Suicidal behavior and prophylactic lithium treatment of major mood disorders: a review of reviews

This paper briefly summarizes and discusses at length two recent reviews. Their main findings were the following: (1) During prophylactic lithium treatment the overall mortality of patients with major mood disorders was much lower than in such patients in general. (2) The frequency of suicidal acts was many times lower in patients on lithium than in patients not on lithium. The limitations of the studies reviewed and the difficulty of interpreting their findings are discussed. It is concluded that prophylactic lithium treatment is indicated in patients with major mood disorders who are at high risk of committing suicide, that is, those with severe depressions or depressions with persistent suicidal thoughts or with suicide attempts in the past.     

Chemical aversion treatment of alcoholism: Lithium as the aversive agent

Animal work indicating flavour aversion produced by chemical aversion therapy (CAT) with lithium might be effective in the treatment of alcoholism led to this treatment being given to 25 patients. The abstinence rate six months later of 36% was significantly better than the 12% rate for an equivalent group of patients, treated with a disulfuram-like drinking deterrent, calcium carbimide. The rate for the CAT group improves to 47% if 8 patients are excluded who did not develop sickness reactions to lithium. CAT with lithium appears safe given proper medical precautions.     

Na+,K(+)-ATPase activity is reduced in hippocampus of rats submitted to an experimental model of depression: effect of chronic lithium treatment and possible involvement in learning deficits

This study was undertaken to verify the effects of chronic stress and lithium treatments on the hippocampal Na+,K(+)-ATPase activity of rats, as well as to investigate the effects of stress interruption and post-stress lithium treatment on this enzyme activity and on spatial memory. Two experiments were carried out; in the first experiment, adult male Wistar rats were divided into two groups: control and submitted to a chronic variate stress paradigm, and subdivided into treated or not with LiCl. After 40 days of treatment, rats were killed, and Na+,K(+)-ATPase activity was determined. In the second experiment, rats were stressed during 40 days, and their performance was evaluated in the Water Maze task. The stressed group was then subdivided into four groups, with continued or interrupted stress treatment and treated or not with lithium for 30 additional days. After a second evaluation of performance in the Water Maze, rats were killed and Na+,K(+)-ATPase activity was also measured. Results showed an impairment in Na+,K(+)-ATPase activity and in Water Maze performance of chronically stressed rats, which were prevented by lithium treatment and reversed by lithium treatment and by stress interruption. These results suggest that the modulation of Na+,K(+)-ATPase activity may be one of the mechanisms of action of lithium in the treatment of mood disorders.     

The impact of comorbidity on the management of pathological gambling

A 30-year-old woman with severe pathological gambling and cyclothymia presented to our program with no previous history of pharmacologic or psychotherapeutic treatment. Pathological gambling is an impulse -control disorder not otherwise specified (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) in which comorbidity is common, particularly with substance abuse, obsessive-compulsive disorder and mood disorders. As described in this case, pathological gamblers with bipolar comorbidity may be effectively treated with mood stabilizers such as lithium. After receiving 10 weeks of lithium treatment, the patient showed improvement in both gambling behavior and affective instability. The identification of specific subtypes among patients with pathological gambling may be relevant to the choice of pharmacologic treatment.     

Cholinergic rebound after chlorpromazine exacerbates lithium muscarinic-induced limbic seizures in rats: implications for psychiatric treatment.

When lithium serum levels were within the (human) therapeutic range, young and old adult male and female rats (housed singly or in groups) all displayed faster limbic seizure onset times in response to a muscarinic cholinergic agonist (pilocarpine 20 mg/kg) if a single systemic dosage of chlorpromazine was injected 24 hours previously. The effect was comparable to injecting an additional 10 mg/kg of pilocarpine. These results strongly suggest that cholinergic rebound from chlorpromazine administrations during lithium treatment could facilitate subclinical electrical lability and very localized neuronal necrosis within the limbic system of clinical patients, resulting in normalization of psychiatric symptoms.     

Drugs employed in the treatment of alcoholism: rat data suggest they are unnecessarily severe

A tacit assumption, which has often been made by practitioners of both chemical aversion therapy (CAT) and deterrent therapy of alcoholism, is that efficacy of a drug depends mainly on how noxious it is. We conducted two experiments which challenge this assumption. These experiments compared five noxious drugs employed in the treatment of alcoholism, with lithium, in regard to their ability to reduce rats' drinking of a familiar, readily consumed, ethanol (10% v/v) solution. In both experiments, the dose of lithium was equivalent, in terms of body weight, to the largest daily recommended human dose: the dose of each of the five, noxious drugs was twice this equivalent. In the first experiment, the CAT drugs emetine, ipecac and succinylcholine were compared with lithium: in the second, the deterrent therapy drugs citrated calcium carbimide and disulfiram were compared. Despite the use of comparatively smaller doses of lithium, none of the noxious drugs administered in either experiment produced stronger ethanol aversions than lithium. This supports the use of lithium in CAT, and suggests that unnecessarily noxious drugs are being used in the treatment of alcoholism.     

