Circumscribed numerical deficit of dorsal raphe neurons in mood disorders.

BACKGROUND: Neurocircuits comprising limbic, striato-pallidal and thalamo cortical brain areas are assumed to be involved in the pathophysiology of mood disorders. All these brain regions receive serotonergic afferents arising from the rostral raphe, mainly the dorsal raphe. Although serotonergic systems appear to be involved in the pathology of mood disorders, there is uncertainty as to whether structural alterations in raphe nuclei exist alongside a functional dysregulation of the serotonergic system. METHODS: In the brains of 12 patients with mood disorders (major depressive disorder N= 6, bipolar disorder N = 6) and 12 normal subjects we performed a morphometric post-mortem study on neuronal morphology in all subnuclei of the dorsal raphe nucleus using Nissl stained 20 microm axial serial sections of the brainstem. RESULTS: The number of neurones of the ventrolateral subnucleus of the dorsal raphe was reduced by 31 % in patients with mood disorders compared with non-psychiatric control subjects. Ventrally located subnuclei of the rostral dorsal raphe (ventrolateral, ventral, interfascicular) taken together also showed a smaller number of neurones. Neurone numbers of the dorsal and the caudal subnucleus and volumes of all single subnuclei appeared to be unchanged. Analysis of morphological neuronal types revealed a smaller number of triangular neurones in the ventrolateral subnucleus. Numbers of ovoid and round neurones in the ventrolateral subnucleus also showed a trend to reduction. No correlation was found between neurone numbers in any subnucleus of the dorsal raphe and duration of illness. Neurone numbers did not differ in any subnucleus between patients with unipolar and those with bipolar affective disorder. CONCLUSIONS: Results indicate that patients with primary mood disorders have a circumscribed numerical neuronal deficiency in the dorsal raphe. This structural deviation may contribute to impaired serotonergic innervation of brain regions which are involved in the pathology of mood disorders.

Serum levels of amitriptyline and therapeutic effect in non-delusional moderately to severely depressed in-patients: a therapeutic window relationship.

In a prospective, open clinical study, the relationship between serum levels of amitriptyline (At) and nortriptyline (Nt) and the therapeutic effect after 6 weeks of treatment was investigated. Serum levels were measured by gas-liquid chromatography and the therapeutic effect was assessed by the Hamilton Depression Rating Scale (HAMD) and the Clinical Global Impression Scale (CGI). A number of 25 non-delusional, moderate to severely depressed inpatients were included. A therapeutic window relationship was detected by means of regression analysis (quadratic model). Low and high serum levels were associated with low therapeutic effect. In an intermediate range, the probability of good therapeutic effect was increased. This relationship reached significance for the serum levels of At (p < 0.05) and a trend for the sum of serum levels of At and Nt (p < 0.1). As expressed by the regression coefficient r2, about 25% to 35% of the variability of therapeutic effect was explained by serum levels. Dichotomized data sets according to limits of final values of HAMD and CGI as well as limits of a therapeutic window of 70 ng/ml and 200 ng/ml (sum of At and Nt) revealed significant differences by means of Fisher's exact test (p < 0.05). Furthermore, increased ratios of serum level of Nt per serum level of At were found to be associated with decreased therapeutic effect. Thus, the present data support the existence of a therapeutic window of serum levels of At in depression. Also taking into account other reports, this therapeutic window can be defined as being between about 70 and 220 ng/ml. The assay of serum levels of At can be used to lower the risk of unsatisfactory therapeutic outcome.

Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine.

