No correlation between lithium serum levels and psychopathological features during the euthymic interval of patients with recurrent affective disorder.

INTRODUCTION: The aim of this prospective study was to investigate the influence of lithium serum levels on subclinical psychopathological features during the euthymic interval in patients with an affective disorder. METHODS: The study included 54 patients with a recurrent affective disorder undergoing a continuous prophylactic lithium treatment (31 unipolar, 23 bipolar). The observation period lasted for 2 years and included 332 visits. Visits consisted of a detailed interview, a continuous measurement of lithium levels and the collection of validated scales including HAMD, YMRS, CGI, VAMS and the SCL-90R. Several correlations between lithium serum levels and different psychopathological features during the euthymic interval were calculated on an individual patient basis and on a group basis to reveal generally occurring correlations. RESULTS: No generally occurring significant correlations between lithium serum levels and specific psychopathological features were found. Only on a single patient level, 32 significant correlations between lithium level and specific psychopathological features were found, partly indicating a negative and partly indicating a positive influence of higher lithium levels on psychopathological symptoms. Nevertheless, in the group analyses no significant correlations were found. DISCUSSION: Higher lithium levels were not associated with an improved psychopathological status, but they were not associated with a worse status (due to a higher burden of side effects) either. According to the literature there is currently no strong evidence to treat patients with a higher lithium level. It is recommended to start with a lower level and to continue with individual adjustments in accordance to prophylactic efficacy and tolerability.

[Mixed affective disorders]. / Gemischt-affektive Störungen.

The Kraepelin concept of "mixed states" has experienced a renaissance over the last two decades. This has been caused by clinical as well as theoretically relevant factors. Of particular clinical relevance is the fact that more than 40% of all patients with bipolar disorders show at least one mixed affective episode during the course of their illness. However, the correct assessment and the precise classification of the symptoms are very important. A diagnosis according to the tight criteria of ICD-10 or DSM-IV, or perhaps based on the moderate Pisa or Cincinnati criteria, is recommended, whereas the use of broader definitions cannot be advised. Mixed schizoaffective episodes are under-diagnosed in comparison to pure affective mixed episodes, although both are defined by ICD-10 as well as by DSM-IV, and the frequency of occurrence is almost the same. Mixed schizoaffective episodes appear to be one of the most severe forms of bipolar disorders. Their clinical relevance is mainly caused by their unfavourable prognosis and difficulty in treatment. Atypical neuroleptics combined with anticonvulsives have proved to be more effective than any other psychopharmacological substances. The occurrence of mixed depressive and manic symptoms during one and the same episode is theoretically important, especially in the sense of their nosological and etiological differentiation.

Resolution of SPECT-determined anterior cerebral hypoperfusion correlated with maintenance ECT-derived improvement in residual symptoms in a case of late-life psychotic depression.

A 70-year-old widow with recurrent psychotic depression was successfully treated with maintenance electroconvulsive therapy (ECT) for 4 years up to the present. Anterior cerebral hypoperfusion visualized by single photon emission computerized tomography (SPECT) before ECT persisted (second SPECT study 14 days after the last ECT session) despite a response to the first course of acute ECT. Only mild symptoms remained. Relapse occurred 2 weeks after the post-ECT SPECT study. The hypoperfusion improved after response to a second course of acute ECT (per SPECT 5 days after the last ECT session), and perfusion was normalized after 2-year maintenance ECT (per SPECT 14 days after the last ECT session). The normalization coincided with improvement in depressive symptoms remaining after the second course of acute ECT. We speculate that the effectiveness of maintenance ECT might have been in part the result of the improvement in residual symptoms and that resolution of the persistent anterior hypoperfusion, which might underlie medical refractoriness, illness chronicity, and relapse tendency in late-life depression, might have been associated with the improvement in residual symptoms achieved by maintenance ECT.

Prediction and prevention of transition to psychosis in young people at incipient risk for schizophrenia.

