Baron Shopsin

Lithium and leukocytosis.

Peripheral blood specimens from 22 hospitalized psychiatric patients and one outpatient were examined for white blood cell (WBG) count changes during treatment with lithium carbonate. Significant leukocytosis occurred during periods of lithium ingestion; this phenomenon was reversible, apparently innocuous, and not related to psychiatric diagnosis or the many variables of hospitalization. While elevations in WBG count are likely the result of a drug effect, they were not dose related or dependent on the concentration of lithium in the peripheral blood. A trend toward neutrophilia and lymphocytopenia emerged for the group but cannot be said to account for the global change in total WBG.

Intra:Extraceliular lithium ratios and clinical course in affective states

Our data suggest that manic or depressed patients may be distinguished from normal individuals or manic‐depressives in illness interphase by red blood cell:plasma lithium ratios. The findings also revealed that the intraerythrocyte concentration of lithium was a sensitive index of clinical change and impending toxicity in psychiatric patients, whereas blood lithium alone was not a reliable indicator. Confirmation of these data would contribute to the concept of biologic heterogenicity within the affective illnesses and may influence the procedure of lithium stabilization and chronic maintenance based on monitoring only blood levels of this ion.

Enhancement of lymphocyte and macrophage function in vitro by lithium chloride.

Abstract Lithium chloride, an inhibitor of adenylate cyclase, augmented several in vitro immune reactions. Lithium increased rosette formation and thymidine incorporation by lymphocytes and phagocytosis by macrophages. Prostaglandin E1 (10−4M), an adenylate cyclase stimulator, inhibited lymphocyte response to phytohemagglutinin. Lithium reversed this effect, suggesting that its actions on lymphocytes may be mediated, at least in part, by inhibiting adenylate cyclase.

Clinical studies with dopamine-receptor stimulants.

Oral administration of ET-495 was found to cause worsening of psychiatric status in 4 out of 7 schizophrenic patients, and to induce a paranoid state and a syndrome of auditory hallucinosis in 2 non-schizophrenics. These observations were compatible with the hypothesized role of dopamine in schizophrenia. However, these psychotogenic effects were far less dramatic than those noted in other studies with amphetamine, methylphenidate or l-Dopa. Possible explanations for this differing psychotogenic potency of receptor stimulators versus presynaptic agonists are presented. Intravenous ET-495 and apomorphine did not show psychotogenic effects.

Serum dopamine- -hydroxylase (D H) activity and affective states.

Using a sensitive assay system recently developed, dopamine-Β-hydroxylase (DΒH) was examined in the serum of 56 psychiatric patients and 33 normal control subjects. Blood values of this enzyme failed to differentiate between the various diagnostic populations explored and were compatible with values obtained for normal control subjects within the same age range. The findings are critically evaluated and their possible relevance discussed with regard to the role of catecholamines in affective disorders.

Adjuvant effects of lithium chloride on human mononuclear cells in suppressor-enriched and suppressor-depleted systems

Lithium enhances several in vitro indices of immune function, including thymidine uptake by mitogen-stimulated human mononuclear cells. To further characterize the mechanism of action of lithium and to determine whether it acts by abrogating suppressor cell activity or by enhancing helper cell function, we have compared the effects of lithium on the mitogenic response of normal, suppressor-depleted and suppressor-enriched mononuclear cell preparations. In normal cultures, lithium enhanced thymidine uptake in response to concanavalin A (Con A) and phytohemagglutinin (PHA). In the suppressor-depleted cultures, thymidine uptake after Con A stimulation was significantly higher than in normal cultures, and was further enhanced by lithium. In the suppressor-enriched system, response to PHA was significantly lower than in normal cultures, and addition of lithium reversed the observed suppression. These results indicate that lithium may be enhancing thymidine uptake in response to mitogen at least in part by abrogating suppressor cell activity. The observed increase in thymidine incorporation in the suppressor-depleted cultures suggests that lithium may also have a direct stimulatory effect on helper cell activity.

