Short-term naloxone administration in schizophrenic and manic patients. A World Health Organization Collaborative Study.

A double-blind study of the behavioral effects of short-term naloxone hydrochloride administration was performed in 32 schizophrenic and 26 manic patients in a World Health Organization collaborative project. There was a significant naloxone-associated reduction in overall physician-rated symptoms in schizophrenic patients concurrently treated with neuroleptic medication (N = 19) but not in medication-free schizophrenics (N = 13). Physician rating of auditory hallucinations showed significant naloxone-associated improvement for the total schizophrenic population, while self-ratings of auditory hallucinations showed improvement only in neuroleptic-treated schizophrenics. While further studies are needed to delineate these effects as to clinical significance, they may bear etiological implications for the psychobiology of schizophrenia, including the possibility of synergistic effects of dopamine and endorphin blockade. Naloxone produced no significant behavioral effects in manic patients. These findings are discussed with relationship to the hypotheses of endorphin involvement in schizophrenia and mania.

Functional PAX-6 gene-linked polymorphic region: potential association with paranoid schizophrenia.

BACKGROUND: Early differentiation of the nervous system and adult CNS neuroplasticity is modulated by PAX-6. We have shown previously that a highly polymorphic, functional AC/AG repeat in the 5' regulatory region of the gene showed significantly increased promoter activity, if containing > or = 29 repeats, and that the heterozygous genotype (< or = 28/> or = 29) revealed increased mRNA PAX-6 levels in human brain tissue compared to the homozygous short variant. METHODS: In a case-control study of 655 unrelated individuals, allele frequencies and genotype distributions of the functional PAX-6 promoter polymorphism were investigated comprising patients with DSM-IV schizophrenia, patients with affective disorders, and population controls. RESULTS: No allelic or genotypic association of the PAX-6 promoter polymorphism to affective disorder or to schizophrenia as one disease entity was observed. After subtyping schizophrenia into paranoid and nonparanoid forms, potential evidence was found for a genotypic association of the high-activity variant with the paranoid subtype of schizophrenia (p = .02). The estimated odds ratio was 1.7 (95% CI .98 to 2.95) for those heterozygous and 1.4 (95% CI .82 to 2.42) for those heterozygous or homozygous for the high-activity variant compared to the homozygous low-activity variant. CONCLUSIONS: Our finding indicates that early developmental genes may be involved in the etiopathogenesis of schizophrenia subtypes via variable transcriptional regulation in the developing and adult human brain.

Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders.

Functional characterization studies revealed that transcriptional activity of the human monoamine oxidase A (MAOA) gene is modulated by a polymorphic repetitive sequence located approximately 1.2 kb upstream of the ATG codon. To investigate the possible influence of the allelic variants of the MAOA gene-linked polymorphic region (MAOA-LPR) on the genetic predisposition to psychiatric disorders, we have performed a case-control association study. 174 patients with affective disorders and 258 patients with schizophrenia according to DSM-IV, as well as 229 population controls were tested. Statistical analysis showed no significant differences in allele or genotype frequencies between control and patient groups. Our results suggest that there is no association between MAOA-LPR genotype and susceptibility to recurrent major depression, bipolar disorder, and schizophrenia in our population.

Methysergide decreases prolactin release after FK 33-824 [Tyr-D-Ala-Gly-MePhe-Met(o)-ol], a potent analogue of methionine enkephalin. A study in man.

This study investigated the mechanisms which may underly the prolactin (PRL) stimulating effects of FK 33-824, a potent enkephalin analogue. FK 33-824 (1 mg) was infused in healthy volunteers before and after pretreatment with 3 mg methysergide, a serotonin receptor blocker. All subjects showed a release of PRL after FK 33-824, which was significantly diminished after pretreatment with methysergide.

The human dopamine transporter gene: the 5'-flanking region reveals five diallelic polymorphic sites in a Caucasian population sample.

The 5'-flanking region of the human dopamine transporter (hDAT) was systematically screened for variants by single strand conformation analysis (SSCA) between -1586 and +97 basepair (bp) relative to the transcription start site. Five diallelic polymorphisms were found, which were shown to be due to single base substitutions: T-67A, G-660C, C-839T, C-1169G, T-1476G. In a population sample of 119 unrelated Caucasians, allele frequencies of the rarer allele were 47% for -67T, 3% for -660C, 45% for -839T, 50% for -1169G, and 8% for -1476G, respectively. Among 15 observed haplotypes, seven haplotypes collected a frequency of about 96% in our sample. T-67A, C-839T, C-1169G, T-1476G were related to potential transcriptional recognition sites. These findings and the occurrence of distinct haplotypes at the hDAT promoter locus in a Caucasian population sample make this region a promising target in the context of linkage and association studies in certain diseases.

