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Bipolar disorder (BD) is a debilitating psychiatric condition with a prevalence of 1-2% in the general population that is characterized by severe episodic shifts in mood ranging from depressive to manic episodes. One of the most common treatments is lithium (Li), with successful response in 30-60% of patients. Synapsin II (SYN2) is a neuronal phosphoprotein that we have previously identified as a possible candidate gene for the etiology of BD and/or response to Li treatment in a genome-wide linkage study focusing on BD patients characterized for excellent response to Li prophylaxis. In the present study we investigated the role of this gene in BD, particularly as it pertains to Li treatment. We investigated the effect of lithium treatment on the expression of SYN2 in lymphoblastoid cell lines from patients characterized as excellent Li-responders, non-responders, as well as non-psychiatric controls. Finally, we sought to determine if Li has a cell-type-specific effect on gene expression in neuronal-derived cell lines. In both in vitro models, we found SYN2 to be modulated by the presence of Li. By focusing on Li-responsive BD we have identified a potential mechanism for Li response in some patients.

We have previously shown that the mortality of patients with recurrent affective disorders in long-term lithium treatment is not higher than that of the general population. In the present study on 471 patients from Denmark and Germany, we examined mortality during the initial year of lithium treatment and during later lithium treatment. During initial lithium treatment, the total mortality was twice as high as in the general population (difference not significant) and the mortality due to suicide 16 times higher. During later lithium treatment, the mortality rates did not differ from those in the general population. Our results indicate that patients with frequent, often severe recurrences, those chosen for prophylactic lithium treatment, are at risk of high mortality, which then diminishes as the prophylactic action of the treatment takes effect.

The authors have carried out an investigation of psychiatric morbidity in families of patients who responded and failed to respond to long-term lithium treatment. The study included 121 probands with RDC primary affective disorders and 903 first-degree relatives and spouses. Seventy-one probands were responders and 50 were nonresponders to long-term lithium treatment. Extended to 20 years, the follow-up of patients and their families provided substantial information relevant for the diagnosis and reliable assessment of lithium response. The diagnoses were based on all available information, SADS-L interviews and RDC criteria. The principal statistical methods were survival analysis and Cox regression analysis. The results revealed a significantly higher frequency of bipolar disorder in the relatives of lithium responders (3.8% vs. 0%). Schizophrenia was more common in the families of nonresponders (2.4% vs. 0.3%). There were no significant differences in the rates of other psychiatric disorders. Both family history and the proband's diagnosis contribute independently to predicting response to long-term lithium.

The reproducibility of in vitro erythrocyte lithium efflux and lithium efflux in the presence of selected membrane transport inhibitors (phloretin, ouabain, 4,4'-diisothiocyano-2,2'-disulphonic acid stilbene, and p-chloromercury-benzene sulphonate) was investigated in bipolar patients and age- and sex-matched control subjects. Efflux experiments were repeated three times in each patient-control pair within a period of 14 days. No differences were detected between patients and control subjects in any of the parameters measured. All components of lithium efflux showed wide day-to-day variation in the same subject in both patients and control subjects. Intersubject variability, however, was significantly greater than intrasubject variation. Since intraindividual variation of phloretin-inhibited lithium efflux was found to be considerable, and no real patient-control differences could be detected, the significance of this in vitro parameter in bipolar affective illness seems somewhat questionable and should be carefully reconsidered. The relevance of these findings to the putative cell membrane dysfunction in this disease is discussed.

1. 1. As part of a systematic investigation of the effects of lithium administration on neuroendocrine function we investigated the luteinizing hormone (LH) response to luteinizing hormone releasing hormone (LHRH) of healthy males. 2. 2. In healthy volunteers after 3 weeks of therapeutic doses of lithium the LH response to LHRH was significantly increased in comparison with the responses prior to lithium administration. 3. 3. An attempt is made to explain these findings by underlying neurotransmitter changes.

39 chronic schizophrenic out-patients were given either fluphenazine decanoate or enanthate for a 1-year double-blind trial. Doses of 25 mg were given for the first 6 months and 37.5 mg for the last 6 months. For both agents the intervals between treatments lengthened significantly over the course of the trial. Fluphenazine decanoate showed a non-significant trend for a longer duration of action coupled with a significantly lower incidence of extrapyramidal side effects.