Lithium as an immunologic adjuvant

Lithium, an adenylate cyclase inhibitor, stimulates a variety of in vitro indices of immune function, including proliferation of lymphocytes in response to mitogens, rosette formation by T-cells and phagocytosis by macrophages. Lithium enhances these immunologic responses at concentrations comparable to those achieved in patients receiving lithium for treatment of manic-depressive disorders. Lithium may prove to have important therapeutic applications as an immune adjuvant, particularly in immune deficiency states associated with excessive C-AMP production.

Dopamine receptor stimulation in the treatment of depression: piribedil (ET-495).

ET-495, a putative central dopamine receptor stimulant, was givem to endogenously depressed individuals, all of whom were largely unresponsive to previous drug treatment. The drug exhibited a rapid and, in some cases, a pronounced antidepressant effect. This effect was short-lived, however, and, within a brief period, depression returned accompanied by a consistent syndrome of anger, irritability, hostility and poor temper control. In one individual with a bipolar history, the induction of a paranoid psychosis and auditory hallucinosis occurred. While the data suggests a role for dopamine in the symptomatic relief of depression in man, they also imply that this monoamine cannot, in and of itself, be considered as the primum movens in either the action of other (established) antidepressant drugs, or as underlying depressive illness.

Lithium-induced Thyroid Disturbance : Case Report and Review

Abstract The appearance of goiter and hypothyroidism was observed in a 41-year-old female maintained on lithium carbonate for approximately two years as a prophylaxis against recurrent manic-depressive illness. After lithium was discontinued, the patient became euthyroid, and the goiter decreased in size. Chemical evidence of hypothyroidism reappeared when treatment with lithium was resumed. Moderately elevated levels of antithyroglobulin antibody were present throughout the investigation, independent of lithium ingestion. Various pathways by which lithium may interfere with thyroid functioning are explored and discussed with reference to pertinent literature. The findings suggest that lithium interferes with thyroxin production resulting in deficiency of the circulating hormone. Our patient was unable to adequately compensate for this deficit because of an underlying chronic thyroiditis, probably Hashimotos Disease. The authors propose that a damaged thyroid gland is prerequisite for uncovering the defect produced by chronic lithium ingestion, in the absence of which, patients usually remain euthyroid albeit some show goiter.

The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study.

Objectives To examine and record the clinical antidepressant effect of exogenous agmatine, an amino acid derived central glutamaergic modulator in endogenously depressed subjects. It was also the authors intention to examine the effects of parachlorophenylalanine (PCPA) in therapeutic responders to determine if serotonergic mechanisms mediate agmatines antidepressant effect. Methodology Exogenous agmatine was ingested in doses of 2‐3mg/day by depressed subjects with Major Depresssive Disorder (MDD), clinically assessed using the 21 item Hamilton Rating Scale for Depression (HAM‐D), the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS). Antidepressant responders volunteered to concommittantly ingest parachlorophenylalanine (PCPA) at starting doses of 250mg/day, and increased until depressive relapse, mitigating side effects, or a maximum dosage of 1250mg/day. Results Three depressed subjects showing total illness remission with exogenous agmatine did not relapse after concomitantly adding PCPA. Effective in relieving both psychomotor agitation and retardation, the antidepressant effect was free of physical or behavioural side effects: gastrointestinal discomfort and loose stools in one subject resolved spontaneously within days. All three subjects refused to risk depressive relapse by temporarily stopping agmatine after PCPA was stopped. Conclusion The antidepressant effect of exogenous agmatine was documented in a small number of MDD subjects, and was not reversed/modified by PCPA confirming findings in animals that therapeutic response is not mediated by serotonergic mechanisms. A NAMDA (N‐methyl‐D‐aspartate) receptor antagonist, agmatines recognized function in brain as inhibitory modulator of excitatory glutamatergic transmission suggests a pivotal role for brain glutamate, contributing to the ripening glutamatergic basis of depression, and a rational basis for future antidepressant pharmacotherapy.