Nonlinear pharmacokinetics of chlorimipramine after infusion and oral administration in patients.

In this study the pharmacokinetics of 75 mg and 150 mg chlorimipramine after infusion and tablets was followed for four weeks in chronically treated patients. The clearance was found to be dose dependent. From the time course of the metabolite desmethylchlorimipramine in plasma it can be concluded, that chlorimipramine tablets are resorbed totally. No correlation between pharmacokinetic and improvement parameters could be found. Doubling of the dosage leads to 3 fold chlorimipramine and 4 fold desmethylchlorimipramine concentrations. The estimated half lives are higher than known hitherto. Especially for chronic treatment with 150 mg chlorimipramine, plasma concentration monitoring is recommended, because 20% of the patients did not reach steady state for chlorimipramine and 60% for desmethylchlorimipramine, in these 4 weeks.

Opiate receptor sensitivity in depressed patients before and after clomipramine treatment.

To measure opiate receptor sensitivity, the effects of naloxone on beta-endorphin and cortisol serum levels were determined before and after 3 weeks of clomipramine treatment (75 mg/day i.v.) in 12 patients with major depressive disorder. The opiate antagonist significantly increased both hormonal levels. The only significant endocrine differences between pre- and post-treatment were basal and maximal cortisol levels, which were elevated before antidepressant therapy. The rise in the cortisol or beta-endorphin serum level after naloxone injection was not affected by clomipramine treatment. There was no significant relationship between depression score and basal or stimulated endocrine variables. These data do not indicate a distinct effect of antidepressants on opiate receptor sensitivity.

Endogenous opiates increase pain tolerance after stress in humans.

This study investigates the role of endogenous opioids in the regulation of pain in humans. Two groups of healthy volunteers were subjected to different stress situations (cold pressor and arithmetic). In a double-blind design the changes in pain tolerance after stress were measured after an injection of either 0.8 mg naloxone or placebo. The cold pressor test raised the pain threshold in the placebo-treated group, but not in the naloxone-treated group. Mental arithmetic had no effect on pain perception. One can conclude therefore that physical stress may change pain perception depending upon the secretion of endogenous opioids.

Peripheral-type benzodiazepine receptors in diagnostic subtypes of schizophrenic patients.

The peripheral-type benzodiazepine receptor (pBZD-R; also called the omega-3 receptor or the mitochondrial benzodiazepine receptor) seems to play a critical role in the production of neurosteroids, which are able to alter the electrical properties of neuronal membranes and thus the firing patterns of neurons. Putative endogenous ligands are the diazepam-binding inhibitor and its processing products, as well as porphyrins, some of them, in the case of porphyria, are well known to give rise to certain aspects of neuropsychiatric disorders, such as schizophrenic-like symptoms. Previous findings of altered benzodiazepine binding sites in post-mortem brain samples and platelets from small samples of schizophrenic patients have been inconclusive. Therefore we investigated characteristic binding parameters (Bmax, Kd) of the granulocytic pBZD-R by using the selective ligand PK11.195 in 53 subjects, fulfilling ICD-10 and DSM-IV criteria of schizophrenia. The binding parameters in our total group of 53 schizophrenic patients did not differ from those in healthy subjects. However, Bmax values were significantly reduced in schizophrenic patients with predominantly negative symptoms (residual type) compared to schizophrenic patients with predominantly positive symptoms, i.e. paranoid (-50%) and catatonic subtype (-38%). Moreover, only residual type schizophrenics exhibited a significantly reduced binding capacity compared to healthy subjects (-38%). More studies are warranted to clarify the functional significance of this binding site in the pathogenesis of negative symptoms.

Acute effects of the synthetic analogue of methionine enkephalin FK 33-824 on depressive symptoms.

Nine patients with endogenous depression have been treated with infusions of the synthetic methionine enkephaline analogue FK 33-824 for two days. Only on the first day acute effects on depressive symptoms could be observed. It cannot be decided if the observed mood alterations on the first treatment day are placebo effects. Depressive patients showed fewer adverse reactions than healthy volunteers. This might be explained by the previously described greater pain tolerance in depressives.

Acute effects of the synthetic analogue of methionine enkephalin FK 33-824 in schizophrenic patients. A double blind trial.

16 patients with paranoid and hallucinatory symptoms, who were concurrently receiving no other medication, participated in a double blind trial. Either 3 mg FK 33-824 or 20 mg diazepam was injected i.m. over a 2-day period, with a subsequent cross-over for the second medication. Both FK 33-824 and diazepam caused a slight decrease in psychopathological symptoms as measured by the BPRS, but no differences could be observed in their effect on schizophrenic symptoms such as hallucinations and delusions.