As part of a prospective clinical study investigating the effects of atypical neuroleptics on autonomic neurocardiac function (ANF), serial standardized recordings of conventional electrocardiograms and computer-calculated measurements of 5-minute resting heart rate variability (HRV) were obtained from 51 medication-free inpatients with schizophrenia (DSM-III-R-diagnosed) before and after an average of 14.1 days of treatment with amisulpride 400 mg/day (N = 12), olanzapine 20 mg/day (N = 13), sertindole 12 mg/day (N = 13), or clozapine 100 mg/day (N = 13). Reference values for the HRV data were obtained from a large group of well-matched healthy controls (N = 70). The most important findings were the following: (1) clozapine, olanzapine, and sertindole all prolonged mean frequency-corrected QTc times, which, in the case of sertindole, proved to be significant (Wilcoxon test p <0.05); (2) sertindole and clozapine significantly increased the mean resting heart rate; and (3) only clozapine significantly reduced the parasympathetic resting tone. The results of the HRV studies are discussed considering the in vitro receptor profiles of the atypical neuroleptics under study. Potential implications for the cardiac safety and tolerance of these drugs are also discussed.

Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone.

BACKGROUND: Major depression (MD) is associated with an augmented risk of cardiovascular mortality. One possible explanation for this association is that MD influences autonomic neurocardiac regulation (ANR). However, previous studies on this subject revealed conflicting results. METHODS: Using an autonomic test battery, which consisted of standardised measurements of heart rate variability (HRV) and blood pressure, we (1) compared ANR between 25 patients with DSM-III-R diagnosed MD and 60 healthy controls, and (2) investigated the autonomic effects of antidepressive treatment with nefazodone. RESULTS: Following multivariate analysis of all tests a significant reduction in HRV could only be shown for the Valsalva ratio amongst the depressives compared to controls. There was a significant inverse correlation between the HRV during deep respiration and both the severity of depression and the duration of the depressive episode. Serial HRV recordings revealed that both the mean resting heart rate and systolic blood pressure significantly decreased after 21 days of nefazodone treatment (average dosage 413 mg/day), whereas after 10 days (average dosage 270.8 mg/day) there were no striking changes compared to the pre-treatment values. During nefazodone treatment no significant changes in parasympathetic tone occurred. LIMITATIONS: ANR was not assessed in a randomised, placebo-controlled fashion. CONCLUSIONS: (1) Patients with MD may suffer from functional disturbances in the interaction between the sympathetic and parasympathetic autonomic tree. (2) The pattern of autonomic changes during treatment suggests that nefazodone induced a dose dependent, serotonergically-mediated down-regulation of the sympathetic tone. This mechanism might be responsible for nefazodone's properties of reducing anxiety.

[Inclusion of psychopathologic methods for diagnosis of early neurotoxic effects from lead and organic solvent mixtures]. / Einbeziehung psychopathologischer Verfahren zur Objektivierung von neurotoxischen Früheffekten durch Blei und Lösemittelgemische.

To verify occupational neurotoxic effects it will be necessary to enlist the help of clinical psychologists and psychiatrists. However, no unified professional test battery exists to date. 119 healthy workers (26 lead-exposed, 45 exposed to mixed organic solvents, and 48 controls) were tested using uniformly standardised psychological and psychiatric methods. Long-term lead-exposed employees showed an increased number of psychoneurovegetative symptoms and deficits in attention performance according to the results of the Seeber-PNF and the Brickenkamp-d2-tests. There was no difference between the control group and persons exposed to the organic solvents test. Many parameters correlated to the dose of the toxic agent in the lead-exposed group. SCL-90-R, AMDP, and HAMD merely hinted at differences between the exposed subjects and the controls. Psychological and pathopsychological methods are necessary but will not suffice to detect early effects after long-term exposure to lead or organic solvents.

Prefrontal enlargement of CSF spaces in agoraphobia: a qualitative CT-scan study.

1. This CT study was designed to assess brain morphology in 21 patients with agoraphobia and 21 normal control subjects matched for age and sex. 2. Internal and external CSF spaces were evaluated by qualitative assessment on a 3-point scale (normal, questionable, abnormal). 3. Patients showed bilateral enlargement of prefrontal CSF spaces (p < .05). The rating abnormal" was given in the left hemisphere to 6 (28.6%) of the patients, to 4 (19%) of the patients in the right hemisphere, but to none (0%) of the normal controls. 4. These findings suggest that alterations in brain morphology are involved in the etiology of agoraphobia.

