DRUGS for MENTAL ILLNESS  

  LITHIUM

In an Australian hospital, in 1948, John Cade hypothesized that manic depression might be due to over- or under- production of a hormone. He collected urine from patients suffering from manic depression, schizophrenia, melancholia, and from normal individuals. He injected concentrates of urine, intraperitineally, into guinea pigs, and found that injections of urine from manic patients was, in some cases, three times as toxic as injections of urine from others. Toxicity was caused by urea - but the amount in the urine of manic depressives was similar to that in normal urine. To  Cade, this suggested that something in the urine of manics augmented the toxicity of urea, which he tried to measure in further experiments - but encountered difficulties with highly insoluble uric acid. To try to overcome the problems, he used lithium urate, and injected a saturated solution of this into guinea pigs and found, unexpectedly, that toxicity was low. He then injected urea with lithium carbonate. Cade then went on to inject lithium carbonate, itself into guinea pigs(1) and - as H I Kaplen and B J Sadock noted in their book, `Clinical Psychiatry` - "While conducting animal experiments, Cade had somewhat incidentally noted that lithium made the animals letharic..."(2).

Cade knew that lithium salts had been used, clinically, since the 19th century to treat epilepsy, gout and cancer, and therefore considered it safe for use in humans and tested lithium carbonate on himself. As he experienced no adverse reactions to the drug, Cade administered the drug to a male patient who had suffered from manic excitement for five years. The patient`s condition improved and after four months of continuous treatment was released from hospital(3).

(NB. Cade only turned to lithium carbonate after difficulties in his experiments with urea. His finding that lithium carbonate made giuinea pigs lethargic was incidental. His self-experimentation was based on the previous clinical experiences with the drug - not on the animal experiments. His decision to try it on a manic patient was after he had found it had not caused adverse reactions on himslef - irrespective of his animal experiments).

Cade published the results of his clinical trial in 1949 and stated that ten manic patients had been given the drug - and each had shown a marked improvement(4). But, as Cade`s results reached America, the US Food and Drug Administration had recalled a number of salt substitutes containing lithium chloride due to toxic adverse reactions - and in some cases death with heavy use. Consequently, little or no work was done with lithium carbonate for five years(5).

Most hospitals and pharmacies had stored cannisters of lithium after the FDA instructions, and in the mid-1950s, many psychiatrists strated their own trials with the drug in manic patients. By the mid-1960s, reports  had appeared in the medical press of the effectiveness of lithium in clinically treating mania and other mental and psychiatric disorders(6)(7). Its use in patients had come through clinical experience.

refs

1. Sneader,W. Drug Discovery. John Wiley & Sons. 1985.

2. Kaplen,HI. Sadock,BJ. Clinical Psychaitry. Williams & Wilkins. 1988.

3. Sneader,W. Drug Discovery. John Wiley & Sons. 1985.

4. Cade,JF. Med J Aust. vol 36. 1949.

5. Georgotes,N. Gershon,S. J Clin Psychopharmacol. vol 1. 1981.

6. Gershon,S. J Neuropsychiatry. vol 1. 1960.

7. Schlagenhauf,G et al. Am J Psychiatry. vol 23. 1966.

ANIMAL "SCREENING" TESTS

of DRUGS for PSYCHOSIS

Primary animal "screening" tests for anti-psychotic drugs are

APOMORPHINE-INDUCED STEREOTYPED BEHAVIOUR

Apomorphine is injected, subcutaneously, into rats in doses of 0.5mg per kg body weight of the animal. After 30 minutes, the test compound is administered, intraperitoneally. The rats are then caged individually and are examined every ten minutes and a scale is recorded as "negative" or "positive" to denote the absence or presence of steroetyped movements such as licking, sniffing, gnawing and biting(1).

In a test with six anti-psychotic drugs - haloperidol, chlorpromazine, thioridazine, sulprine, clozapine, and metochlorpramide - the experimenters found that two - sulprine and clozapine - were nearly inactive, and admitted that "this [test] fails to predict the actual clinical efficiency of these drugs"(1).

APOMORPHINE-INDUCED CLIMBING BEHAVIOUR

The test substance is injected, intraperitoneally, into mice. After 15 minutes, apomorphine is injected, subcutaneously. The mice are then placed in an individual cage with wire mesh walls. After being allowed 15 minutes to become accustomed to the new environment, the mice are observed at one minute intervals and recordings are made, in seconds, of how long the mice spend in a vertical postion(1).

When the experimenters tested the six (previously-mentioned) drugs, they noted that the test was susceptible to false-positives(1).

INDUCED CATALEPSY

The test compound is injected, interperitoneally, into male albino rats. At half-hour intervals, the rats are assessed for catalepsy by placing each paw of the rat on a 2.5cm high cork. The rat is considered to be cataleptic if all four paws remain on the cork for more than ten seconds(1).

After testing the six (previously-mentioned) anti-psychotic drugs, the experimenters commented "this test may produce false-negatives for compounds which have a clinical neuroleptic effect, yet simultaneously exhibit a low incidence of extra-pyramidial side effects"(1).

refs

1. Worms,P. Lloyd,KG. Pharmac Ther. vol5. 1979.