Combined treatment with haloperidol and lithium is a frequently employed strategy for the treatment of acute psychoses. Although this combination regime is safe in most clinical situations, under certain circumstances It has resulted in neurotoxicity, with organic brain syndrome, and ultimately, in some patients, irreversible brain damage and death. Plasma lithium levels In these neurotoxic patients are generally within the clinically acceptable range of 0.7–1.5 mEq/l, but RBC-lithium levels, when reported are abnormally elevated. To account for these observations we hypothesized that in vivo haloperidol will alter the transport of lithium across the RBC membrane and thus cause an Increase in RBC lithium levels. We report preliminary results from a study that tested this hypothesis by measuring RBC lithium transport in vitro , in patients treated with a) haloperidol only, b) haloperidol, followed by haloperidol and lithium, c) combined haloperidol and lithium. In eight manic depressive patients in vivo haloperidol alone, or in combination with lithium resulted in a statistically significant (p in vitro RBC Li + uptake values. These results are interpreted as supportive of our hypothesis, that in vivo haloperidol alters the transport of lithium across the RBC membrane, and this effect can be detected by the use of a sensitive in vitro test. Work is currently in progress to evaluate, whether the RBC Li + transport alteration is due to a direct effect of the drug on the cell membrane or secondary to some circulating factor, and to extend these findings to a larger sample of patients.

Erythrocyte lithium influx and efflux were investigated in vitro in patients with bipolar affective disorders and in age- and sex-matched healthy controls. To explore the components of lithium influx

Among the three lithium preparations tested, no significant difference was found in the bioavailability, as expressed in serum and erythrocyte lithium concentrations and urinary lithium output. The side effect reports, however, varied significantly among the types of lithium under study. The slower the absorption of a particular preparation, the fewer the side effects. The results of this study support the view that preference should be given to lithium preparations with slow-release properites, particularly in side-effect-prone subjects.

It has generally been assumed that psychotropic drugs do not influence results on the dexamethasone suppression test (DST), except in some specific situations. Yet they directly affect the activity of many neurotransmitter systems, which in turn regulate hypothalamic-pituitary-adrenal (HPA) axis functioning. Several reports have shown correlations between the intake of or recent withdrawal from psychoactive substances and changes in DST results. A review of the DST literature reveals that these effects have not been controlled in most DST studies. It is therefore possible that the consequences of intake of psychotropic agents may have contributed to the debate surrounding the DST by producing unappreciated spurious DST results.

1. The possible predictive value of cortisol non-suppression by dexamethasone for therapeutic response to antidepressants was investigated both in “endogenous” and “neurotic” depression. Seventy-four female patients who fulfilled the RDC of Major Depressive Disorder (Study 1) and 44 female patients with the diagnosis of “Neurotic Depression” of ICD-9 (Study 2) were given DST and then treated with antidepressants, their clinical response being assessed after four weeks of drug treatment. 2. Forty-three out of the 74 patients with Primary Major Depression were non-suppressor. The DST non-suppressors showed a significantly more frequent therapeutic response to maprotiline than to amitriptyline. DST suppressors, on the other hand, responded better to amitriptyline treatment than non-suppressors. 3. In the neurotic depression group 23 patients were subclass ified as Primary Minor Depression, and 52 % of them showed non-suppressor response to DST. Twenty-one patients were diagnosed as Secondary Depression, with a history of chronic neurosis. One patient only (5 %) was the non-supressor. Patients with Primary Minor Depression showed good therapeutic response to antidepressants more frequently, than patients with Seconday Depression.

1. We studied growth hormone and prolactin responses to insulin hypoglycemia and TSH responses to TRH in symptom-free bipolar patients and healthy controls. 2. There were no significant differences in prolactia and growth hormone responses to hypoglycemia between stabilized bipolar patients and healthy controls, both tested medication-free. When lithium was administered to both groups, only bipolar patients showed a dramatic reduction in prolactin and growth hormone responses. 3. Both bipolar patients in remission and healthy controls showed an increase of TSH response to TRH when treated with lithium in comparison with the testings before lithium administration. 4. The subjects, both patients and volunteers, showed a comparable degree of hypoglycemia on and off lithium. 5. The observed difference in responsivenes s of bipolar patients warrants further systematic investigation and offers interesting possibilities for practical utilization.