On the relationship of nortriptyline: amitriptyline ratio to clinical improvement of amitriptyline treated depressive patients.

The antidepressant effect of amitriptyline was studied in 28 endogenous depressive patients. They received 150 mg amitriptyline once nightly in a sustained release form for 4 weeks. Blood samples were drawn 12 hrs. after medication. Amitriptyline concentrations were between 35--300 ng/ml Nortriptyline concentrations were between 20--330 ng/ml. No correlations were found between plasma concentrations of amitriptyline, nortriptyline, or their sum, and the clinical outcome of treatment. Plasma levels of amitriptyline depended on neither the age nor the sex of the patients. A significant correlation was found between the ratio of nortriptyline to amitriptyline concentrations in serum (demethylation ratio) and clinical improvement. The demethylation ratio appeared to be relatively constant after a few days of treatment. The results suggest that monitoring the demethylation ratio of endogenous depressive patients treated with amitriptyline may predict therapeutic effects of the treatment. They also suggest that a balance between noradrenergic and serotonergic mechanisms is necessary to improve antidepressant treatment with amitriptyline.

Single oral dose pharmacokinetics of amitriptylinoxide and amitriptyline in humans.

Eleven healthy volunteers were examined in a pharmacokinetic study. After oral administration of 50 mg amitriptylinoxide or 50 mg amitriptyline the plasma levels of amitriptylinoxide and its main metabolites amitriptyline and nortriptyline were investigated over 24 hours. The results indicate that amitriptylinoxide is more rapidly absorbed than amitriptyline and eliminated with a mean half-life of 1.5 hours. The change with time in the levels of amitriptyline formed from the oxide is similar to that of amitriptyline after ingestion of amitriptyline. However, the plasma concentration of amitriptylinoxide, reflected by the area under the time curve (AUC), exceeds that of its metabolite amitriptyline twelvefold.

[Manneristic catatonia. A psychotropic drug refractory chronic progressive course]. / Die manierierte Katatonie. Eine durch Psychopharmaka in ihrem chronisch progredienten Verlauf nicht beeinflussbare Erkrankung.

Manneristic catatonia, one form of Leonhard's systematic schizophrenias, is illustrated in nine case notes. The essential syndrome of this rare disorder (described by Leonhard in the preneuroleptic era) consisted in mannerisms and progressive stiffness of psychomotor activity. Mannerisms often developed from obsessive and compulsive ideas; whereas distress disappeared, repetitive behavior developed into a stereotype. Complex movements (e.g. not to shake hands; mutism) became mannerisms. With disease progression stiffness of facial expression and gestures and an impairment of voluntary motor activity became increasingly prominent. There were no signs of (neuroleptic-induced) parkinsonism. Manneristic catatonia affects preponderantly men and exhibits an early age of onset (median: 23 years). In none of the cases a family history of psychiatric illness was noted. Severe obstetric and birth complications as well as the high prevalence of supratentorial and cerebellar CT/MR abnormalities in this patient group point to deviations of prenatal brain maturation. The median yearly dose of neuroleptics was 83.1 g chlorpromazin equivalents. The characteristic psychopathology was not essentially influenced by modern psychopharmacological treatment neither in the beginning nor in the long run irrespective of the time of onset of the disease. Continuous high-dose neuroleptic treatment is not efficacious in this distinct group of systematic schizophrenias. Behavioural training in a rehabilitation unit is the treatment of choice from the early beginning.

[Additional treatment to lithium prophylaxis of affective psychoses (author's transl)]. / Verhaltenstherapie in der Gruppe als psychologische Zusatzbehandlung bei der Lithiumprophylaxe affektiver Psychosen.

Ten endogenous-depressive patients under lithium maintenance therapy participated in a group behaviour therapy program for the modification of behavioural problems that are typical for this group of patients. The problem intensity as measured individually through a "problem barometer" as well as the score on the Pt-scale of the MMPI were reduced significantly over the ten treatment sessions. Concurrently, patients' self image regarding depressive components and social resonance improved. The effects were still present after a 3-month follow-up period. It is concluded that in lithium treated patients behaviour therapy methods can be used in the modification of typical behaviour disorders.

Cortical and striatal neurone number in Huntington's disease.