The treatment of psychotic disorders, particularly schizophrenia, had been viewed with pessimism until a recent shift in focus from established or chronic illness to earlier phases of illness around the onset highlighted opportunities for enhanced recovery. Associated with this change in focus of research and clinical efforts has been the recognition that the biological and social changes underpinning the development of psychotic disorders may already be active in the pre-psychotic or prodromal phase. It has therefore been suggested that efforts toward the prevention of psychotic disorders should focus on the emerging illness. This article provides a review of work that has been conducted at the PACE Clinic in Melbourne, Australia since 1994. This clinical research program was established to develop strategies for the identification of young people at high risk of developing a psychotic disorder within a short period of time- primarily by virtue of recent mental state changes. Additionally, biological and psychological processes that have been proposed to underlie the development of illness have been investigated and potential preventive interventions have been evaluated.

How long should patients with psychotic depression stay on the antipsychotic medication?

BACKGROUND: Patients who have major depression with psychotic features have greater morbidity and mortality than patients with nonpsychotic major depression. In particular, relapse and recurrence have been reported to occur more frequently in patients with psychotic depression than nonpsychotic depression. Despite the frequent relapse and recurrence in major depression with psychotic features, there are few studies of the efficacy of continuation and maintenance treatments. METHOD: Forty patients with a diagnosis of unipolar DSM-III-R major depression with psychotic features were treated with fluoxetine and perphenazine for 5 weeks after granting written informed consent. The patients who responded to treatment continued to receive the combination for an additional 3 months. If a patient was stable for 4 months on treatment with the combination, the patient was then gradually tapered off perphenazine treatment. For patients who exhibited impending relapse, perphenazine was restarted. Impending relapse was defined as any of the following: (1) symptoms meeting DSM-IV criteria for major depressive disorder (with or without psychotic features), (2) a total score of > or = 17 on the HAM-D, or (3) the presence of any psychotic symptoms. After 1 year of taking fluoxetine, patients were tapered off fluoxetine treatment. Data were gathered from 1992 to 1997. RESULTS: Thirty patients responded to the initial 5 weeks of treatment with perphenazine and fluoxetine. After taper of perphenazine following 4 months of treatment with fluoxetine and perphenazine, 22 (73%) of the 30 patients exhibited no signs of relapse over the next 11 months (8 months of fluoxetine monotherapy followed by a taper of fluoxetine and 3 additional months of assessment). Patients who showed signs of relapse after taper of the antipsychotic were more likely to have had a longer duration of the current episode and a history of more frequent past episodes and were more likely to be younger (under the age of 30 years). CONCLUSION: The data from this study suggest that a majority of patients who have major depression with psychotic features do not require treatment with antipsychotic medication for more than 4 months.

Estrogen administration does not reduce the rate of recurrence of affective psychosis after childbirth.

BACKGROUND: High rates of postpartum relapse occur in women with histories of bipolar or schizoaffective disorder. These relapses may be triggered by the postdelivery fall in circulating estrogen through alteration of central neurotransmitter (especially dopaminergic) systems. This study tested the hypothesis that estrogen administration after childbirth would prevent postpartum relapse and would alter dopamine receptor sensitivity. METHOD: Twenty-nine pregnant women with a Research Diagnostic Criteria diagnosis of hypomania (bipolar II), mania (bipolar I), or schizoaffective disorder participated in an open clinical trial. Three transdermal dose regimens of estrogen (17beta-estradiol) were tested. Starting doses were 200 (N = 13), 400 (N = 3), and 800 (N = 13) micro g/day, beginning within 48 hours after delivery and reduced by one half every 4 days for a total of 12 days. On the fourth day after starting estradiol therapy (before relapse occurred), subjects participated in a neuroendocrine challenge test that measured the sensitivity of the central nervous system (tubero-infundibular) dopaminergic system (plasma prolactin and growth hormone responses to apomorphine). RESULTS: Estradiol at all dose regimens did not reduce the rate of relapse. However, of the 12 women who relapsed, those who had taken the highest dose of estradiol (800 micro g/day) needed less subsequent psychotropic medication (fewer chlorpromazine equivalents) and were discharged sooner than those who had taken either of the 2 lower doses. No differences in neuroendocrine responses to apomorphine were detected between women receiving the high-dose and the lower-dose regimens. CONCLUSION: The results do not support the hypothesis that a fall in circulating concentrations of estrogens precipitates relapse in subjects at risk of postpartum affective psychosis. The use of prophylactic estrogen in such circumstances is therefore highly questionable.