1. 1. The phloretin-sensitive component of lithium (Li + ) efflux from erythrocytes has been reported to be significantly reduced in patients with bipolar affective disorders. The value of this finding depends on how reproducible the efflux measurements are. We have therefore investigated the intra-individual day-to-day reproducibility of this parameter, and total erythrocyte Li + efflux in patients with bipolar affective disorders and in age and sex matched healthy controls. 2. 2. Six carefully selected, typical bipolar patients and age and sex matched healthy volunteers were studied. These experiments were repeated under identical conditions on 3 occasions within a brief time period (21 days). 3. 3. We have found that both the total erythrocyte Li + efflux and the phloretin-sensitive Li + efflux exhibited considerable day-to-day intra-individual variability in both patients and healthy controls. The standard deviation of total efflux values was as large as ± 31.1% of the mean in some subjects. Mean phloretin-sensitive Li + efflux for patients was found to be 0.066 ± 0.02 mEq/1 RBC, and for controls 0.048 ± 0.01 mEq/1 RBC, in agreement with values reported in the literature. However, in some individuals standard deviation of this parameter, was as high as ± 50% of the mean. This variation was not the result of the biochemical technique, since all measurements were carried out in duplicate, and these differed less than 5%. 4. 4. These findings suggest, that in view of the small absolute values of the phloretin-sensitive Li + efflux, and its considerable day-to-day variation, the relevance of this biochemical parameter to the postulated cell membrane defect in affective disorders should be interpreted with some caution and needs further evaluation.

1. 1. Neuroendocrine strategies in affective disorders have explored both resting values of hormones and hormonal responses to stimuli such as hypoglycemia, TRH, LHRH, dexamethasohe, methadone and morphine. The abnormalities established to date have involved growth hormone, cortisol and TSH responses in particular. Prolactin has not been investigated to the same extent. We therefore describe several prolactin studies exemplifying selected neuroendocrine strategies. 2. 2. Our studies of prolactin responses included acute cases of either primary or secondary depression, stabilized bipolar patients, and healthy controls both off and on lithium. We found prolactin response to hypoglycemia significantly reduced in primary but not secondary depressions. 3. 3. Lithium administration led to flattened prolactin responses to hypoglycemia in stabilized bipolar patients but not in healthy controls. The flattened response in patients was observed already after 3 weeks of lithium, and remained flattened after years of treatment. The findings suggest a greater degree of prolactin reponse reduction in those patients showing most pronounced stability on lithium treatment.

The mode of action of lithium in the treatment of bipolar affective disorder is unknown. Among its actions are effects on release and response to catecholamines in experimental animals. We have therefore examined its effect on peripheral catecholamines in man. After 3 weeks of administration of therapeutic doses of lithium carbonate, healthy volunteers showed a differential response of catecholamines to insulin stimulation. Although the response of plasma norepinephrine remained unchanged, epinephrine response was dramatically reduced. These findings provide additional evidence for the separate neural regulatiof the adrenal medulla and sympathetic nerve endings. Further studies are necessary to determine whether these effects on peripheral epinephrine are paralleled by changes in central epinephrine.

1. 1. Amphetamine induced growth hormone (GH) response (Study 1) and TRH Induced TSH response (Study 2) were assessed in patients with endogenous depression (n = 20 and n = 22, respectively), who underwent a dexamethasone suppression test (DST) on the following day. 2. 2. The GH response to the amphetamine was significantly lower in the group of depressed patients than in the healthy controls (n = 13). 3. 3. There was no difference between the DST nonsuppressors (n = 12) and suppressors (n = 8) in the GH peak values. This data strongly suggests that the two tests are independent from each other. 4. 4. There was no significant relationship between the DST and TRH-TSH results. 5. 5. Patients with blunted TSH response to TRH have had significantly higher cerebrospinal fluid 5-HIAA levels.