Drug-induced mania
by
Peet M, Peters ST
University Department of Psychiatry,
Northern General Hospital, Sheffield, England.
Drug Saf 1995 Feb; 12(2):146-53

ABSTRACT
Mania can occur by chance association during drug treatment, particularly in patients predisposed to mood disorder. Single case reports are unreliable, and evidence must be sought from large series of treated patients, particularly those with a matched control group. Drugs with a definite propensity to cause manic symptoms include levodopa, corticosteroids and anabolic-androgenic steroids. Antidepressants of the tricyclic and monoamine oxidase inhibitor classes can induce mania in patients with pre-existing bipolar affective disorder. Drugs which are probably capable of inducing mania, but for which the evidence is less scientifically secure, include other dopaminergic anti-Parkinsonian drugs, thyroxine, iproniazid and isoniazid, sympathomimetic drugs, chloroquine, baclofen, alprazolam, captopril, amphetamine and phencyclidine. Other drugs may induce mania rarely and idiosyncratically. Management involves discontinuation or dosage reduction of the suspected drug, if this is medically possible, and treatment of manic symptoms with antipsychotic drugs or lithium.

It is well known that antidepressants such as Prozac and Paxil can prompt intense manias in adults with bipolar disorder, when given without mood stabilizing drugs.

Which other antidepressants flick the switch?

Anti-bipolar therapy:
mechanism of action of lithium
by
Jope RS
Department of Psychiatry
and Behavioral Neurobiology,
University of Alabama at Birmingham,
35294-0017, USA.
jope@uab.edu
Mol Psychiatry 1999 Mar; 4(2):117-28

ABSTRACT
This review introduces the concepts that multiple actions of lithium are critical for its therapeutic effect, and that these complex effects stabilize neuronal activities, support neural plasticity, and provide neuroprotection. Three interacting systems appear most critical. (i) Modulation of neurotransmitters by lithium likely readjusts balances between excitatory and inhibitory activities, and decreased glutamatergic activity may contribute to neuroprotection. (ii) Lithium modulates signals impacting on the cytoskeleton, a dynamic system contributing to neural plasticity, at multiple levels, including glycogen synthase kinase-3beta, cyclic AMP-dependent kinase, and protein kinase C, which may be critical for the neural plasticity involved in mood recovery and stabilization. (iii) Lithium adjusts signaling activities regulating second messengers, transcription factors, and gene expression. The outcome of these effects appears likely to result in limiting the magnitudes of fluctuations in activities, contributing to a stabilizing influence induced by lithium, and neuroprotective effects may be derived from its modulation of gene expression.

The prophylactic efficacy of lithium -
transient or persistent?
by
Kleindienst N, Greil W, Ruger B, Moller HJ
Psychiatric Hospital of the University of Munich, Germany.
niko@psy.med.uni-muenchen.de
Eur Arch Psychiatry Clin Neurosci 1999; 249(3):144-9

ABSTRACT
It has been reported recently that the prophylactic efficacy of lithium is a transient phenomenon in many patients. Other studies suggest sustained efficacy against affective recurrences for many years. As this issue is of major therapeutic relevance, published literature considering changes in lithium efficacy over time has been reviewed. The present review includes a critical evaluation of the data and the methodology which yielded these controversial results. Considering the published data discussed in this review, the balance of evidence does not indicate a general loss of lithium efficacy in the prophylaxis of major affective disorders. A supposed persistence of the prophylactic effects in general does not, however, exclude the reappearance of affective recurrences after years of successful treatment in individual cases. Possible reasons for this phenomenon are discussed.

Lithium augmentation in treatment-resistant
depression: meta-analysis of placebo-controlled studies
by
Bauer M, Dopfmer S
Department of Psychiatry,
Klinikum Benjamin Franklin,
Freie Unversitat Berlin, Germany.
mjbauer@mednet.ucla.edu
J Clin Psychopharmacol 1999 Oct; 19(5):427-34

ABSTRACT
The addition of lithium to the treatment regimens of previously nonresponding depressed patients has been repeatedly investigated in controlled studies. The authors undertook this meta-analysis to investigate the efficacy of lithium augmentation of conventional antidepressants. An attempt was made to identify all placebo-controlled trials of lithium augmentation in refractory depression. Only double-blind studies that involved participants who had been treated with lithium or placebo addition after not responding to conventional antidepressants were to be included in the meta-analysis. Further inclusion criteria were the use of accepted diagnostic criteria for depression and the use of response criteria based on the acceptable measurement of depression as an outcome variable. Studies were located by a search of the MEDLINE database, a search in the Cochrane Library, and an intensive search by hand of reviews on lithium augmentation. Nine of 11 placebo-controlled, double-blind studies were included in this meta-analysis. Aggregating three studies with a total of 110 patients that used a minimum lithium dose of 800 mg/day, or a dose sufficient to reach lithium serum levels of > or = 0.5 mEq/L, and a minimum treatment duration of 2 weeks, the authors found that the pooled odds ratio of response during lithium augmentation compared with the response during placebo treatment was 3.31 (95% confidence interval, 1.46-7.53). The corresponding relative response rate was 2.14 (95% confidence interval, 1.23-3.70), the absolute improvement in response rate was 27% (95% confidence interval, 9.8%-44.2%), and the number of patients needed to be treated to obtain one more responder was 3.7. Inclusion of six more studies that fulfilled inclusion criteria but which treated subjects with additional lithium for less than 2 weeks or with a lower lithium dose (total, 234 patients) resulted in even higher estimates. Lithium augmentation seems to be the treatment strategy in refractory depression that has been investigated most frequently in placebo-controlled, double-blind studies. The authors conclude from this meta-analysis that with respect to efficacy, lithium augmentation is the first-choice treatment procedure for depressed patients who fail to respond to antidepressant monotherapy.


Lithium at 50: have the neuroprotective
effects of this unique cation been overlooked?
by
Manji HK, Moore GJ, Chen G
Department of Psychiatry and Behavioral Neurosciences,
Wayne State University School of Medicine,
Detroit, Michigan 48201, USA.
Biol Psychiatry 1999 Oct 1; 46(7):929-40

ABSTRACT
Recent advances in cellular and molecular biology have resulted in the identification of two novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithium treatment has been demonstrated to markedly increase the levels of the major neuroprotective protein, bcl-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bcl-2 are also observed in cells of human neuronal origin, and are observed in rat frontal cortex at lithium levels as low as approximately 0.3 mmol/L. Bcl-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bcl-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase kinase 3 beta (GSK-3 beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the neurodegeneration observed in Alzheimer's disease). Consistent with the increases in bcl-2 levels and inhibition of GSK-3 beta, lithium has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long term beneficial effects in the treatment of mood disorders via underappreciated neuroprotective effects. To date, lithium remains the only medication demonstrated to markedly increase bcl-2 levels in several brain areas; in the absence of other adequate treatments, the potential efficacy of lithium in the long term treatment of certain neurodegenerative disorders may be warranted.