Twenty-five-year followup of the Israeli High-Risk Study: current and lifetime psychopathology.

Current and lifetime psychopathology was assessed in 50 Israeli children of parents with schizophrenia who were either of kibbutz families and raised collectively with the help of child care workers, or of urban families and raised by their parents. Index subjects were compared with 50 matched control children of healthy parents by means of the Schedule for Affective Disorders and Schizophrenia-Israel. Subjects were evaluated in adulthood at a mean age of 31 years; schizophrenia was found exclusively among children of ill parents, and no effect of town or kibbutz rearing on risk for schizophrenia was observed. Major affective illness was more common among kibbutz index subjects. Affective symptomatology observed in some index parents was evenly distributed among town and kibbutz parents and was not related to the diagnosis of affective disorders in at-risk children. Current adult functioning was similar between town-and kibbutz-raised subjects (and in general reflected good adjustment); an excess of personality disorders was found among index subjects. The present findings support the concept that both familial and environmental factors operate in the expression of psychopathology.

Overview and summary: twenty-five-year followup of high-risk children.

We report a 25-year followup of a group of 50 children at genetic risk for schizophrenia (by virtue of having a parent with the disorder) and 50 matched controls. The children who eventually developed schizophrenia spectrum disorders, including schizophrenia, were identifiable by cognitive-psychophysiological, neurointegrative, and social/personality traits in the preteenage period. The children at risk were also more likely to develop other Axis I disorders, chiefly affective. Moreover, the risk of Axis I disorders was significantly greater among children raised in the group atmosphere of a kibbutz than among those raised in their own nuclear families in cities and towns in Israel. The study is a unique contribution to knowledge of factors underlying the development of psychopathology.

Seasonality of the episodes of recurrent affective psychoses. Possible prophylactic interventions.

This study is an attempt to ascertain whether evidence for seasonal variations of the episodes of recurrent affective psychoses can be found in patients in Greece. Due allowance has been made for the fact that different socio-cultural and above all climatological factors prevail in Greece as opposed to other countries, which might be relevant in the phenomenon of seasonality. The seasonal distribution of the psychotic episodes, either depressive or manic, has been examined for 533 patients with various forms of affective psychoses, admitted to and treated in the State Mental Hospital of Athens, Greece, during the last 50 years. Statistically significant seasonal variation with peaks in spring was found for both depressive and manic episodes of various subgroups of patients, divided according to the I.C.D.-9.

5-HT brain function in affective disorder: d,l-fenfluramine-induced hormone release and clinical outcome in long-term lithium/carbamazepine prophylaxis.

