Subsensitivity of the 5-hydroxytryptamine1A (5-HT1A) receptor-mediated hypothermic response to ipsapirone in unipolar depression

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces hypothermia in humans. To explore 5-HT1A receptor-mediated thermoregulation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) received 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly attenuated hypothermic responses to IPS. The impaired hypothermic response following 5-HT1A receptor activation in unipolar depression could have resulted from subsensitivity of the (presynaptic) 5-HT1A receptor and/or related effector mechanisms, thus supporting the hypothesis that altered serotonergic activity may be present in affective disorders. Future studies of the hypothermic response to direct-acting 5-HT1A ligands, such as IPS should facilitate the assessment of 5-HT receptor function in various affective disorders and its involvement in psychotropic drug effects.     

Serum protein and red cell enzyme polymorphisms in affective disorders

Frequencies of serum groups (Hp and Gc) and red cell enzyme types (PGM1, 6-PGD and ES D) were studied in 195 patients with affective disorders. The patients were classified into four groups: (1) bipolar (manic-depressive) psychosis; (2) unipolar, recurrent, depressive psychosis; (3) non-psychotic reactive depression, and (4) unclassifiable. The Hp2 gene was increased in reactive and unclassifiable patients, the PGM1 1 gene was increased in bipolar patients and the ES D1 gene in reactive patients. No associations were found between affective disorders and the Gc and 6-PGD systems.     

HLA antigens and affective disorders

A total of 168 patients with different types of affective disorders were examined with respect to their HLA antigens. The frequency of the A10 antigen was found to be increased in the patients particularly in those with the unipolar type of disease. The frequency of the A1 antigen was decreased among unipolar patients. A decreased frequency of the B7 antigen was found in the total material of patients, and in particular in those with a bipolar type of disease. Our results were in disagreement with findings by other investigators. So far there is no conclusive evidence for association between any HLA antigen and affective disorders.     

Affective Disorders among Patients with Borderline Personality Disorder

Background

The high co-occurrence between borderline personality disorder and affective disorders has led many to believe that borderline personality disorder should be considered as part of an affective spectrum. The aim of the present study was to examine whether the prevalence of affective disorders are higher for patients with borderline personality disorder than for patients with other personality disorders.

Methods

In a national cross-sectional study of patients receiving mental health treatment in Norway (N = 36 773), we determined whether psychiatric outpatients with borderline personality disorder (N = 1 043) had a higher prevalence of affective disorder in general, and whether they had an increased prevalence of depression, bipolar disorder or dysthymia specifically. They were compared to patients with paranoid, schizoid, dissocial, histrionic, obsessive-compulsive, avoidant, dependent, or unspecified personality disorder, as well as an aggregated group of patients with personality disorders other than the borderline type (N = 2 636). Odds ratios were computed for the borderline personality disorder group comparing it to the mixed sample of other personality disorders. Diagnostic assessments were conducted in routine clinical practice.

Results

More subjects with borderline personality disorder suffered from unipolar than bipolar disorders. Nevertheless, borderline personality disorder had a lower rate of depression and dysthymia than several other personality disorder groups, whereas the rate of bipolar disorder tended to be higher. Odds ratios showed 34% lower risk for unipolar depression, 70% lower risk for dysthymia and 66% higher risk for bipolar disorder in patients with borderline personality disorder compared to the aggregated group of other personality disorders.

Conclusions

The results suggest that borderline personality disorder has a stronger association with affective disorders in the bipolar spectrum than disorders in the unipolar spectrum. This association may reflect an etiological relationship or diagnostic overlapping criteria.     

Blood groups and affective disorders

Frequencies of ABO, Rh, MNSs, P, Kell, Lewis and Duffy blood groups were studied in a total of 219 patients with affective disorders. The patients were classified into four groups: (1) bipolar (manic-depressive) psychosis; (2) unipolar recurrent depressive psychosis; (3) nonpsychotic 'reactive' depression, and (4) 'unclassifiable'. The following statistically significant results were found: an increased frequency of the blood group factor B among psychotic (bipolar and unipolar) patients compared to nonpsychotic patients, a decreased frequency of the SS phenotype in the unclassifiable group and an increased frequency of the K(+) phenotype among the nonpsychotic patients. Previous results concerning differences between bipolar and unipolar patients with respect to the A and O blood types were not confirmed in this investigation.     

