Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response.

BACKGROUND: Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD). METHOD: To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes. We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts. RESULTS: The non-Li group had smaller hippocampal volumes than the controls or the Li group (F 2,102 = 4.97, p = 0.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t(51) = 2.00, p = 0.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t(43) = 2.62, corrected p = 0.02). CONCLUSIONS: Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.

Comparison of the effects of ketamine and memantine on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial.

N-methyl D-aspartate (NMDA)-antagonists decrease neurotoxicity by inhibiting Ca2+ influx which is of interest for the treatment of acute cerebrovascular insults and chronic neurodegenerative disorders. Currently, there is no surrogate marker for quantification of NMDA-receptor-mediated drug effects, which hampers dose-finding clinical studies. As prolactin and cortisol liberation is in part influenced through NMDA-receptors we investigated whether the elevation of prolactin or cortisol plasma levels is a class effect of NMDA-antagonists and might be an appropriate marker for studying NMDA-antagonistic potency. Fifteen healthy male volunteers participated in this placebo-controlled, randomized, three-way crossover trial. Ketamine (0.5mg/kg), memantine (0.16 mg/kg; i.e., a well tolerated standard dose) or placebo were infused over 60 min. Ketamine increased serum prolactin and cortisol levels (p < 0.001), whereas memantine and placebo did not affect hormone levels. Further studies are needed to define whether higher doses of memantine or other NMDA antagonists can induce hormone release.

Current aspects of valproate in bipolar disorder.

For more than 30 years, lithium has been the drug of choice for the treatment of bipolar disorder. However, it has numerous adverse effects, a relatively slow onset of action, many common drug-drug interactions, and a narrow therapeutic index. Because of these problems, researchers looked for alternative and/or adjunctive treatments in bipolar disorder, focusing on the anticonvulsants carbamazepine and valproate. The existing data of valproate are reviewed pointing out its promises and limitations in psychiatric diseases. Growing data indicate that valproate is a well tolerated and effective agent in bipolar disorder. Controlled studies prove its use in acute mania, often with a rapid onset of action. Open studies suggest that the drug also reduces the frequency and intensity of recurrent manic and depressive episodes over extended periods. Its acute and prophylactic antidepressant effects are probably minor to its antimanic efficacy. Recent data support the specific therapeutic efficacy of valproate in certain subtypes of bipolar illness: rapid cycling variant, mixed mania, bipolar disorder associated with panic attacks, comorbid alcohol or substance abuse, with neurological features or secondary to organic illnesses. These features make valproate interesting as an alternative treatment for patients who generally respond less well to lithium or as a useful adjunct in the treatment of complicated patients who do not respond to single agents. However, further controlled studies are warranted to provide clear guidelines for the treatment with valproate.

Mortality of patients who dropped out from regular lithium prophylaxis: a collaborative study by the International Group for the Study of Lithium-treated patients (IGSLI).

Excess mortality has repeatedly been found in patients with recurrent affective disorders. In previous studies our group has shown that during long-term lithium treatment the mortality of such patients is not significantly higher than that of the general population. In the present study, we extended our investigation to 273 patients from the earlier IGSLI cohort who subsequently dropped out from regular lithium prophylaxis. The standardized mortality ratio (SMR) for the whole group was 2.5, significantly higher (P < 0.01) than 1.0, which is the SMR of the general population. Furthermore, the SMR of the patients from each of the participating countries, namely Denmark, Germany and Austria, was significantly higher than 1.0. These findings strengthen the evidence accumulated in previous investigations that regular long-term lithium treatment does in fact markedly reduce the excess mortality of patients with recurrent affective disorders.

How to interpret findings on mortality of long-term lithium treated manic-depressive patients?! Critique of different methodological approaches.

Many studies have shown that patients with affective disorders have a mortality markedly higher than that of the general population. Studies of manic-depressive patients given prophylactic lithium treatment have yielded varying results. Some authors have reported mortalities which were more than four times that of the general population. Others have found mortalities which did not differ significantly from that of the general population. In order to examine these discrepancies we re-analysed the data of a previous study by IGSLI, using three different methods to calculate the Standardised Mortality Ratio (SMR). The data base was enlarged by adding mortality data from two additional centres. The results indicate that the discrepancies may result from the common use of a 'cumulative' approach which produces a distortion of the data if the treatment duration is not taken into consideration properly. An analysis which eliminates this artefact and takes the treatment duration into account ('year-by-year' approach) provides the strongest evidence that the mortality of lithium treated patients is not significantly different from that of the general population.

Excess cardiovascular and suicide mortality of affective disorders may be reduced by lithium prophylaxis.