Tyrosine hydroxylase immunoreactivity in the locus coeruleus is reduced in depressed non-suicidal patients but normal in depressed suicide patients.

Noradrenergic neurons of the locus coeruleus (LC) have been implicated in the neurobiology of depression and suicidal behavior. The current postmortem study determined numbers of noradrenergic neurons by immunostaining the synthesizing enzyme tyrosine hydroxylase in the LC of 12 non-elderly depressed patients with a mood disorder as compared to 12 age- and sex-matched normal controls. Six patients were suicide victims, the other six patients died of natural causes. Non-suicidal patients had fewer neurons immunoreactive for tyrosine hydroxylase (TH-ir) than suicide victims or controls. No difference appeared between the number of TH-ir neurons in suicide patients and controls. Numbers of pigmented LC neurons were equal in patients and controls. The differences of TH-immunoreactivity could neither be attributed to drug influences nor to polarity of depressive disorder (i.e., unipolar/bipolar). Numbers of TH-ir neurons correlated positively with mean doses of tri- or tetracyclic antidepressants. Results of this study suggest a presynaptic noradrenergic deficit of the LC in depressed non-suicidal patients. Indirect evidence is provided that suicide is not related to decreased noradrenergic function and that traditional antidepressants may enhance noradrenergic activity of the LC in depressed patients.

Unipolar-bipolar dichotomy of mood disorders is supported by noradrenergic brainstem system morphology.

BACKGROUND: The biological basis of unipolar-bipolar dichotomy of mood disorders was investigated in this postmortem study by morphological comparison of the locus coeruleus (LC) as the main source of noradrenergic transmission in the brain. METHODS: Numbers and the rostro-caudal as well as ventro-dorsal distribution of neuromelanin-containing neurones in the LC were determined in brainstem of 12 patients with bipolar disorder (n = 6) or major depression (n = 6), and 12 normal comparison subjects. RESULTS: Bipolar patients had significantly more neurones on both sides of the LC as a whole than patients with major depression. Topographical analysis revealed that this difference was restricted to the rostral two thirds and the dorsal part of the LC, in which bipolar patients showed at least a trend to higher neurone numbers as compared to unipolar patients or to controls. LIMITATIONS: Small case numbers. CONCLUSIONS: Results suggest differences of innervation arising from the LC of bipolar patients as compared to patients with major depression. These first data of brainstem transmitter system morphology in unipolar and bipolar disorder are in line with neuroanatomical studies of other brain regions indicating a biological basis of the unipolar-bipolar dichotomy of mood disorders.

Reduced volume of limbic system-affiliated basal ganglia in mood disorders: preliminary data from a postmortem study.

Volumes of basal ganglia in postmortem brains of 8 patients with mood disorders and 8 control subjects without neuropsychiatric disorder were determined. Morphometry of serial whole-brain sections under the control of postmortem artifacts revealed reduced volumes of the left nucleus accumbens (-32%, P = 0.01), the right and left external pallidum (-20%, P = 0.04), and the right putamen (-15%, P = 0.04) in the patient group compared with the control group. These results suggest that, in particular, the limbic loop of the basal ganglia involving the nucleus accumbens and the pallidum is affected in mood disorders.

[Quantitative assessment of brain morphology with CT in agoraphobia]. / Qualitative Untersuchung der Hirnmorphologie im CT bei Agoraphobien.