Serological markers in unipolar and bipolar affective disorders

ABO blood groups and haptoglobin types have been studied with special reference to their association with unipolar and bipolar affective disorders. The associations of serogenetic markers show statistically significant differences between unipolars and controls, bipolars and controls, and unipolars and bipolars. The results are largely in agreement with those reported in previous studies.     

Red cell adenylate kinase phenotypes in the affective disorders

Summary The red cell adenylate kinase (AK) phenotype was determined by starch gel electrophoresis in 96 adult Caucasian subjects with affective disorders (24 with bipolar illness and 72 with unipolar illness). The phenotype frequencies and the gene frequencies of the bipolar group closely resembled that of the control subjects (180 subjects drawn from the population of a large institution for the mentally retarded), the unipolar group however, showed a significant increase in the frequency of the AK² allele.The significance of these results have been discussed in relation to the known genetic and biochemical findings in the affective disorders. It is suggested that the mechanism involved may be a reduction of the enzyme activity in the tissues of subjects with the AK 2:1 phenotype. This may present a selective disadvantage in the form of a decrease in control of energy metabolism in general, and control of adenine nucleotide levels in nervous tissue in particular.     

Thyrotropin nyctohemeral pattern in primary depression : Differences between unipolar and bipolar women

The nyctohemeral patterns of serum thyrotropin (TSH) levels were studied in thirteen female patients suffering from primary affective illness (5 bipolars and 8 unipolars); they were compared to the nyctohemeral profiles obtained in six normal female subjects. The periodogram analysis showed striking differences in TSH circadian rhythms between unipolar and bipolar patients. The nyctohemeral TSH patterns in bipolar patients were similar to those obtained in controls. Unipolar patients, compared to controls, had a significantly lower 24-hour TSH mean, a lower sleep-wake ratio of TSH and an absence of nocturnal rise of TSH. The alterations of the circadian rhythm of TSH secretion observed in the depressive phase of unipolar illness may be a relevant neuroendocrine indicator of hypothalamic-pituitary dysfunction in primary depressive illness.     

Dermatoglyphic analysis in bipolar affective disorder and schizophrenia--"continuum of psychosis" hypothesis corroborated?

Dermatoglyphic features are thought to be indicators of events in the early embryonal stages. They might also be associated with the developmental disorders of the central nervous system (CNS) including schizophrenia. Dermatoglyphic features of 92 male patients with bipolar affective disorder (BPAD) (unipolar depression and schizoaffective psychosis were excluded from the study) were compared with those of 195 males with schizophrenia (SCH) and both with those of 200 male controls (control group-CG). DSM-III-R criteria were used for the diagnostic evaluation. Quantitative analysis showed only one statistically significant difference between BPAD and SCH patients groups, regarding the c-d ridge count of the left hand. The canonical discriminant analysis did not permit correct classification (only 59.23% of cases were correctly classified) between BPAD and SCH. Numerous quantitative dermatoglyphic features of both BPAD and SCH differed significantly from those of the control subjects. Finger ridge counts as well as palmar ridge counts were markedly lower in BPAD and SCH as compared to the controls. These findings are not in contradiction with the hypothesis claiming that psychoses are a set of diverse expressions (due also to noninherited factors) of a single underlying entity.     

Schizophrenia and Affective Disorders—Cosegregation with a Translocation at Chromosome 1q42 That Directly Disrupts Brain-Expressed Genes: Clinical and P300 Findings in a Family

