BRITISHJOURNAL OF PSYCHIATRY %20%2001), 01), 178 %suppl. 41), s14s148^ 8^ s156 Use of antipsychotic drugs and lithium in mania experience over the following 30 years indi- cated that lithium is far short of an ideal treatment, even when administered expertly JOHN COOKSON to `concordant' patients. There is a striking difference between the results of early con- trolled trials and the outcome on lithium in open clinical practice, where a smaller pro- portion of patients appear to be `lithium re- sponders'; some even doubt the validity of the clinical trials %Moncrieff, 1997). The benefits of lithium therapy have to be balanced against the difficulties in its Background Studies highlighting the Mania or a manic episode is a severe phase management ± with poor compliance in pa- difficulties associated withlithium suggest in the course of bipolar disorders, the con- tients with bipolar disorder and the occur- dition termed `manic±depressive illness' by rence of withdrawal mania ± and the risks that the role of antipsychotic drugs and Kraepelin in the 19th century. A contem- of side-effects and toxicity %Cookson, mood stabilisersin bipolardisorder should porary textbookdescribed the difficulty of 1997). The latter includes the possibility be reconsidered. managing a patient with mania ± using of permanent neurological sequelae with drugs of limited efficacy, mainly sedative cerebellar damage %Schou, 1984). Aims Toreview the efficacyandmode or anaesthetic, such as chloral and ur- Since the 1970s anticonvulsant drugs, of action of antipsychotic drugsin mania, ethane, or potentially toxic drugs, such as first carbamazepine and more recently and to consider the differences between potassium bromide. The sedative anticon- valproate and, in open studies, lamotrigine officialguidelines and routine clinical vulsant paraldehyde was also used. With- and topiramate, have displayed antimanic out sedation the patient would need three effects in at least a proportion of patients practice in the use of these agents for or four attendants, skilled in `a certain kind %Dunn%Dunn et aletal, 1998).,1998). mania. of tact', and spacious, safe accommodation %Clouston, 1896). Thomas Clouston stated MethodMethod Review of research, guideline- the need for a drug in mania as follows: MODE OF ACTION OF and practice-basedliterature. ``what we want and have not yet got is a LITHIUM AND THE MOOD medicine that will cause really natural, rest- STABILISERS ResultsResults Guidelines recommend lithium ful, refreshing sleep, and one that will stay or valproate as first-line treatments for or slacken the morbid energising of the Lithium has numerous effects on biological mania, and antipsychotic agents only as brain cells in the convolutions, without systems, especially at high concentrations `adjuncts'for`adjuncts' for agitation, dangerous affecting the appetite or the nutrition.'' %see Wood & Goodwin, 1987). As the Fifty years later the use of bromides re- smallest alkaline cation, lithium can substi- behaviour or psychosis.However, in mained extensive, but barbiturates such as tute for sodium, potassium, calcium and routine practice, antipsychotic drugs are amylobarbitone %amobarbital) were in use, magnesium in biological systems. It pene- often prescribed.The effectiveness of and paraldehyde remained popular %Sargant trates cells via sodium and other channels these agentsinmania hasbeen established & Slater, 1946). Electroconvulsive therapy but is extruded less efficiently than sodium %ECT) was also being used in mania, by the sodium±potassium active transport by several studies; newer atypical following its introduction in 1935. system. Thus, the plasma±cell ratio for compounds demonstrate antimanic The situation changed dramatically, lithium is much lower than that for sodium. efficacy with a reducedincidence of first in 1949 when John Cade in Australia Within the cell, lithium interacts with sys- neurological side-effects. discovered the effects of lithium in mania tems that normally involve other cations, %Cade, 1949), and in 1952 with the devel- including transmitter release and second- Conclusion Antipsychotic drugs are opment of the first antipsychotic pheno- messenger systems, such as adenylate cy- importantinthetreatmentofbipolarimportantinthe treatmentof bipolar thiazine, chlorpromazine. It remained to clase, the phosphoinositol cycle and protein disorder and mania.Future studies should Schou, working in Aarhus, Denmark, to es- kinase C; these actions effectively block tablish the use of lithium in mania on the particular transmitters and hormones. evaluate the long-term efficacy and safety basis of a controlled study %Schou et aletal,, Receptor upregulation is also reduced, ofnewer atypicalantipsychotic agents, and 1954), and by 1968 