The mortality of patients suffering from affective disorders is much higher than that of the general population; this excess is due to both suicides and cardiovascular disease. During long-term lithium treatment, the overall mortality has not been found to differ significantly from that of the general population but the question remains whether this lowering, if it is in fact caused by lithium, is due to a reduction in suicide frequency or cardiovascular mortality, or both. We analysed data from 827 previously studied patients and used a procedure that estimated both overall mortality and cause-specific mortalities by single-case analysis. For overall mortality, the ratio of observed deaths (among the patients) to expected deaths (in the general population) was 1.14, which is not significantly different from 1.0; this was also found in our previous analysis. In the whole patient group, comprising 5600 patient years under lithium treatment, seven suicides were observed and 1.3 expected, resulting in a standard mortality ratio of 5.22; this is significantly > 1.0, but markedly lower than that found in patients with affective disorders not given lithium. Cardiovascular mortality was not found to be higher in our patients than in the general population. In view of the fact that a placebo-controlled mortality study under long-term conditions is neither ethically nor practically feasible, our findings cannot prove definitively that long-term lithium treatment counteracts factors responsible for the excess suicide and cardiovascular mortality of affective disorders. However, our observations are compatible with such a notion.

[The interactions of antidepressant drugs]. / Interaktionen von Antidepressiva.

An overview is presented of interactions of currently frequently used antidepressants with various other drugs. The effects of interactions of tricyclic antidepressants, tetracyclics, monoamine oxidase (MAO) inhibitors, lithium and carbamazepine are comparatively well documented, their pharmcodynamic and pharmacokinetic characteristics extensively researched and well known to the practitioner. These interactions concern synergic effects, enzyme inhibition, enzyme induction in the liver, competitive inhibition of absorption and reciprocal effects on the receptor. With regard to lithium, problems of renal clearance and circulation are also important. On the other hand, interactions of reversible and selective MAO-A inhibitors (RI-MA) and selective serotonin reuptake inhibitors (SSRI) with various other drugs are in the process of elucidation. Very threatening interactions are known to be caused by a combination of SSRI and MAO inhibitors (serotonergic syndrome). SSRI and tricyclic antidepressants dispensed concurrently cause an increase in the plasma level of the tricyclic antidepressant. Hence, the practitioner must become aware of this high responsibility towards the patient when prescribing even on single drug, which must be selected with the utmost care.

Mortality during initial and during later lithium treatment. A collaborative study by the International Group for the Study of Lithium-treated 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 comparative efficacy of carbamazepine low and high serum level and lithium carbonate in the prophylaxis of affective disorders.

The prophylactic efficacy of carbamazepine slow release (CBZ) at ke different blood levels and lithium carbonate slow release (LI) was compared in a retrospective/prospective, randomized, 2-year open trial. 84 patients with a DSM-III-R diagnosis of recurrent affective disorder who had no prophylactic medication in the 2 years preceding the trial (no LI nonresponders), were randomly allocated to three treatment groups: CBZ low (15-25 mumol/l), CBZ high (28-40 mumol/l) and LI (0.6-0.8 mumol/l). Fifty-eight patients completed the full observation period of 2 years, 26 patients dropped out. There were no statistically significant differences in the efficacy of the prophylactic treatment for bipolar patients. For the unipolar patients, the group with a low CBZ serum level showed no reduction in the duration of episodes. The two other treatment groups seem to be equal in attenuation of a unipolar course of an affective disorder.

The effect of long-term lithium treatment on the mortality of patients with manic-depressive and schizoaffective illness.

Clinical research centers in Aarhus, Berlin, Hamilton and Vienna collected mortality data for 827 manic-depressive and schizoaffective patients given lithium treatment for more than 6 months. The average duration of the treatment was 81 months and the total time on lithium 5600 patient-years. For each patient, the mortality risk was calculated by entering the appropriate national life tables for the general population. The number of observed deaths was 44; the number of expected deaths was 49.7. The standardized mortality ratio, 0.89, did not differ significantly from 1.0. The mortality of manic-depressive patients is 2-3 times that of the general population. Our data show that the mortality of manic-depressive and schizoaffective patients given long-term lithium treatment does not differ significantly from that of the general population.

The use of carbamazepine in the treatment of schizophrenic and schizoaffective psychoses: a review.

This article reviews current literature on the clinical efficacy of carbamazepine (CBZ) administration in schizophrenic and schizoaffective psychoses. With respect to the use of CBZ in cases of aggression, overactivity and other behavioral dyscontrol syndromes, only a few, mainly open, studies have been conducted. Attention to the efficacy of CBZ in schizophrenia and related psychoses was rather late in developing, with most of the studies done since 1981. Although the results of the different controlled and uncontrolled experiments are very difficult to compare, the results generally indicate beneficial effects--particularly if CBZ is used as an adjunct to neuroleptic medication. Suggestions for future research strategies to maximize the usefulness of CBZ in schizophrenia and related disorders are given.

A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder.

A multicenter randomized 4-week interindividual double-blind study was carried out in 58 hospitalized patients with major depressive disorder (DSM III 296.23, 296.22, 296.33, 296.32, 296.53 and 296.52) to test the dose-effect relationship of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram: 3 x 0.25 mg, 3 x 0.50 mg and 3 x 1.00 mg rolipram/day. With respect to the desired effect, the 3 x 0.50 mg dosage stood out from the others in almost all relevant parameters. With respect to the response rate, the efficacy of the 3 x 0.25 mg dosage was about the same as that reported in the literature for placebo. The inferior performance of the 3 x 1.00 mg dosage compared to the 3 x 0.50 mg dosage might indicate a reverse U-shaped dose-effect relationship. There was good tolerance to all three dosages. There were no findings that might cast doubt on the safety of the dosages tested.

