Lithium chlorpromazine

A 76-year-old man developed severe intractable diabetes insipidus which was attributed to lithium (395). He was hospitalized for over 2 weeks and eventually died from intestinal hemorrhage. Vigorous efforts were made to treat his polyuria, electrolyte disturbances, hypernatremia, and dehydration. He had been taking chlorpromazine, lithium, and furosemide, along with other medications, and the diagnosis of lithium-induced nephrogenic diabetes insipidus was considered because of a lack of alternative explanations. 

I 986) Glassman JN +, J Clin Psychiatry 47(10), 523 (along with chlorpromazine, lithium, and triazolam)... 

Chlorpromazine (lithium delays its gastric emptying with a consequent longer exposure to gut wall catabolic enzymes)... 

It can be argued that the introduction of lithium salts into the practice of psychiatry in 1949 heralded the beginning of psychopharmacology, as it predated the discovery of chlorpromazine, imipramine, monoamine oxidase inhibitors and resperine. Lithium came into clinical use serendipitously, the Australian psychiatrist Cade having by chance given it to a small group of manic patients and found that it had beneficial effects. 

Largactil is a proprietary preparation of chlorpromazine, an aliphatic antipsychotic with marked sedation and moderate antimuscarinic and extrapyramidal side-effects. Serenace is a proprietary preparation of haloperidol, a butyrophenone antipsychotic with marked extrapyramidal side-effects, moderate sedation but not very likely to cause hypotension. Tegretol is a proprietary preparation of carbamazepine, an anti-epileptic drug indicated in partial and secondary generalised tonic-clonic seizures, primary generalised tonic-clonic seizures, trigeminal neuralgia and in the prophylaxis of bipolar disorder unresponsive to lithium. 

Carbamazepine (CBZ) has been compared to placebo once, to lithium in two controlled trials, and to chlorpromazine in one trial. Pooling these data revealed a 50% response to CBZ, 56% for lithium, and 68% for chlorpromazine. Onset of response to CBZ was 7-14 days. 

Prior to the availability of atypical antipsychotics, typical antipsychotics were used to diminish the acute agitation of mania. Onset of action is typically observed within 3 to 7 days. In a meta-analysis of chlorpromazine trials, efficacy was 54%, which was substantially less than that of lithium, but comparable to that of other mood stabilizers (range, 12%-70%). Risk of extrapyramidal effects and tardive dyskinesia limits the use of these medications beyond the acute phase. 

Johnson G, Gershon S, Burdock E, et al Comparative effects of lithium and chlorpromazine in the treatment of manic states. Br J Psychiatry 119 267-276, 1971... 

Takahashi R, Sakuma A, Itoh K, et al Comparison of efficacy of lithium carbonate and chlorpromazine in mania report of collaborative study group on treatment of mania in Japan. Arch Gen Psychiatry 32 1310-1318, 1975 Takahashi Y, Kato K, Hayashizaki Y, et al Molecular cloning of the human cholecystokinin gene by use of a synthetic probe containing deoxyinosine. Proc Natl Acad Sci U S A 82 1931-1935, 1985... 

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. 

All prototypes of modern psychopharmaceuticals (lithium, chlorpromazine, meprobamate, imipramine and chlordiazepoxide) were discovered in a period of about 10 years (Fig. 2.1). Neither before nor since has such a series of... 

Shopsin B, Kim SS, Gershon S. A controlled study of lithium vs. chlorpromazine in acute schizophrenics. Br J Psychiatry 1971 119 435-440. 

In addition, Platman (92) studied 13 patients on lithium and 10 on chlorpromazine (CPZ), finding lithium consistently superior overall, but not statistically significant on any individual rating scale. The general state of patients on lithium was markedly superior to those on CPZ because the majority were discharged with no other treatment, whereas all of the patients on CPZ required additional concurrent drugs. Because the author did not present data on individual patients, these results could not be included in our meta-analysis, but his results are also consistent with the outcome in Table 10-4. Due to the small sample size, the results should be interpreted cautiously. 

Takahashi R, Sakuma A, Itoh K. Comparison of efficacy of lithium carbonate and chlorpromazine in mania. Arch Gen Psychiatry 1975 32 1310-1318. 

Prien RF, Caffey EM, Klett CJ. Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Arch Gen Psychiatry 1972,26 146-153. 

Braden W, Fink EB, Qualls CB, et al. Lithium and chlorpromazine in psychotic inpatients. Psychiatry Res 1982 7 69-81. 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

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). 

Two studies have directly addressed the question of lithium s specificity for mania or affective psychosis, as it is sometimes called. In one of these studies a group of 78 patients admitted with an acute psychotic episode diagnosed as mania, schizophrenia or schizoaffective disorder were randomised to receive lithium or chlorpromazine. The authors hypothesised that patients diagnosed as manic would respond better to lithium and those diagnosed with schizophrenia would respond better to chlorpromazine. In contrast they found that there was no difference in the effects of the different drugs on people with different diagnostic labels and that the only discernible effect was the inferiority of lithium in severely disturbed patients (Braden et al. 1982). A similar study published in 1988 claimed to show that lithium had specificity for... 

Prien, R. E, Caffey, E. M., Jr., Klett, C. J. 1972, Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group, Arch.Gen.Psychiatry, vol. 26, no. 2, pp. 146-153. 

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