A family with a (1;11)(q42;q14.3) translocation significantly linked to a clinical phenotype that includes schizophrenia and affective disorders is described. This translocation generates a LOD score of 3.6 when the disease phenotype is restricted to schizophrenia, of 4.5 when the disease phenotype is restricted to affective disorders, of 7.1 when relatives with recurrent major depression, with bipolar disorder, or with schizophrenia are all classed as affected. This evidence for linkage is among the strongest reported for a psychiatric disorder. Family members showed no distinctive features by which the psychiatric phenotype could be distinguished from unrelated cases of either schizophrenia or affective disorders, and no physical, neurological, or dysmorphic conditions co-occurred with psychiatric symptoms. Translocation carriers and noncarriers had the same mean intelligence quotient. Translocation carriers were similar to subjects with schizophrenia and different from noncarriers and controls, in showing a significant reduction in the amplitude of the P300 event-related potential (ERP). Furthermore, P300 amplitude reduction and latency prolongation were measured in some carriers of the translocation who had no psychiatric symptoms-a pattern found in other families with multiple members with schizophrenia, in which amplitude of and latency of P300 appear to be trait markers of risk. The results of karyotypic, clinical, and ERP investigations of this family suggest that the recently described genes DISC1 and DISC2, which are directly disrupted by the breakpoint on chromosome 1, may have a role in the development of a disease phenotype that includes schizophrenia as well as unipolar and bipolar affective disorders.     

TaqIB allele polymorphism of the dopamine receptor D2 gene in patients with endogenous psychoses

The genotype at theTaqIB locus of the dopamine receptor D2 (DRD2) gene was established by PCR in 113 healthy donors and 340 patients with endogenous psychoses. The allele and genotype frequencies in patients with affective psychoses significantly differed from those in controls and in patients with schizophrenia. The proportion of B2/B2 homozygotes decreased with increasing contribution of the affective component to the clinical manifestation of schizo-affective and affective disorders. TheTaqIB polymorphism was assumed to play a role in mood aberrations in patients with mental disorders.     

Allele polymorphism of the dopamine transporter gene in patients with endogenous psychoses: Association with pathological syndromes

A study was made of the association of the allele polymorphism of the 3′VNTR locus of the dopamine transporter (DAT) gene with schizophrenia, schizo-affective psychosis, and affective disorders. Three alleles (440, 480, and 520 nt) were found and the allele and genotype frequencies estimated in all groups. The allele and genotype frequencies in patients with depression significantly differed from those in controls and in patients with bipolar affective psychosis and schizophrenia. The results were correlated with the averaged MMPI profiles of controls and affective patients. In the latter group, 480/480 homozygotes significantly differed from patients with the other genotypes in the mean score on Hypochondria and Hysteria scales. The possible association of the DAT-3′VNTR polymorphism and individual syndromes, which are related to different mechanisms of psychological defense, is discussed.     

Psychosis and genes with trinucleotide repeat polymorphism

Abnormal expansion of genes with trinucleotide repeat (TNR) polymorphism has been found in a number of neuropsychiatric disorders. These disorders and the major psychoses, schizophrenia and bipolar affective disorder, appear to share an interesting phenomenon: genetic anticipation. Because TNR expansion correlates with anticipation, these unstable DNA sites are considered important candidate loci for the major psychoses. We investigated genes with TNR polymorphisms, includingB1, B33, B37, and theN-cadherin gene, in unrelated Caucasian North American and Italian schizophrenics (n = 53 to 74), and matched controls. Also, unrelated Caucasian North American patients with bipolar I affective disorder were screened for the B33 andN-cadherin genes (n = 49 and 63, respectively). No unusually long alleles that would suggest abnormal expansion of the TNR were observed for any of these genes. Also, no statistically significant results were found in tests for genetic association between any of these genes and schizophrenia. For B37, a trend toward a difference in allele counts between schizophrenics and controls was observed. However, no clear evidence for a role of these TNR-containing genes in schizophrenia or bipolar affective disorders was found.     

