H.H. Stassen

Mortality of patients with mood disorders: follow-up over 34–38 years

BACKGROUND All follow-up studies of causes of death in affective disordered patients have found they have markedly elevated suicide rates and a less reproducible increased mortality from other causes. The reported rates by gender, disorder type and treatment are more variable. METHODS Hospitalised affective disordered patients (n=406) were followed prospectively for 22 years or more. Later, mortality was assessed for 99% of them at which time 76% had died. RESULTS Standardised Mortality Rates (observed deaths/expected deaths) for patients were elevated especially for suicide and circulatory disorders in both men and women. Women actually had higher suicide rates but that did not take into account the twofold increase in general population rates for men. Unipolar patients had significantly higher rates of suicide than bipolar Is or IIs. In all groups long term medication treatment with antidepressants alone or with a neuroleptic, or with lithium in combination with antidepressants and/or neuroleptics significantly lowered suicide rates even though the treated were more severely ill. Although at the age of onset the suicide rates were most elevated, from ages 30 to 70 the rates were remarkably constant despite the different courses of illness. LIMITATIONS The patients were identified as inpatients and followed prospectively. The treatments were uncontrolled and are not quantifiable but were documented during the follow-up. CONCLUSIONS Men and women hospitalised for affective disorders have elevated mortality rates from suicide and circulatory disorders. Unipolars have higher suicide rates than bipolar Is or IIs. Long term medication treatment lowers the suicide rates, despite the fact that it was the more severely ill who were treated.

Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions

OBJECTIVES To analyse the time course and some risk factors for a diagnostic change from major depression to bipolar disorders (BP) over an average of 20 years from the onset of the disorders. METHODS Patients (406) with major mood disorders hospitalised at some time between 1959 and 1963 were followed-up until 1985. The analysis also included the course prior to hospitalisation. Survival analyses and Cox regression models were applied. RESULTS A diagnostic change from depression to bipolar I occurred in about 1% of the patients per year and to bipolar II disorders in about 0.5% per year. Risk factors for a change from depression to BP-I disorder were male sex and an early onset of the disorder; risk factors for a change from depression to BP-II disorder were female sex, a later onset of the disorder and a positive family history of mania. CONCLUSIONS Across the entire lifetime, every new episode of depression brings a new risk for mania; more than half of our severe mood disorder cases became bipolars. The risk of depression developing into bipolar disorder remains constant lifelong. LIMITATIONS The diagnostic classification of ICD-9 met RDC criteria for bipolar disorder in only 90% of cases. Part of the data collected in retrospect may be less reliable; the prospective data were only collected every 5 years from 1965 to 1985 using multiple sources; mild manifestations between the follow-ups may have been partially missed. The sample of subsequent hospital admissions for major depression and mania represents a severe group of patients and generalisations to ambulatory cases may not be possible. Not all risk factors for diagnostic conversion described in the literature could be assessed in this study.

How specific are deficits in mismatch negativity generation to schizophrenia

BACKGROUND Mismatch negativity (MMN) is an auditory event-related potential that provides an index of auditory sensory memory. Deficits in MMN generation have been repeatedly demonstrated in chronic schizophrenia. Their specificity to schizophrenia has not been established. METHODS Mismatch negativity to both duration and frequency deviants was investigated in gender- and age-matched patients with schizophrenia or schizoaffective disorder (n = 26), bipolar disorder (n = 16), or major depression (n = 22) and healthy control subjects (n = 25). RESULTS Only patients with schizophrenia demonstrated significantly smaller mean MMN than did healthy control subjects. Detailed analyses showed significantly smaller MMN to both duration and frequency deviants in patients with schizophrenia than in healthy control subjects; however, the reduction of frequency MMN in patients with schizophrenia was not significant in the comparison across all groups. Mismatch negativity topography did not differ among groups. No consistent correlations with clinical, psychopathologic, or treatment variables were observed. CONCLUSIONS Mismatch negativity deficits, and by extension deficits in early cortical auditory information processing, appear to be specific to schizophrenia. Animal and human studies implicate dysfunctional N-methyl-D-aspartate receptor functioning in MMN deficits. Thus MMN deficits may become a useful endophenotype to investigate the genetic underpinnings of schizophrenia, particularly with regard to the N-methyl-D-aspartate receptor.

Time course of improvement under antidepressant treatment: A survival-analytical approach

A meta-analysis of an earlier multicenter, double-blind efficacy study comparing placebo, oxaprotiline and amitriptyline was performed in order to test the survival-analytical approach in modelling the onset of improvement and response to treatment with antidepressants. The sample consisted of moderately depressed male (n = 154) and female (n = 275) patients (aged 17-73), diagnosed according to DSM-III criteria for major depression. Of these, 120 were treated with oxaprotiline, 120 with amitriptyline and 189 with placebo. Efficacy criteria were Hamilton Depression (HAMD) and Anxiety (HAMA) and Zung Self-Rating scales. Up to eight ratings over a period of 40 days were available for analysis. The results showed that the sensitivity in discriminating between groups was substantially enhanced through the inclusion of drop-outs and consideration of the effect of time to withdrawal from the study due to lack of improvement. Withdrawal from the trial due to inefficacy occurred earliest under placebo (50% within the first 8 days), whereas less than 40% dropped out within the first 12 days under active treatments. The most interesting and unexpected finding of the analysis was that the time course of improvement among responders was independent of the treatment modality, and thus identical in all three groups. Specifically, the efficacy of any of the given treatments was reflected only by the total number of responders or nonresponders. Once triggered, the time course of recovery from illness becomes identical to that of spontaneous remissions as observed, for example, under placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression.

