This article is a review of the various treatments that are currently available, in particular in France, for the treatment of
bipolar disorders. This article specifically addresses the use of novel
antipsychotic agents as alternative
therapy to a
lithium therapy and/or the use of conventional
antipsychotics. The prevalence of
bipolar disorder over a lifetime is around 1% of the general population.
Bipolar disorder consists of alternating depressive and
manic episodes. It mainly affects younger subjects, and is often associated with alcohol and
drug addictions. There are two main subtypes of
bipolar disorder. According to the DSM IV-R, type 1 of
bipolar disorder is characterised when at least one
manic episode (or a mixed episode) has been diagnosed. Type 2 of
bipolar disorder is related to patients enduring recurrent depressive episodes but no
manic episode. Type 2 affects women more frequently as opposed to type 1 affecting individuals of both sexes. Manic-
depressive disorder (or cyclo-thymic disorder) appears in relation to patients who has never suffered
manic episode, mixed episode or severe depressive episode but have undergone numerous periods with some symptoms of depression and hypomanic symptoms over a two-year period during which any asymptomatic periods last no longer than two months. The average age of the person going through a first episode (often a depressive one) is 20 years-old. Untreated bipolar patients may endure more than ten manic or depressive episodes. Finally, in relation to 10 to 20% of patients, the
bipolar disorder will turn into a fast cycle form, either spontaneously or as a result of certain medical treatments. Psychiatrists are now able to initiate various treating strategies which are most likely to be effective as a result of the identification of clinical subtypes of the
bipolar disorder.
Lithium therapy has been effectively and acutely used for patients with pure or elated
mania and its prophylaxis. However,
lithium medication may worsen depressive symptoms when used for a long term maintenance
therapy. Additionally, mixed
mania, rapid cycling type patients and
bipolar disorder associated with
substance abuse do not respond well to
lithium therapy. In addition to the
lithium therapy or in place of a
lithium therapy, one can report the frequent use of
antipsychotic agents in respect of patients with
bipolar disorder during both the acute and maintenance phases of treatment.
Antipsychotic agents have been used for almost forty years and may be used in combination with a
lithium therapy. Conventional
antipsychotics are effective but they may induce late
dyskinesia,
weight gain, sedation, sexual dysfunction and depression. These adverse side effects often lead to non compliance in particular in circumstances where
antipsychotic agents are combined with a
lithium therapy. A number of alternative somatic treatment approaches have been reported for patients who do not respond well or who are intolerant to
lithium therapy. As such,
valproate has received regulatory approval for the acute treatment of
mania and
carbamazepine has been indicated for this condition in a number of countries.
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. In addition,
clozapine has been shown to produce significant
weight gain and
sialorrhea as well as significant
anticholinergic effects. As a result,
clozapine should not be prescribed in the first place. As opposed to
clozapine, there are open-label reports and controlled studies in respect of
risperidone and
olanzapine. Two recent double-blind studies of acute
mania found
olanzapine to be more effective than placebo. Based on these two studies,
olanzapine has recently been approved for the indication of
mania. The effects of
olanzapine and
divalproex in the treatment of
mania have also been compared in a large randomized clinical trial. The
olanzapine treatment group had significantly greater mean improvement of
mania ratings and a significantly greater proportion of patients achieving protocol-defined remission. Significantly more
weight gain and cases of dry mouth, increased appetite and
somnolence were reported with
olanzapine while more cases of
nausea were reported with
divalproex. The comparison of
olanzapine with
lithium for the treatment of
mania has also been the subject of a double-blind randomized controlled trial. That study shows no differences between the two drugs. While these studies support the idea that
olanzapine has direct acute anti-manic effects, a number of authors are of the opinion that
olanzapine may have specific prophylactic mood-stabilizing properties.
Olanzapine would appear to be effective in the maintenance treatment, as it exhibited both antimanic and
antidepressant effects. Systematic trials have shown that
risperidone may be effective and safe in the treatment of acute
mania, as an add-on
therapy with
lithium or
valproate (open studies and two controlled double-blind studies) and as monotherapy (open studies). In an open, multi-center, 6-month study,
risperidone seems to be effective and safe as long-term adjunctive
therapy in treatment-resistant bipolar and schizo-
affective disorders, with no exacerbation of manic symptoms.
Risperidone had few adverse side effects (and where there were any, they were mostly mild), mostly consisting of APS and
weight gain. A naturalistic comparison of
clozapine,
risperidone and
olanzapine in the treatment of
bipolar disorder suggests that the efficacy and tolerability of the three treatments are similar. One major differentiation factor of these drugs appears to be
weight gain, particularly between
olanzapine and
risperidone. However, this may partially be caused by the use of mood-
stabilizing agents. Bipolar and schizo-affective patients now require combination
therapy approach because of the cyclic nature of these disorders. Many studies report the combination of mood-
stabilizing agents with conventional
antipsychotics and atypical
antipsychotics. Combination
therapies produce a number of adverse side effects. Atypical
antipsychotics (other than
clozapine) are now rated as first-line agents for adjunctive treatment of
mania because they produce less adverse side effects. Atypical
antipsychotics are also rated as first-line agents for combined treatment of psychotic depression and they are strongly preferred when an
antipsychotic is required for long-term maintenance.