This CT study was designed to assess brain morphology in agoraphobia. 21 patients and 21 normal control subjects matched in age and sex were investigated. Frontal and parietooccipital cortex, temporal cortex, lateral ventricles and third ventricle were evaluated by qualitative assessment on a 3-point scale (normal, questionable, abnormal). Patients showed significant bilateral enlargement of prefrontal cortical cerebrospinal fluid (CSF) spaces (p < .05). The rating "abnormal" was given to none (0%) of the normal controls, but to 6 (28.6%) of the patients in the left hemisphere, and to 4 patients (19%) in the right hemisphere, respectively. No qualitative differences were seen in the temporal cortex, lateral ventricles and third ventricle. These findings support the hypothesis that alterations in brain morphology are involved in the etiology of agoraphobia. The lack of a correlation between CSF enlargement and duration of illness suggests that prefrontal CSF enlargement is a neurobiological vulnerability marker in agoraphobia.

[Qualitative evaluation of brain structure in CT in panic disorders]. / Qualitative Bewertung der Hirnstruktur im CT bei Panikstörungen.

This CT study was designed to assess brain morphology in panic disorder with and without agoraphobia. Twenty-one patients and 21 normal control subjects matched for age and sex were investigated. Frontal and parieto-occipital cortex, temporal cortex, lateral ventricles and 3rd ventricle were evaluated by qualitative assessment on a 3-point scale (normal, questionable, abnormal). Patients showed significant bilateral enlargement of cortical cerebrospinal fluid (CSF) spaces (p < 0.01). The rating "abnormal" was given to none (0%) of the normal controls, but to 7 (33.3%) of the patients. Explorative analysis showed that these abnormalities were predominantly located in prefrontal regions. No qualitative differences were seen in the temporal cortex, lateral ventricles or third ventricle. These findings support the hypothesis that alterations in brain morphology are involved in the etiology of panic disorder. The lack of a correlation between CSF enlargement and duration of illness suggests that frontal CSF enlargement is a neurobiological vulnerability marker in panic disorder.

The relationship between serum concentration and therapeutic effect of haloperidol in patients with acute schizophrenia.

Haloperidol is the most commonly used antipsychotic drug in the therapy of acute schizophrenia. Clinicians have been using therapeutic drug monitoring in an attempt to improve clinical application of this drug. The scale of interest in this area is emphasised by the large number of studies (about 50) concerning the serum concentration-therapeutic effect relationship (SCTER) of haloperidol, including 35 studies on patients with acute schizophrenia. However, conflicting results concerning the existence and position of a therapeutic window have emerged. This article aims to provide a comprehensive review of the study design of studies in patients with acute schizophrenia before the study data are used for decision-making. For this purpose, a reproducible system for the evaluation of studies in this special area, a so-called total study score (TSS), was developed on an empirical basis. Thus, insufficient study design was found to be a reason for negative results. On the other hand, in spite of a great variability, the majority of studies with good design provided evidence for a significant SCTER: a bisigmoidal dependence of clinical effect on haloperidol serum concentration. The therapeutic effects of haloperidol increase at low concentrations, and the concentration has a maximum effect at about 10 micrograms/L and again decreasing at higher concentrations. The data of 552 patients also fit to this model in a single scatter plot (pseudo-r2 = 0.076, p < 0.001). The position of the therapeutic window was determined at about 5.6 to 16.9 micrograms/L. Patients treated with serum concentrations within this optimal range had a significantly better response compared with outside this range (p < 0.001, Student t-test). Therefore, a quantitative synthesis of all available data by means of effect-size analysis provides a mean effect-size (g) = 0.499 +/- 0.182 (standard deviation) for the comparison of haloperidol-treatment with serum concentrations within versus outside the therapeutic window. Thus, because of this moderate positive effect, serum concentration assay of haloperidol is recommended for patients with acute schizophrenia in a therapeutic drug monitoring programme. The modalities of haloperidol therapeutic drug monitoring in clinical practice are discussed, e.g. patient selection, method and time for serum concentration measurement, influence of premedication and comedication, interpretation of results and dose adjustment. Clinical investigations into this subject should focus on covariates which are responsible for the variability of the SCTER. Serum concentration assay is advised for investigations of nonresponse to exclude patients with pseudo-drug resistance.