Prolactin (PRL) and Cortisol (CORT) responses to d,l-fenfluramine (FEN) challenge (60 mg) were examined in patients with affective disorders on two occasions under euthymic conditions: drug-free before admission to prophylactic treatment and after about 9 months of medication with lithium or carbamazepine. Response to treatment was assessed by a complex algorithm using continuous ratings in outpatient clinic over a period of 2 years. In general, treatment resulted in a delayed and diminished CORT release (n.s.); subgroup analysis revealed an attenuated CORT response (P < 0.05) in responders, whereas nonresponders showed no change in CORT secretion pattern except an enhanced CORT baseline value (P < 0.05). Cross-sectional comparison of responders with nonresponders under medication yielded a trend for greater CORT stimulation in nonresponders. This result was not affected by FEN/NorFEN or lithium/carbamazepine serum levels, baseline CORT values, age, sex, diagnostic distribution, number of appointments to the outpatient clinic or duration of medication at the time of FEN test session. Before onset of prophylactic medication responders and nonresponders could not be discriminated significantly regarding stimulated hormone release, probably due to the small sample size (n = 17). CORT response to FEN was increased in drugfree unipolar patients compared to bipolar (P < 0.05) and to schizoaffective patients (P < 0.1). In accordance with its well-documented presynaptic 5-HT-agonistic action lithium medication resulted in a significantly greater increase in CORT release than carbamazepine (P < 0.05). Evaluation of PRL stimulation showed patterns of secretion quite similar to those of CORT, without reaching statistical significance in most cases. Perhaps due to methodological differences in assessing treatment response, these data do not confirm former results, which supposed an enhanced 5-HT net activity in long-term prophylactic lithium treatment. Because of high interindividual variances of hormone parameters, the FEN-test procedure is not a useful tool for the prediction of therapeutical outcome in terms of clinical routine use. Relations of stimulated hormone response as a marker of central serotoninergic activity and clinical outcome are discussed.

Intensity dependence of auditory evoked potentials and clinical response to prophylactic lithium medication: a replication study.

A predictor of clinical response to prophylactic lithium treatment in affective psychoses would be of considerable importance. In a pilot study, responders to prophylactic lithium medication, as compared with nonresponders, were characterized by a steeper slope of the amplitude/stimulus-intensity function (ASF slope) of the N1/P2 component of the auditory evoked potential. We tried to replicate this finding in 34 stabilized outpatients with affective illness who had been treated with lithium for at least 3 years. As in the pilot study, responders were again characterized by steeper ASF slopes than nonresponders. Since a steep ASF slope seems to indicate low central serotonergic function, it is speculated that a steep ASF slope characterizes those patients with a serotonin deficit who respond to serotonin agonists like lithium.

Multiple-risk cohorts and segmenting risk as solutions to the problem of false positives in risk for the major psychoses.

This paper briefly reviews the past promise, current results, and problems that have resulted from application of the risk group approach to understanding the etiology of the major psychoses. The ultimate objective is to stimulate a change in methods that it is hoped will lead to the knowledge required to warrant intervention. Methods of intervention are not reviewed because it is considered more important at this time to improve our understanding of the life course of these disorders. Interventions can be justified when a body of well-agreed-upon findings has accumulated indicating the developmental pathways to the major psychoses, including the situational contexts. It is assumed that the timing and mode of intervention will be evident when these pathways have been delineated.

[Effectiveness of finlepsin in the prophylactic therapy of phasic affective psychoses]. / Effektivnost' finlepsina pri profilakticheskoi terapii fazno protekaiushchikh affektivnykh psikhozov.

The article presents new, specified results of the use of finlepsin (carbamazepine) for the secondary prophylaxis in patients with endogenic affective psychoses. The data have emanated from a 5-year observation of the course of therapy of 73 patients. A positive effect was observed in 83% of cases, including 27.7% of cases with complete disappearance of circulation. No significant differences in the drug efficacy have been found in patients with manic-depressive psychosis versus schizophrenia. Yet, in most of the schizophrenics the phases have disappeared, while patients with manic-depressive psychosis have presented only partial improvement. The authors recommend that doses at the initial stages of treatment be increased in a gradual manner. Variants of a positive therapeutic time-course are described. They have also determined a period of time (3.5-4 months) after which the continuation of the therapy should be considered inadvisable in case of no favourable effect.

[Comparative features of the preventive action of carbamazepine and lithium carbonate in affective and schizoaffective psychoses]. / Sravnitel'nye osobennosti profilakticheskogo deistviia karbamazepina i uglekislogo litiia pri affektivnykh i shizoaffektivnykh psikhozakh.