Genetic variation of the 5-HT2A receptor gene and bipolar affective disorder

Abnormalities of the serotonergic system have classically been associated with the origin of affective disorders through the biochemical action of therapeutic agents and their role in affective and perceptual states. In the present study, we hypothesized that genetic variation in the 5-hydroxytryptamine (serotonin) type 2A (5-HT_2A ) receptor gene (HTR2A) might have an effect on the aetiology of bipolar affective disorder. Four different polymorphisms in the HTR2A gene were studied in 88 patients with bipolar affective disorder and 113 healthy controls, all of Spanish origin. No significant association was observed between any of the four polymorphisms at the HTR2A locus, whether tested individually or as haplotypes, and bipolar affective disorder. The lack of association suggests that HTR2A is not a major risk factor for bipolar affective disorder. Received: 4 December 1996 / Accepted: 15 April 1997     

The Relationship between Sleep-Wake Cycle and Cognitive Functioning in Young People with Affective Disorders

Although early-stage affective disorders are associated with both cognitive dysfunction and sleep-wake disruptions, relationships between these factors have not been specifically examined in young adults. Sleep and circadian rhythm disturbances in those with affective disorders are considerably heterogeneous, and may not relate to cognitive dysfunction in a simple linear fashion. This study aimed to characterise profiles of sleep and circadian disturbance in young people with affective disorders and examine associations between these profiles and cognitive performance. Actigraphy monitoring was completed in 152 young people (16–30 years; 66% female) with primary diagnoses of affective disorders, and 69 healthy controls (18–30 years; 57% female). Patients also underwent detailed neuropsychological assessment. Actigraphy data were processed to estimate both sleep and circadian parameters. Overall neuropsychological performance in patients was poor on tasks relating to mental flexibility and visual memory. Two hierarchical cluster analyses identified three distinct patient groups based on sleep variables and three based on circadian variables. Sleep clusters included a ‘long sleep’ cluster, a ‘disrupted sleep’ cluster, and a ‘delayed and disrupted sleep’ cluster. Circadian clusters included a ‘strong circadian’ cluster, a ‘weak circadian’ cluster, and a ‘delayed circadian’ cluster. Medication use differed between clusters. The ‘long sleep’ cluster displayed significantly worse visual memory performance compared to the ‘disrupted sleep’ cluster. No other cognitive functions differed between clusters. These results highlight the heterogeneity of sleep and circadian profiles in young people with affective disorders, and provide preliminary evidence in support of a relationship between sleep and visual memory, which may be mediated by use of antipsychotic medication. These findings have implications for the personalisation of treatments and improvement of functioning in young adults early in the course of affective illness.     

Psychiatric morbidity in patients with alcoholic liver disease.

Seventy one patients with alcoholic liver disease and an equal number with non-alcoholic liver disease were interviewed using the schedule for affective disorders and schizophrenia. Forty seven (66%) of the group with alcoholic liver disease had or had had psychiatric illnesses compared with 23 (32%) of the control group (p less than 0.001). Affective disorder, particularly major depression, neurotic disorders, and antisocial personality, were all more common among the patients with alcoholic liver disease than the controls. No patient had schizophrenia or other forms of psychosis. Among the patients with alcoholic liver disease 11 men (24%) and 14 women (54%) had an affective or a neurotic disorder that had antedated their heavy drinking, and 30 (77%) of those who had had such a problem at any time had symptoms at the time of interview. Abstinence from alcohol is essential for patients with severe alcoholic liver disease. In view of the high prevalence of psychiatric disorders in these patients psychiatric assessment is important to increase the patients'' likelihood of complying with such advice.     

Polymorphism in the Human Serotonin Transporter Gene in Endogenous Psychoses

Associations of the VNTR-17 and 5-HTTLPR polymorphisms of the serotonin transporter gene with affective disorders, including depression, have been found. These polymorphisms were analyzed in two groups of Russian probands: patients with endogenous psychoses and control individuals without mental disorders (423 and 277 persons, respectively). No associations were found between VNTR-17 genotypes or alleles and the diseases. However, the frequency of10/10 (VNTR-17) homozygotes increased with age in both patients and healthy persons. The results of the analysis of the 5-HTTLPR polymorphism suggest an association of the short (s) allele of the 5-HTTLPR polymorphism with schizophrenia and schizoaffective psychoses, but not with affective disorders.     