Three cases of severe mania successfully treated with high-dosage lithium-carbonate.

Three female patients suffering from severe mania, who failed to respond to increasingly high dosages of highly potent neuroleptics, were put on a high-dose regime of lithium carbonate. With rapidly increasing daily doses of lithium carbonate, blood levels of approximately 1.3-1.51 mmol/l were achieved. When high lithium levels had been attained the patients showed a considerable improvement between 75 and 82 percent on the Bech-Rafaelsen Scale. At the same time it proved possible to reduce additional medication. Not toxic effects of lithium carbonate were observed. The consequences for clinical practice (e.g. shortened duration of hospitalization) are discussed.

Temporal stability of diagnostic criteria for functional psychoses. Results from the Vienna follow-up study.

200 first admissions with functional psychoses were interviewed with PSE and rated simultaneously according to different diagnostic criteria (ICD-9, RDC, DSM-III, St. Louis, Taylor, Vienna Research Criteria). At follow-up 7 years later 186 patients could be traced and a course diagnosis was applied to each patient. Temporal stability of diagnostic criteria was calculated for ICD-9, RDC and DSM-III by stability coefficient and kappa values and was used as a criterion for validity. Schizophrenia and affective disorder display considerable stability over time, no matter whether one uses ICD-9, RDC or DSM-III. The data for schizoaffective disorder are less impressive, the stability coefficient is much higher for schizoaffective bipolar than for schizoaffective depressive patients.

Computerized documentation for lithium outpatients (routine and research data).

To follow up the status and further outcome of patients with recurrent affective and schizoaffective disorders treated in a lithium/prophylactic treatment outpatient (LOP) clinic the authors have developed a documentation system based on a database, which ASCII files. This system should be useful as a basis for optimal treatment and is helpful for special research purposes regarding prophylactic treatment (lithium salts, carbamazepine, antidepressants, etc.). The documentation system consists of two parts, one for routine documentation system consists of two parts, one for routine monitoring including basic data, global course, and routine form with side-effects, and another one for research purposes with documentation of laboratory findings, EEG, and documentation of every cycle which can be added easily. Moreover, with this documentation system it will be possible to compare results from different research centres.

Effect of lithium on the EEG of healthy males and females. A probability mapping study.

This study is based on 20 healthy volunteers (10 males and 10 females). Between 675 and 1,225 mg lithium carbonate per day was applied for 10 days. EEG was recorded before (day 0) and after lithium intake (day 10) with 19 electrodes and quantified by spectrum analyses. Absolute power and coherence values, between adjacent electrodes and between electrodes on homologous sites of both hemispheres, were computed for five frequency bands. For the evaluation of differences of the EEG parameters obtained on days 0 and 10, a nonparametric paired permutation test was applied. The obtained descriptive error probabilities were presented in topographic maps. Under lithium, the absolute power increased in the entire frequency range, but most distinct in the theta and beta 1 band. The local coherence analyses revealed a clear lateralization: increase in the left hemisphere and decrease in the right. The interhemispheric coherence decreased occipitally and frontally. A comparison of the EEG changes under lithium in males and females showed clear differences in the topographic distribution of power as well as coherence changes.

Cognitive disturbances in chronic schizophrenia: formal thought disorder and basic symptoms.

We investigated 37 chronic schizophrenic patients with two objective rating scales (AMDP and Brief Psychiatric Rating Scale; BPRS) and compared the questioned symptoms with the Frankfurter Beschwerde Fragebogen (FBF), a questionnaire for subjective complaints which are close to the uncharacteristic 'basic' symptoms of schizophrenic patients. It was pointed out that the questions in the FBF relate mainly to uncharacteristic symptoms like disturbances of perception, concentration, attention, perceiving, and memory. These subjective symptoms of the FBF show a few correlations with the AMDP/BPRS rating. The total score of the FBF gave no further information about social functioning of patients with cognitive disturbances.

New developments in the classification and diagnosis of functional mental disorders.

Six new developments in the classification and diagnosis of functional mental disorders are described. These are: the standardization of data collection, the formulation of operational diagnostic criteria, the multiaxial approach to psychiatric diagnosis, the development of compromise classification systems, the polydiagnostic approach, and, finally, the idea of validating diagnostic concepts instead of taking them for granted. The merits and pitfalls of each of these new developments are discussed. It is concluded that both the traditional categorical diagnostic approach and the introduction of diagnostic compromise systems are an obstacle to progress in psychiatric research. On the other hand, a blind belief in operational diagnostic criteria also has its drawback. Only efforts at standardized data collection, at using a multiaxial and polydiagnostic approach, and regarding psychiatric diagnoses as hypothesis, will contribute to progress in psychiatric research.