Neuroleptics mania

Depression and mania are both affective disorders but their symptoms and treatments are quite distinct. Mania is expressed as heightened mood, exaggerated sense of self-worth, irritability, aggression, delusions and hallucinations. In stark contrast, the most obvious disturbance in depression is melancholia that often co-exists with behavioural and somatic changes (Table 20.1). Some individuals experience dramatic mood swings between depression and mania. This is known as "bipolar disorder which, like mania itself, is treated with lithium salts or neuroleptics. 

Adverse effects of the TCAs on the brain include confusion, impaired memory and cognition and occasionally delirium some of these effects have been reported to occur in up to 30% of patients over the age of 50. These effects may occasionally be confused with a recurrence of the s)nnptoms of depression and are probably due to the central antimuscarinic activity of these drugs. Tremor also occurs frequently, particularly in the elderly, and may be controlled by the concurrent administration of propranolol. Neuroleptics are normally not recommended to be used in combination with TCAs as they are liable to accentuate the side effects of the latter drugs. The risk of seizures, and the switch from depression to mania in bipolar patients, has also been reported following TCA administration. 

The long-term toxic effects of lithium, such as nephrogenic diabetes insipidus, which has been calculated to occur in up to 5% of patients, and the rare possibility of lithium combined with neuroleptics being neurotoxic, has stimulated the research for other drug treatments. However, apart from the neuroleptics, these drugs have not been studied as extensively in the treatment of acute mania, but are worthy of consideration because of their reduced side effects. 

In CONCLUSION, lithium is universally accepted as a mood-stabilizing drug and an effective antimanic agent whose value is limited by its poor therapeutic index (i.e. its therapeutic to toxicity ratio). Neuroleptics are effective in attenuating the symptoms of acute mania but they too have serious adverse side effects. High potency typical neuroleptics appear to increase the likelihood of tardive dyskinesia. Of the less well-established treatments, carbamazepine would appear to have a role, particularly in the more advanced stages of the illness when lithium is less effective. 

Rapid control of an acute attack of mania may require the use of a neuroleptic (see below). 

These are usually treated with sedative neuroleptics (as for schizophrenia, above). Treatment must also aim to support the patient socially including for instance advising on legal protection from the financial or other consequences of mania. One of the risks of treatment is the sudden mood swing at the end of the manic episode, with acute depression possibly triggered by the neuroleptics. Because of the concern for the manic episode and symptoms, return to normal is viewed with relief, and the downswing may go un-noticed, with the concomitant suicidal risk. 

Treatment of individual episodes is described above. The treatment or monitoring of individual episodes of mania or depression should also take into account the risk of a swing to the opposite polarity induced by the treatment of the current episode (i.e., depression triggered by neuroleptic treatment of manic episode, or mania following antidepressant treatment). The speed of such a swing may take unwary physicians by surprise. 

For more than 40 years, Li+ has been used to treat mania. While it is relatively inert in individuals without a mood disorder, lithium carbonate is effective in 60 to 80% of all acute manic episodes within 5 to 21 days of beginning treatment. Because of its delayed onset of action in the manic patient, Li+ is often used in conjunction with low doses of high-potency anxiolytics (e.g., lo-razepam) and antipsychotics (e.g. haloperidol) to stabilize the behavior of the patient. Over time, increased therapeutic responses to Li+ allow for a gradual reduction in the amount of anxiolytic or neuroleptic required, so that eventually Li+ is the sole agent used to maintain control of the mood disturbance. 

Secunda SK, Katz MM, Koslow SH, et al Mania diagnosis, state measurement and prediction of treatment response. J Affect Disord 8 113-121, 1985 Seeman MV Neuroleptic prescription for men and women. Social Pharmacology 3[3) 219-236, 1989... 

Sernyak MJ, Griffin RA, Johnson RM, et al Neuroleptic exposure following inpatient treatment of acute mania with lithium and neuroleptic. Am J Psychiatry 151 133-135, 1994... 