Age-related changes of n-3 and n-6 polyunsaturated fatty acids in the anterior cingulate cortex of individuals with major depressive disorder

Accumulating evidence finds a relative deficiency of peripheral membrane fatty acids in persons with affective disorders such as unipolar and bipolar depression. Here we sought to investigate whether postmortem brain fatty acids within the anterior cingulate cortex (BA-24) varied according to the presence of major depression at the time of death. Using capillary gas chromatography we measured fatty acids in a depressed group (n=12), and in a control group without lifetime history of psychiatric diagnosis (n=14). Compared to the control group, the depressed group showed significantly lower concentrations of numerous saturated and polyunsaturated fatty acids including both the n-3 and n-6 fatty acids. Additionally, significant correlations between age at death and precursor (or metabolites) in the n-3 fatty acid pathway were demonstrated in the depressed group but not in control subjects. In the n-6 fatty acid family, the ratio of 20:3(n-6)/18:2(n-6) was higher in patients than in control groups, whereas the ratio of 20:4(n-6)/20:3(n-6) was relatively decreased in patients. Lastly, a significant negative correlation between age and the ratio of 20:4(n-6) to 22:6(n-3) was found in patients, but not in controls. Taken together, decreases in 22:6(n-3) may be caused, at least in part, by the diminished formation of 20:5(n-3), which is derived from 20:4(n-3) through a Δ5 desaturase reaction. The present findings from postmortem brain tissue raise the possibility that an increased ratio of 20:4(n-6) to 22:6(n-3) may provide us with a biomarker for depression. Future research should further investigate these relationships.     

Changes in the Circadian Rhythm in Patients with Primary Glaucoma

Purpose

The current study was undertaken to investigate whether glaucoma affects the sleep quality and whether there is any difference between patients with primary glaucoma (primary open angle glaucoma, POAG and primary angle-closure glaucoma, PACG) and healthy subjects, using a validated self-rated questionnaire, the Pittsburgh Sleep Quality Index (PSQI).

Methods

The sleep quality of patients with POAG and PACG was tested against normal controls. Subjects were divided into three sub-groups according to age. Differences in the frequency of sleep disturbances (PSQI score >7) were assessed. The differences of sleep quality within the three groups and within the POAG group depending on the patients’ intraocular pressure (IOP) and impairment of visual field (VF) were also studied.

Results

92 POAG patients, 48 PACG patients and 199 controls were included. Sleep quality declined with age in control and POAG group (tendency chi-square, P<0.05). The prevalence of sleep disturbances was higher in POAG and PACG group than in the control group, the differences were statistically significant. The prevalence of sleep disturbances was higher in patients with PACG, compared to POAG patients in the age interval of 61–80. In POAG group, the ratio of patients with sleep disorders increased with augmented impairment of VF, but the differences were not statistically significant (χ²-test, P>0.05). No significant differences were found in POAG group between patients with a highest IOP in daytime and at nighttime (χ²-test, P>0.05).

Conclusions

The prevalence of sleep disorders was higher in patients with POAG and PACG than in controls. PACG patients seemed to have a more serious problem of sleep disorders than POAG patients between 61 to 80 years old. No correlation was found between the prevalence of sleep disorders and impairment of VF or the time when POAG patients showed a highest IOP.     

Renal function after long-term treatment with lithium.

Daily urine volumes, plasma creatinine concentrations, and creatinine clearance were measured in 106 patients with unipolar and bipolar affective disorders attending a "lithium" clinic. Urine volumes exceeded 3.51 in only six patients, plasma creatinine concentrations exceeded 150 mumol/1 (1.7 mg/100 ml) in only five, and creatinine clearance was below 50 ml/min in 16. Renal function was assessed by measuring creatinine clearance and renal tubular function, including response to 20 hours of water deprivation, in a representative sample of 30 patients from the lithium clinic and 30 psychiatric patients matched for age and sex who were taking other psychotropic drugs. Creatinine clearance and tubular function, including urine osmolality after water deprivation, were not significantly different between the two groups. Urinary excretion of arginine vasopressin (AVP), however, was much greater in the lithium-treated patients, who therefore had a diminished tubular responsiveness to AVP. The findings do not support suggestions that long-term lithium treatment results in seriously impaired renal function, renal damage, and polyuria. Compared with other series, however, the patients were being maintained with low serum lithium concentrations, which apparently area as effective prophylactically as higher concentrations.