Flavor aversions produced by contingent drug injection: Relative effectiveness of apomorphine, emetine, and lithium

Shortly after rats began drinking saccharin solution, different groups of them were injected with different doses of apomorphine, emetine, or lithium. A control group was not injected at all. Six days later, the rats were given free access to saccharin solution and to water. Aversions to saccharin solution were obtained in all injected groups and tended to become more pronounced as the dose level increased. At similar dose levels, lithium produced the most pronounced aversions, apomorphine produced the weakest aversions, and emetine was intermediate. A follow-up study with squirrel monkeys confirmed that lithium produces more pronounced aversions than either emetine or apomorphine. From these results, it seems worthwhile to try lithium in the chemical aversion treatment of alcoholism.     

Prediction of lithium response in young adult psychotic patients

Through an assessment of affectivity by means of the Crabtree - Horsham Affective Trait Scale, the author was able to predict, with 83-90% accuracy, who would and who would not be judged to be lithium responsive in a sample of hospitalized young adult psychotic patients who received a trial of lithium carbonate. The scale combines an assessment of the psychosis, premorbid personality, family pedigree, family interactional character and the presence or absence of a history of minimal brain dysfunction and drug-induced hypomania. Treatment outcome was found to be significantly better in the group of high affect psychotic patients who received a trial of lithium, when compared with the comparison group of high affect psychotic patients who did not.     

Seasonally-related inpatient admission of affective patients

Over a period of four years, 316 emotionally disordered patients were inspected for the frequency of seasonally conditioned hospitalisation, considering however solely the most recent prior hospitalisation within the four-year period. A cautious interpretation of the results would suggest significant differences in the seasonal frequency of emotional disorders that have resulted in hospitalisation. Manic depressive disorders, endogenous depression, and involutional depressions treated in hospital occur with the greatest frequency in autumn. These results suggest the possibility of employing thymoleptic treatment, notably to effect an influence on biorhythms, for instance, lithium, deprivation of sleep, and bright-light therapy.     

Side-effects of lithium therapy]

Side-effects and complications of lithium therapy were examined by evaluation of data registered from 73 patients. Transitory subjective complaints would often occur during the initial phase of therapy, but they do not require any additional therapy. Occasional development of struma and sometimes high increase of body weight require regular controls of these values. Disposing factors concerning the possible occurrence of epileptic seizures and extra-pyramidal disorders under lithium therapy are Melipramin as well as organic cerebral lesions.     

Note on aversion learning to the shape of food by monkeys

Vervet and grivet monkeys were repeatedly tested eating bar- and circle-shaped cookies. One subject was always injected with lithium immediately after eating cookies with the circle shape and learned to avoid the circular cookies while continuing to eat the bar-shaped cookies. Another subject received similar treatment except that lithium injections were always delayed 30 minutes after access to the circle-shaped cookies. She also acquired a discriminative aversion. Aversion learning was not observed with 60-minute delayed toxicosis or with lithium injections administered unpaired with access to the cookies. The two types of cookies differed only in shape, and conditioning and test sessions were conducted in total darkness to preclude the use of visual cues. Therefore, the avoidance observed in subjects conditioned with immediate and 30-minute delayed toxicosis represents a conditioned aversion to the shape of the cookies as revealed by tactile cues. These findings illustrate that monkeys can learn to select food on the basis of tactile stimuli when such stimuli are conditioned with delayed aversive stimulation.     

Rapid Cycling

Rapid cycling is not a distinct disorder, but is a particularly severe form of bipolar disease. One in six patients with bipolar disease seen by psychiatrists either as an outpatient or as an inpatient suffers from four or more episodes per year. If at least four episodes occur within one year, this high-frequency phase is called ?rapid cycling“ (RC). Treatment for bipolar disorder with RC usually includes trialling mood stabilizers, such as lithium, anticonvulsants, and modern antipsychotics.In four out of five RC patients, treatment improves disease progression; however, some patients exhibit RC for many years.Specific studies have raised the suspicion that administering antidepressive therapy could facilitate an unfavorable course of bipolar affective disorder. The present case demonstrates disease progression and treatment attempts in a patient with distinct RC progression.     

