Mood Disorder Subjects Research Articles

Identifying blood biomarkers for mood disorders using convergent functional genomics

There are to date no objective clinical laboratory blood tests for mood disorders. The current reliance on patient self-report of symptom severity and on the clinicians' impression is a rate-limiting step in effective treatment and new drug development. We propose, and provide proof of principle for, an approach to help identify blood biomarkers for mood state. We measured whole-genome gene expression differences in blood samples from subjects with bipolar disorder that had low mood vs those that had high mood at the time of the blood draw, and separately, changes in gene expression in brain and blood of a mouse pharmacogenomic model. We then integrated our human blood gene expression data with animal model gene expression data, human genetic linkage/association data and human postmortem brain data, an approach called convergent functional genomics, as a Bayesian strategy for cross-validating and prioritizing findings. Topping our list of candidate blood biomarker genes we have five genes involved in myelination (Mbp, Edg2, Mag, Pmp22 and Ugt8), and six genes involved in growth factor signaling (Fgfr1, Fzd3, Erbb3, Igfbp4, Igfbp6 and Ptprm). All of these genes have prior evidence of differential expression in human postmortem brains from mood disorder subjects. A predictive score developed based on a panel of 10 top candidate biomarkers (five for high mood and five for low mood) shows sensitivity and specificity for high mood and low mood states, in two independent cohorts. Our studies suggest that blood biomarkers may offer an unexpectedly informative window into brain functioning and disease state.

Association of a Triallelic Serotonin Transporter Gene Promoter Region (5-HTTLPR) Polymorphism With Stressful Life Events and Severity of Depression

Objective: The lower expressing allele of the serotonin transporter gene 5′ promoter region (5-HTTLPR) polymorphism is reported to be associated with susceptibility to depression and suicidality in response to stressful life events. The authors examined the relationship of a triallelic 5-HTTLPR polymorphism to stressful life events, severity of major depression, and suicidality. Method: Mood disorder subjects (N=191) and healthy volunteers (N=125), all Caucasian subjects of European origin, were genotyped for the triallelic 5-HTTLPR polymorphism (higher expressing allele: L A ; lower expressing alleles: L G , S). All subjects underwent structured clinical interviews to determine DSM-IV diagnoses, ratings of psychopathology, stressful life events, developmental history, and suicidal behavior. CSF 5-HIAA was assayed in a subgroup of subjects. Results: Lower expressing alleles independently predicted greater depression severity and predicted greater severity of major depression with moderate to severe life events compared with the higher expressing L A allele. No associations with suicidal behavior and CSF 5-HIAA were found. Conclusions: Lower expressing transporter alleles, directly and by increasing the impact of stressful life events on severity, explain 31% of the variance in major depression severity. The biological phenotype responsible for these effects remains to be elucidated.

Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects.

Serotonin 5-HT2A receptor (5-HT2A) binding is reported to be altered in individuals with suicidal behavior, mood disorders, and aggressive-impulsive traits. Genetic association with major depression, suicidal behavior, and aggressive-impulsive traits has not been established. This study examines the possible association of the 5-HT2A gene C102T polymorphism with the receptor binding kinetics, and clinical overt phenotypes. The study population included 63 healthy volunteers and 152 subjects with mood disorders, 56 of whom had a history of suicide attempts. All were Caucasian. Platelet 5-HT2A binding kinetics (Bmax and KD) were assayed and adjusted for seasonal variation. All subjects were genotyped for the T102C polymorphism. Clinical phenotype was determined by structured clinical interview. The TT genotype was associated with higher Bmax in all subjects (F=3.53, df=2,211; p=0.03), controlling for diagnosis. Bonferroni-adjusted post hoc testing showed higher binding in the TT compared with TC genotype in the control group (F=7.56, df=2,60, p=0.001), but not in the mood-disordered subjects. No difference was found in genotype and allele distribution between the mood-disordered subjects, with and without suicide attempt history, and controls. Bmax was not related to a diagnosis of mood disorders. The TT genotype appears associated with higher platelet 5-HT2A Bmax in the healthy population, but this genotypic effect appears absent in mood disorders and unrelated to psychopathology.

