to support use of lithium as first-line therapy in the maintenance treatment of bipolar disorder [e. The use of prophylactic agents grouping together conventional mood stabilizers and antipsychotics is considered on an individual basis, based on efficacy and tolerability, with no explicit guidance given by the World Federation of Societies of Biological Psychiatry WFSBP Grunze et al.
First-line suggestions include lithium, quetiapine, divalproex, and lamotrigine monotherapy. To these are added asenapine and aripiprazole oral and LAI.
An important distinction that these guidelines make is for the use of olanzapine as second-line therapy, on account of its metabolic effects, as well as pointg out use of some SGAs adjunctively for short periods of time Yatham et al. A good example of the issues regarding use of antipsychotics in maintenance treatment in BD comes from the clinical care of people presenting with first episode mania, within first episode psychosis FEP services Jauhar et al.
First-line pharmacotherapy will almost always be with SGAs, which will be continued for at least a year to 18 months, and then either continued or discontinued.
Treatment with SGAs in this cohort is associated with more prominent metabolic effects and weight gain, which will have effects on treatment adherence, which can be poor Whale et al. This is the biggest factor predicting relapse Zipursky et al. To date, there is little data on use of lithium or other mood stabilizers in this population over the longer-term, and whether this has an effect on treatment adherence or illness course.
Given that lithium is the gold standard, and that antipsychotics have differential effects at various poles of illness, when should antipsychotic monotherapy be considered? This would pertain to people who are unable to tolerate, do not have a good response or do not wish to take lithium. Monotherapy with a LAIs could be considered for those who have problems with adherence. The use of combination antipsychotics is generally discouraged, on account of increased side-effect burden, and lack of clear efficacy-even in augmentation of clozapine for people with treatment-resistant psychoses.
In these cases use of adjunctive aripiprazole is justified, in keeping with trial evidence Raghuthaman et al.
There is little evidence to guide decision-making, regarding length of antipsychotic maintenance treatment. In cases of combination therapy e. Second generation antipsychotics are increasingly used for maintenance treatment in bipolar disorder, as monotherapy or adjunctive therapy. Although lumped together as one class, their pharmacological properties, efficacy and tolerability in bipolar disorder are varied. This is particularly the case for prevention of depressive episodes, where their clinical effects appear less pronounced with the exception of quetiapine, and possibly asenapine and lurasidone.
For people who are intolerant or unable to adhere to lithium use, maintenance treatment with antipsychotics seems reasonable, with individualized care regarding side effects and their management-and possible use of other agents for prevention of depression e. Future studies examining the neurobiology of treatment response in bipolar depression, as well as longer-term trials with various compounds, focusing on treatments acting on differing poles of illness are required.
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Int J Neuropsychopharmacol. A small number of patients with schizophrenia treated with risperidone, olanzapine, or quetiapine experience a first episode of hypomania or mania. It is not apparent if this is a true drug-induced event or coincidental.
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