The preventive properties of carbamazepine were studied and compared to those of lithium carbonate in patients suffering from affective and schizoaffective psychoses. Thirty-nine patients were examined. Of these, 19 patients received preventive treatment with carbamazepine and 20 with lithium carbonate. As to the preventive efficacy of carbamazepine, it turned out superior to lithium carbonate in all respects, particularly in cases of the monopolar depressive type of illness. The data obtained made it possible to analyze the possibilities of overcoming disadvantages of the preventive therapy with lithium carbonate by means of the use of carbamazepine or combined treatment with both the drugs, which considerably widens the potentialities of the preventive therapy of recurrent affective diseases. The method for the preventive therapy with carbamazepine and combined treatment including the use of lithium carbonate and carbamazepine are described.

[Comparative characteristics of the preventive properties of short-acting and delayed-action lithium carbonate in endogenous affective psychoses]. / Sravnitel'naia kharakteristika profilakticheskikh svoistv karbonata litiia kratkovremennogo i retardirovannogo deistviia pri éndogennykh affektivnykh psikhozakh.

The use of prolonged-action lithium carbonate preparations (quilonormretard and micalite) in 53 patients with manic-depressive psychosis and schizophrenia has shown that those drugs possess pronounced prophylactic properties. An open, two-stage control examination of 35 patients has demonstrated an advantage of the prolonged-action lithium carbonate preparations over instant-action ones in preventing relapses of affective and schizoaffective psychoses. Peculiarities of the prolonged-action lithium carbonate preparations on the quantitative and qualitative characteristics of the disease course are discussed.

[An economic evaluation in the pharmacokinetic prediction of preventive carbamazepine therapy]. / Ekonomicheskaia otsenka farmakokineticheskoi prediktsii preventivnoi terapii karbamazepinom.

The paper is concerned with the data of economic evaluation of pharmacokinetic prediction of the individual efficacy of preventive carbamazepin therapy of patients suffering from affective and schizoaffective psychoses. The study was carried out with the aid of the indicators of "direct" and "indirect" expenditures characterizing the efficacy of the use of carbamazepin in the treatment period as compared to the control one, using the pharmacokinetic predictors of the efficacy and without them. The potential economic efficacy of carbamazepin therapy appreciably increases provided the differential diagnostic indications for drug administration are specified. Such a technique of economic analysis of the data of psychopharmacokinetic studies enables their quantitative estimation and determination of economically important research priorities in that area.

[Unsolved problems in the indications for lithium prophylaxis in affective and schizoaffective disorders]. / Ungelöste Probleme bei der Indikationssetellung zur Lithiumprophylaxe affektiver und schizoaffektiver Erkrankungen.

The validity of various criteria for a prophylactic lithium indication was examined by means of the natural course of 356 unipolar depressive, bipolar manic-depressive, and schizoaffective patients. The prerequisite for a lithium prophylaxis was the occurrence of two or more episodes (excluding the index episode) within a 5-year's follow-up. The so far applied criteria for a lithium indication mentioned in the literature have proven to be too restrictive as far as this study is concerned, as the majority of the patients in need of lithium have been excluded from such a treatment. In this study new criteria have been deduced from the hypothetical examination of observed courses.

[Effects of lithium on normal psychic functions as a restriction on prophylactic use]. / Wirkungen von Lithium auf normale psychische Funktionen als Bedingungen für die Prophylaxe.

Within the context of psychological research on the mechanism of lithium prophylaxis mainly three questions are to be raised and hopefully answered: a) Can psychic effects of lithium be demonstrated during the free interval of manic-depressive patients under long-term lithium medication? b) Supposed that such lithium-induced effects could be demonstrated during the free interval, do they possess any significance for the prophylactic effect? c) Supposed that such prophylactically significant effects exist, do they refer to typical properties of the premorbid personality in which subjects with affective psychoses differ from normal subjects? A double-blind study in 14 manic-depressive patients during the free interval showed effects of lithium on learning, free recall, experience of time, and visual perception. The direction of the effects, i.e, increase or decrease versus corresponding values obtained under placebo, seems to be determined by the individual personality.