[Intercorrelation of psychopathological, morphologic, neurophysiologic an psychometric parameters in schizophrenic patients]. / Interkorrelation psychopathologischer, morphologischer, neurophysiologischer und psychometrischer Parameter bei schizophrenen Patienten.

The present study was designed to determine the intercorrelation between schizophrenic symptoms, brain morphology, electrophysiological and neuropsychological variables. 44 patients, who met ICD-10 criteria for schizophrenic disorder, were included. At baseline, after 3 and 6 weeks BPRS, CGI, psychometric measurements and QEEG/ERP were performed. A CT scan was performed only at the beginning of the study. Data were evaluated by a multivariate test for data with an inherent structure. One of the most interesting findings is a correlation between BPRS total score and theta EEG power at baseline as well as under treatment. In conclusion, the study suggests the usefulness of multimethodological approaches in order to optimise diagnostic procedures in schizophrenia.

Side effects of low dose neuroleptics and their impact on clinical outcome in generalized anxiety disorder.

1. The present study was designed to determine the impact of neuroleptic side effects on clinical outcome in generalized anxiety disorder. 2. 205 outpatients entered the study. In an open label design fluspirilene 1.5 mg per week was administered for a period of 6 weeks. 3. Consistent with previous studies fluspirilene demonstrated again anxiolytic properties and was in general tolerated well. 4. However, in responders significantly less side effects were observed than in nonresponders. The interaction between tolerability and clinical outcome is the main finding of the present study. 5. In conclusion, the data suggest, that neuroleptic treatment of generalized anxiety disorder should be guided by paying more attention to potential side effects. If under neuroleptic treatment of generalized anxiety disorders side effects are observed, pharmacotherapy should be discontinued, because this fact predicts an unfavourable clinical outcome.

Frontal CSF enlargement in panic disorder: a qualitative CT-scan study.

Brain morphology was assessed qualitatively in CT scans of 21 patients with panic disorder and 21 normal control subjects. Patients showed significant bilateral enlargement of frontal cerebrospinal fluid (CSF) spaces. These findings suggest that alterations in brain morphology are involved in the etiology of panic disorder.

Single-subject experiments to determine individually differential effects of anxiolytics in generalized anxiety disorder.

In the pharmacotherapy of chronic generalized anxiety disorder (GAD) rationally grounded guidelines on the treatment to choose in individual cases are not evident in the literature. The present study was designed to address this question in 30 patients with chronic GAD. Within a period of 31 weeks amitriptyline 30 mg/day, flupentixole 1.5 mg/day, clotiazepam 15 mg/day and placebo were administered 4 times for 1 week, double-blind and at random to each patient. U tests showed that in 19 patients one agent was superior to the other substances (p < 0.05). There was no significant difference between the drugs in 11 patients. However, a meta-analysis across all single-subject experiments showed that in individual patients suffering from chronic GAD differential effects of anxiolytic agents can be found by means of single-subject experiments (p < 0.001). The findings lend further support to the hypothesis that, in an approach to optimize pharmacological treatment of patients suffering from chronic GAD, single-subject experiments may be useful.

Test therapy in the treatment of generalized anxiety disorders with low dose fluspirilene.

1. The present double-blind study was designed to determine under three different conditions (0.5 mg, 1.0 mg, 1.5 mg per week) whether response or non-response within a two-week test-therapy predicts clinical outcome after 6 weeks of fluspirilene treatment in generalized anxiety disorders. 2. 106 outpatients entered the study. The period of observation was 6 weeks. 3. Confirming previous reports of their study group the authors found a significant reduction of anxiety in all treatment groups. However, this effect was mainly observed with the highest dose administered. The main finding of the study is that there is a significant correlation between initial response after 2 weeks of test therapy and therapeutic success after 6 weeks in fluspirilene treatment of generalized anxiety disorders. 4. Decreases in somatic anxiety, psychic anxiety and Hamilton-total-score within the first 2 weeks correlate with the baseline-to-week 6 decreases of the corresponding item and with the global clinical assessment of efficacy after 6 weeks. 5. By means of test therapy patients with an unfavourable outcome are identified and, if medication is discontinued, are prevented from an ineffective longterm treatment.