The total cortical and striatal neurone and glial numbers were estimated in five cases of Huntington's disease (three males, two females) and five age- and sex-matched control cases. Serial 500-microns-thick gallocyanin-stained frontal sections through the left hemisphere were analysed using Cavalieri's principle for volume and the optical disector for cell density estimations. The average cortical neurone number of five controls (mean age 53 +/- 13 years, range 36-72 years) was 5.97 x 10(9) +/- 320 x 10(6), the average number of small striatal neurones was 82 x 10(6) +/- 15.8 x 10(6). The left striatum (caudatum, putamen, and accumbens) contained a mean of 273 x 10(6) +/- 53 x 10(6) glial cells (oligodendrocytes, astrocytes and unclassifiable glial profiles). The mean cortical neurone number in Huntington's disease patients (mean age 49 +/- 14 years, range 36-75 years) was diminished by about 33% to 3.99 x 10(9) +/- 218 x 10(6) nerve cells (P < or = 0.012, Mann-Whitney U-test). The mean number of small striatal neurones decreased tremendously to 9.72 x 10(6) +/- 3.64 x 10(6) (-88%). The decrease in total glial cells was less pronounced (193 x 10(6) +/- 26 x 10(6)) but the mean glial index, the numerical ratio of glial cells per neurone, increased from 3.35 to 22.59 in Huntington's disease. Qualitatively, neuronal loss was most pronounced in supragranular layers of primary sensory areas (Brodmann's areae 3,1,2; area 17, area 41). Layer IIIc pyramidal cells were preferentially lost in association areas of the temporal, frontal, and parietal lobes, whereas spared layer IV granule cells formed a conspicuous band between layer III and V in these fields. Methodological issues are discussed in context with previous investigations and similarities and differences of laminar and lobar nerve cell loss in Huntington's disease are compared with nerve cell degeneration in other neuropsychiatric diseases.

Susceptibility for schizophrenia is not influenced by a functional insertion/deletion variant in the promoter of the serotonin transporter gene.

A possible dysregulation of serotonergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses. In the present study we analysed allelic and genotypic variations of a recently described functional polymorphic region in the promoter of the human serotonin transporter gene (5-HTTLPR) and a variable tandem repeat (VNTR) in intron 2 of the 5-HTT gene. We investigated 413 unrelated individuals, 180 schizophrenic patients and 233 blood donors as controls. With regard to the 5-HTTLPR, both the schizophrenic and the control group did not significantly differ between genotype frequencies (chi2, p = 0.920) and allele frequencies (chi2, p = 0.836). The odds ratio for subjects with schizophrenia who were homozygous for the short allele was 1.04 (95% CI 0.59-1.84). No evidence of allelic association to specific schizophrenia subtypes was found. The 5-HTT associated VNTR also showed no significant differences between either the allelic or the genotypic distributions. Haplotype analysis revealed a significant overall linkage disequilibrium at a level of p = 0.00004. Our findings indicate that both polymorphisms are unlikely to play a substantial role in the genetic predisposition to schizophrenic disorders.

Insertion/deletion variant (-141C Ins/Del) in the 5' regulatory region of the dopamine D2 receptor gene: lack of association with schizophrenia and bipolar affective disorder. Short communication.

A possible dysregulation of dopaminergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses, in particular of paranoid-hallucinatory states, and of the manic episodes of bipolar affective disorder. In the present study we analysed allelic and genotypic variations of a recently described functional deletion/insertion variant (-141C Ins/Del) in the 5' flanking region of the human dopamine D2 receptor gene. We investigated a total of 620 unrelated individuals, comprising 260 schizophrenic patients, 70 patients with bipolar affective disorder, and 290 population controls. Analysis of the -141C Ins/Del variant revealed that the schizophrenic, bipolar affective and control groups did not differ significantly regarding genotype frequencies and allele frequencies. No evidence of an allelic association with either a family history of schizophrenic psychosis or a diagnosis of schizophrenia of the paranoid type (according to ICD 10) was found. Our findings indicate that the -141C Del variant in the 5' flanking region of the human dopamine D2 receptor gene is unlikely to play a substantial role in genetic predisposition to major psychiatric disorders in Caucasians.

Consensus on minimal criteria of clinical and neuropathological diagnosis of schizophrenia and affective disorders for post mortem research. Report from the European Dementia and Schizophrenia Network (BIOMED I).

The sophisticated analysis of and growing information on the human brain requires that acquisition, dissection, storage and distribution of rare material are managed in a professional way. In this publication we present the consensus of the European work group "European Dementia and Schizophrenia Network", granted by the BIOMED I project of the EU, on minimal neuropathological and clinical requirements to include brains of patients with schizophrenia and affective disorders in post mortem studies. The description of clinical prerequisites in different EU countries and institutions is followed by a consensus on tissue handling, a consensus on minimal neuropathological criteria and a consensus on minimal clinical diagnostic criteria including clinical vignette, family, social, education/professional and general medical histories, general physical history including neurostatus, neurological, psychiatric, medication and general pathological histories, psychostatus, laboratory tests and a history provided by family/health care giver questionnaire. This publication should give help to interconnect different European brain bank centers on a basis of standardized protocols.