the prophylactic effi- perhaps accounting for the value of lithium the place of anticonvulsantsincombinationanticonvulsantsin combination cacy of lithium in bipolar disorder was as an adjunct to other drugs. One of the with antipsychoticsin bipolar disorder. established. Cade's discovery can be major sites of action of anticonvulsant regarded as the beginning of the modern drugs is the membrane ionic channels for Declaration of interest J.C. has era of effective drug treatment in psychiatry conductance of cations ± sodium, calcium lectured and been a member of advisory %Shorter, 1997). and potassium; these control the electrical By 1963, the use of lithium in mania excitability of neurons and the release of panels for Janssen,Eli Lilly and Glaxo was recommended for difficult cases, but transmitters %Upton, 1994). Because they Wellcome.He has also run funded trials of haloperidol was considered particularly show selectivity for particular channels, anti- risperidone, olanzapine and lamotrigine. useful %Sargant & Slater, 1963). However, convulsant drugs may alter cation function s14 8 Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 09:42:27, subject to the Cambridge Core terms of use. USE OF ANTIPSYCHOTIC DRUGS AND LITHIUM IN MANIA in a more specific way than lithium. High corresponding to a `number needed to treat' antipsychotic pharmacotherapy for the re- doses of antipsychotic drugs can also inter- %NNT) %Laupacis et aletal, 1988) of about 4 duction of manic excitement and for extre- fere with these channels, and their actions %95% CI 3±22). Few patients had a return mely unstable bipolar patients. In contrast, could be quantified in the same way as to normal functioning within 3 weeks. the 1994 guidelines of the APA advise the receptor-blocking affinities are %Task Force, Thus, in routine practice for acute mania, use of antipsychotic agents in mania only 1991).1991). both lithium and valproate are useful as ad- as `adjuncts' to mood stabilisers %particu- juncts to antipsychotic drugs, rather than as larly lithium or valproate) or to ECT, when monotherapy. Lithium has a delayed effect, mania is associated with `agitation', dan- RECENT PRACTICE taking a few days to begin, and 2±8 weeks to gerous behaviour or psychosis %American approach its full effect on mania ± some- Psychiatric Association, 1994). These The recognition of the shortcomings of times even longer. This limits lithium as a guidelines recognise also that antipsychotic lithium has required a reconsideration of treatment for acute mania and makes mono- agents or benzodiazepines may be useful to the role of antipsychotic agents and of the therapy risky for all but the mildest cases. `enhance compliance' with mood stabili- so-called `mood stabilisers' %lithium and The study also validated the concept of sers, or while the latter drugs are develop- the anticonvulsants) in bipolar disorder. lithium non-responders, as patients identi- ing their effect. The guidelines do not It was noted that while doses of anti- fied as such before entry to the study define what is meant by `agitation' in the psychotic drugs given to psychiatric in- showed less improvement on lithium than context of mania, and this is ambiguous. patients in a private university centre did did other patients. Carbamazepine is licensed The guidelines appear to have been not increase from 1989 to 1993, there in the UK for use in patients with bipolar based upon four important principles: was a doubling %to 84%) in the proportion disorder for whom lithium is not suitable; of cases prescribed adjunctive treatment %a)%a)MoodMood stabilisers are effective in manic valproate was licensed for use in bipolar ill- with anticonvulsants and a rise to 70% in states generally, although having a ness in the UK in 2001, although widely the number receiving adjunctive lithium delayed action. prescribed before that. %Baldessarini et aletal, 1995).,1995). %b)%b)AntipsychoticsAntipsychotics are beneficial by virtue Patients who respond to lithium tend to The preference of American %New York) of reducing hyperactivity or by seda- be those with classical mania rather than the psychiatrists for high-potency antipsychotics tion, rather than by a more general anti- mixed or schizoaffective form %Himmel- in mania was illustrated in a study by Chou manic effect. hochhoch et aletal, 1976; Goodnick& Meltzer, et aletal %1996) of 528 patients with mania in 1984; Swann et aletal, 1986). Patients with %c)%c)Antipsychotics,Antipsychotics, but not mood stabi- New Yorkstate hospitals in 1990. Ninety- elated-grandiose mania showed a better re- lisers, reduce psychotic symptoms in two per cent received antipsychotic medi- sponse than those with the destructive-para- mania.mania. cation, 61% lithium, 54% both and 22%