[Differential pharmacologic therapy of generalized anxiety disorders--results of a study with 30 individual case experiments]. / Psychopharmakologische Differentialtherapie generalisierter Angststörungen--Ergebnisse einer Studie mit 30 Einzelfallexperimenten.

In pharmacotherapy of generalized anxiety disorders (GAD) different psychopharmacological agents (neuroleptics, diazepines, antidepressants) proved to be effective. However, there is a lack of predictors of therapeutic response. The present study was designed to address this question in 30 patients with treatment refractory GAD (12 male, 18 female). Amitriptyline 30 mg/d, flupentixol 1.5 mg/d, clotiazepam 15 mg/d, and placebo were administered double-blind and randomly. Each agent was given 4 times for one week. To avoid carry-over effects, all treatment weeks were interrupted by one week's wash-out periods. Thus each single-case experiment comprised 31 weeks. Primary efficacy criterion was Hamilton total score at the end of each treatment week. Statistical analysis (U-test) showed that in 19 patients one agent was significantly (p < 0.05) superior to the other substances (clotiazepam n = 11, flupentixol n = 3, amitriptyline n = 5). Placebo was not superior in any of these 30 patients. There was no significant difference between the drugs in 11 patients. However, metaanalysis showed that in chronic GAD, by means of single-case experiments, differences in efficacy between different drugs can be found (p < 0.01). ANOVA showed no drug x time interaction.

Brain morphology assessed by computed tomography in patients with geriatric depression, patients with degenerative dementia, and normal control subjects.

To determine whether patients with geriatric depression have specific alterations in brain morphology, internal (ventricles) and external (frontal, temporal, and parieto-occipital) components of the cerebrospinal fluid (CSF) spaces were examined. Planimetric measurements of computed tomographic (CT) scans from patients with geriatric depression were compared with measurements from two age- and sex-matched control groups: normal control subjects and patients with primary degenerative dementia. Scans of 34 patients (6 men, 28 women; mean age = 70.7 years) who met DSM-III-R diagnostic criteria for major depression, 29 patients with DSM-III-R primary degenerative dementia (8 men, 21 women; mean age = 71.2 years), and 43 nonpsychiatric control subjects (10 men, 33 women; mean age = 70.8 years) were evaluated. The areas of the frontal and parieto-occipital sulci, the Sylvian fissures, and the lateral and third ventricles were measured separately for the right and left hemispheres. Compared with the control subjects, patients with geriatric depression revealed a remarkable enlargement (up to 125%) of the left Sylvian fissure on several levels and a more subtle enlargement of the ventricles, cortical sulci, and right Sylvian fissure (20-50%). The laterality index differed significantly between depressed patients and normal control subjects (but not between the demented patients and the normal control group) only for the Sylvian fissure. Demented patients showed a considerable brain atrophy that affected all CSF components (enlargement of 30-160%) but the left temporal region was less affected than in the depressed patients. Compared with the findings in geriatric depression, ventricular enlargement was significant in dementia.(ABSTRACT TRUNCATED AT 250 WORDS)

[Validity of the neuroethological model of obsessive-compulsive disorder]. / Zur Gültigkeit des neuroethologischen Modells der Zwangsstörung.

In the aetiology and pathogenesis of obsessive-compulsive disorders (OCD) multiple factors play a role. Among biographic, genetic and behavioral factors, biological mechanisms seem to be of relevance. Some authors have proposed a neuroethiological model. This model implies a disconnection in neural circuits, linking prefrontal cortex, basal ganglia and thalamus. This review article addressed the question as to whether brain imaging studies support this theory. Conclusions drawn from these studies must be viewed cautiously because findings are not consistent and because of methodological limitations. The validity of a neuroethiological model in OCD seems questionable.