Despite this favorable result, lithium was hardly considered as a psychopharmaceutical for many years. There were a variety of reasons for this. Firstly, mania is not a very common psychosis and there is spontaneous remission in many cases. There were thus not so many occasions where lithium treatment was indicated. Secondly, lithium salts were considered to be toxic because for some time they had been given in excessive doses to patients with heart failure and in this way, had led to a number of fatalities (Cade, 1970). Thirdly, a few years after Cade s first publication psychiatrists attention had been claimed by chlorpromazine and the subsequent neuroleptics and antidepressants, thus explaining why lithium almost fell into oblivion. It was onl> in the 1960s that it once more attracted some interest, after the Danish psychiatrist Mogens Schou had shown that lithium salts were not only useful in the manic phase of manic depressive illness but also could prevent depressive episodes in patients suffering from bipolar psychoses. 

Investigators have attempted to assess the impact of antipsychotics on the cognitive and the behavioral disturbances characteristic of schizophrenia. The antipsychotics decrease typical, but nonspecific, positive symptoms such as hallucinations and delusions ( Table 5-4). Thus, labeling them as antischizophrenic agents is too restrictive inasmuch as they also benefit such disparate disorders as psychotic depression or mania, iate-onset paraphrenia, and organic-induced psychosis. As the symptoms reduced by neuroleptics are typical of psychosis in general, these agents are best conceptualized as a type of antipsychotic. 

TABLE 10-4. Lithium versus neuroleptics acute mania... 

Muller-Oerlinghausen B, Retzow A, Henn FA, et al. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania a prospective, randomized, double-blind, placebo-controlled, multicenter study. J Clin Psychopharmacol 2000 20 195-203. 

FIGURE 7—35. Combination treatments for bipolar disorder (bipolar combos). Combination drug treatment is the rule rather than the exception for patients with bipolar disorder. It is best to attempt monotherapy, however, with first-line lithium or valproic acid, with second-line atypical antipsychotics, or with third-line anticonvulsant mood stabilizers. A very common situation in acute treatment of the manic phase of bipolar disorder is to treat with both a mood stabilizer and an atypical antipsychotic (atypical combo). Agitated patients may require intermittent doses of sedating benzodiazepines (benzo assault weapon), whereas patients out of control may require intermittent doses of tranquil-izing neuroleptics (neuroleptic nuclear weapon). For maintenance treatment, patients often require combinations of two mood stabilizers (mood stabilizer combo) or a mood stabilizer with an atypical antipsychotic (atypical combo). For patients who have depressive episodes despite mood stabilizer or atypical combos, antidepressants may be required (antidepressant combo). However, antidepressants may also decompensate patients into overt mania, rapid cycling states, or mixed states of mania and depression. Thus, antidepressant combos are used cautiously. 

Mania can occur in any age group. Acute manic episodes in the elderly may best be managed with high potency neuroleptics. The use of lithium is not contraindicated in the elderly provided renal clearance is reasonably normal. The dose administered should be carefully monitored, as the half-life of the drug is increased in the elderly to 36-48 hours in comparison to about 24 hours in the young adult. The serum lithium concentration in the elderly should be maintained at about 0.5 mEq/litre. It is essential to ensure that the elderly patient is not on a salt-restricted diet before starting lithium therapy. The side effects and toxicity of lithium have been discussed in detail elsewhere (see p. 198 et seq.), and, apart from an increase in the frequency of confusional states in the elderly patient, the same adverse effects can be expected as in the younger patient. 

In addition to acute and chronic schizophrenia, the neuroleptics are sometimes used in the management of mania, delirium, and severe agitation, whatever the cause of these symptom complexes. It must be noted that unlike parkinsonism, where a definite dysfunction in the DA system has been established, for schizophrenia and other psychiatric diseases, no unequivocal evidence has yet been presented to prove that there is a disturbance of the DA system (e.g., dopaminergic overactivity or receptor hypersensitivity). In untreated schizophrenics the production of DA metabolites is normal. Conflicting results have been obtained in studies of the DA receptors in schizophrenics (11,12,13), but in the case of patients who have not received neuroleptics, the receptor density and affinity appear to be normal (13). The "dopamine hypothesis" in these disorders derives from the beneficial effects of drugs that block DA receptors. 

Trials of lithium in patients with acute psychosis (and not just mania) showed that lithium was inferior for the treatment of severely overactive patients, presumably because of its toxicity, but comparable to neuroleptics for the treatment of less overactive patients, regardless of diagnosis (Braden et al. 1982 Johnstone et al. 1988). A trial conducted in the 1960 comparing opium and chlorpromazine in acute schizophrenic patients showed equivalent improvement over three weeks with both drugs (Abse, Dahlstrom, Tolley 1960). 

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