A flavor paired with lithium chloride blocks the formation of a pentobarbital-lithium chloride association

Thirsty rats were used in order to determine whether a vinegar solution, which had been paired with an injection of lithium chloride, could block the formation of an association between a pentobarbital- and a lithium chloride-induced state. During phase 1 the rats in the blocking group had a 2.0% vinegar solution paired with an injection of 240 mg/kg of lithium chloride, during phase 2 these rats were reexposed to the vinegar prior to each injection of 20 mg/kg of pentobarbital and 240 mg/kg of lithium chloride, and during phase 3 these rats were given access to a novel 0.75% saccharin solution and were injected with pentobarbital after saccharin removal. Animals with this history did not form an association between the pentobarbital- and lithium chloride-induced states during phase 2 as evidenced by their refusal to consume the saccharin solution over repeated pairings of saccharin with pentobarbital during phase 3. Control groups that received forward pairings of pentobarbital and lithium chloride, in the absence of a previously conditioned vinegar solution during phase 2, formed an association between pentobarbital and lithium chloride. These findings indicate that drug states and flavors can interfere with each others' capacity to predict the occurrence of lithium chloride.     

Depression of an instrumental response by a single devaluation of its outcome

In three experiments rats were trained to make two different instrumental responses for different outcomes. Then the outcomes were given a single differential conditioning experience with lithium chloride. That differential treatment was sufficient to produce differential instrumental responding in a subsequent test. Re-exposure to the devalued outcome was not necessary for an impact on instrumental performance.     

Taste/tactile cue discriminations in taste-aversion learning foIIowing depletion of noradrenaIine

Four experiments were performed to investigate the effect of noradrenaline (NA) depletion, following systemic DSP4 treatment, upon a tastehactile discrimination in taste-aversion learning. In Experiments 1 and 2 , noisy bottle (A) + lithium chloride pairings were alternated with saccharin (B) + saline pairings, and vice versa, during Phase I conditioning. The particular order of reinforcement presentation in each case was then reversed, so that a noisy bottle (A) + saline pairing was now altered with a saccharin (B) + lithium chloride pairing, etc., during Phase II (reversal) conditioning. In Experiments 3 and 4 , saccharin in noisy bottle (AB) + lithium chloride pairings alternated with either noisy bottle (A) + saline or saccharin (B) + saline pairings, and vice versa, during Phase I conditioning; the order of reinforcement presentation was then reversed, as above. None of the four experiments performed offered any evidence of impairments of the discrimination task as a result of NA depletion. These results are discussed in the context of associative preparedness and of discrimination learning in operant tasks and recent findings on compound conditioning, following the loss of NA.     

Course and form variations of cyclothymic phases in lithium therapy

The authors have attempted by means of a statistical survey to quantify changes in the course and, in particular the phase-related and non-phase-related form of cyclothymic phases during long-term lithium treatment.     

Selective associations in one-day-old rats: taste-toxicosis and texture-shock aversion learning

One-day-old rats learned aversions to a novel taste paired with lithium-induced distress and to a tactile stimulus paired with brief electric shocks. However, aversions did not develop when taste was paired with shock or when the tactile stimulus was paired with lithium treatment. The aversions occurred only when lithium treatment immediately followed taste exposure and when shock was concurrent with exposure to the tactile stimulus. These findings indicate that selective associations in aversion learning are mediated by innate mechanisms that govern conditioning in the absence of extensive ontogenetic experience. The present research also shows that selective associations are sufficient for the occurrence of long-delay learning.     

Clinical trial of contemnol tablets (lithium retard Spofa)

A report on the clinical testing of the lithium-retard medicament Contemnol (Spofa). It details the way lithium-retard treatment is objectively and subjectively superior to the earlier and still current general lithium treatment.     

Noradrenaline loss and the disruption of between-CS stimulus generalisation effects in aversion learning

In stimulus blocking the previous conditioning to one stimulus, A, followed by conditioning to the compound stimulus, AB, results in less conditioning to the other stimulus, B. Three experiments were performed to study the effect of the prior pairing of a stimulus A (noisy bottle) with lithium chloride followed by stimulus AB (saccharin plus noisy bottle) and lithium chloride pairings upon the strength of the aversion to the target stimuls B (saccharin) in NA-depleted and control rats. The results obtained were not in keeping with a "blocking" explanation since enhancement, rather than blocking, of the saccharin aversion was obtained, and confirm several recent demonstrations of the "anti-blocking" effect from investigations using the conditioned suppression procedure. DSP4 treatment attenuated the aversion-enhancement ("anti-blocking") effects in all three experiments. The possibility that DSP4-induced noradrenaline depletions may cause some disruption of between-CS associations leading to a lesser higher order conditioning or stimulus generalisation is discussed and the present findings do add further evidence to the conclusion that noradrenaline is intimately involved in attentional processes.