The catechol-O-methyltransferase (COMT) is a major degrading enzyme in the metabolic pathways of catecholaminergic neurotransmitters such as dopamine and norepinephrine. This study investigated whether the functionally relevant Val108/158Met gene variant is associated with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM-IV criteria) participating in a randomized clinical trial with both drugs. In patients treated with mirtazapine, but not paroxetine, allelic variations in the COMT gene were associated with differential response. COMTVAL/VAL and COMTVAL/MET genotype carriers showed a better response than COMTMET/MET-bearing patients in the mirtazapine group. Moreover, carriers of the COMTVAL/VAL or COMTVAL/MET genotype had significantly greater HAMD-17 (Hamilton Rating Scale for Depression 17 item version) score reductions than COMTMET/MET homozygotes from week 2 to 6, respectively, in the mirtazapine group. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the COMT gene.

Genetic aspects of the EEG: an investigation into the within-pair similarity of monozygotic and dizygotic twins with a new method of analysis

A considerable number of previous studies emphasized the importance of genetic factors in the spontaneous EEG. In this context MZ twins were found to resemble their co-twins as much as they resemble themselves over time, whereas investigations into the within-pair similarity of DZ twins yielded very inconsistent findings. To test these conclusions, we re-analysed the EEGs of an earlier twin study (24 MZ pairs/25 DZ pairs) by means of a new method of analysis. In our study, MZ twins proved to be less like one another than each person is to himself over time. However, this result might be because the EEG data were not optimal for the applied method of analysis, but the existence of true within-pair differences cannot be excluded. Contrary to earlier findings in the literature, the analysis of the EEG of DZ twins showed that, for a sufficiently representative sample, the within-pair similarity is significantly above the inter-individual similarity between unrelated persons.

Schizophrenia and smoking: Evidence for a common neurobiological basis?

Several previous investigations have suggested that the gene for the alpha 7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for the heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective, and bipolar patients we have aimed 1) to confirm the potential association between schizophrenia and the alpha 7-nicotinic receptor, 2) to test the diagnostic specificity of alpha 7-receptor subunits with respect to psychiatric diagnoses, and 3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the alpha 7-nicotinic receptor gene CHRNA7. Highly significant differences (P < 0.0001) between the allele distributions of patients and controls were detected for these two markers with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding. Our results suggested an unspecific vulnerability that depended on the severity of overall psychopathology in terms of the co-occurrence of psychopathology with no clear-cut boundary between the diagnostic entities. In comparison with healthy controls, this vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives. As to the question of alpha 7-receptor differences between smokers and nonsmokers among the healthy control subjects, our analysis revealed no significant differences, thus indicating that the differences between patients and controls are more than just a smoker/nonsmoker distinction. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:173-177, 2000.

Effect of neuroleptics on positive and negative symptoms and the deficit state

The concept of negative symptoms tries to operationalize a deficit syndrome observed in schizophrenia, but also in other disorders. The instruments for the measurement developed so far are unclear in their dimensional structure and validity. Further methodological development is needed. A new scale for measuring negative symptoms was derived from the AMDP-system and applied to results of drug trials with clozapine, fluperlapine, and haloperidol. The three drugs were equally effective on negative symptoms of acute and chronic schizophrenics.

Classification of Schizo-Affective Patients by Multidimensional Scaling and Cluster Analysis

269 patients with schizophrenia, schizo-affective or affective disorders admitted to a hospital in Zürich were examined by the AMP system and the syndrome checklist of Wing and co-workers. The data were analyzed using a special set-theoretical similarity measure for nonlinear graduations, multidimensional scaling to achieve a metric representation of the similarity matrices, and a cluster analysis, originally described by Meisel in 1972.

The MAOA T941G polymorphism and short-term treatment response to mirtazapine and paroxetine in major depression.

This study investigated the possible association of the MAOA T941G gene variant with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM‐IV criteria) participating in a randomized double‐blind controlled clinical trial. Female mirtazapine‐treated patients homozygous for the T‐allele had a significantly faster and better treatment response than TG/GG‐patients. In males, we failed to show an association between MAOA T941G gene variant and mirtazapine response. In the paroxetine‐treated group, there were no significant differences in treatment response between MAOA T941G genotype groups. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the MAOA gene, at least in female patients. An independent replication of our finding is needed. If replicated, genotyping of this locus could become a promising tool to predict response to mirtazapine treatment in females suffering from major depression.