Migraine headache and mood disorders: a descriptive study in an outpatient psychiatric population

Background: Information is sparse concerning migraine distribution in mood disorder subjects based mainly on psychiatric disorder. Methods: In a sample of 283 normothymic mood disorder outpatients on maintenance treatment with serotonin reuptake inhibitors (SSRIs) or lithium, we investigated migraine distribution and clinical variables possibly related to comorbidity risk between mood disorder and migraine. Results: Some 26.8% of the sample met criteria for migraine with migraine age of onset earlier than mood disorder age of onset; familiarity for mood disorder and migraine was strictly related to comorbidity risk in probands. Long-term treatment with lithium salts subjectively improved migraine outcome. Conclusions: These results could support the bidirectional association between the two clinical forms, considering the familial and pharmacological patterns.

Early onset of lithium prophylaxis as a predictor of good long-term outcome.

The recurrence rates during lithium preventive treatment were investigated in a sample of 270 Mood Disorder subjects subdivided according to their onset time for lithium prophylaxis as very early (within 5 years from the onset of illness), early (6-10 years), late (11-20 years) and very late (more than 21 years). 131 subjects of the sample followed for 4 years prolonged the observation for a further period of 8 years. Results indicated that beginning lithium therapy within the first ten years of illness predicts better preventive outcomes than beginning prophylaxis later, both in major depression, recurrent and bipolar patients.

Dopamine D2 receptor gene not associated with symptomatology of mood disorders

Dopamine D2 receptor gene (DRD2) variants have been implicated in the pathogenesis of psychiatric disorders. Many studies have, however, failed to replicate the original association of DRD2 with schizophrenia and mood disorders. A possible reason for this may lie in the definition of phenotype, which is traditionally based on psychiatric diagnosis. In this study we investigated the possibility that variants of the DRD2 gene might be associated with symptomatology in a sample of mood disorder subjects. Forty-seven inpatients affected by bipolar disorder (Diagnostic and Statistical Manual of Mental Disorders IV) were assessed at admission by the Operational Criteria for Psychotic Illness and were typed for DRD2 variants using polymerase chain reaction techniques. DRD2 was not associated with excitement, depression, delusion, and disorganization symptoms. Gender did not influence results significantly. Among early onset subjects DRD2*1 was associated with disorganized symptoms. In our sample DRD2 variants did not markedly influence psychopathology among mood disorder subjects. We observed a trend toward higher disorganization among DRD2*1 subjects.

Prefrontal cortical networks related to visceral function and mood.

At least twenty-two architectonic areas can be distinguished within the orbital and medial prefrontal cortex (OMPFC). Although each of these areas has a distinct structure and connections, they can be grouped into two "networks," defined by cortico-cortical connections that primarily interconnect areas within each network. The networks also have different connections to the striatum, medial thalamus, and other brain regions. The orbital network consists of most of the areas in the orbital cortex. It receives several sensory inputs (olfactory, gustatory, visceral afferent, somatic sensory, and visual) that appear to be related to feeding. It also receives many limbic inputs from the amygdala, entorhinal and perirhinal cortex, and subiculum, including a specific projection from the ventrolateral part of the basal amygdaloid nucleus. The orbital network may therefore serve as a substrate to integrate viscerosensory information with affective signals. The medial network consists of areas on the medial frontal surface together with a few select areas in the orbital cortex. These areas have few direct sensory inputs, and their limbic inputs are somewhat different than those to the orbital network (e.g., from the ventromedial part of the basal amygdaloid nucleus). However, they provide the major output from the OMPFC to the hypothalamus and brain stem (especially the periaqueductal gray). The medial network may therefore serve as a visceromotor system to provide frontal cortical influence over autonomic and endocrine function. Connections between the networks presumably allow information flow from viscerosensory to visceromotor systems. In addition to a probable role in eating behavior, this system appears to be involved in guiding behavior and regulation of mood. Lesions of the ventromedial prefrontal cortex result in sociopathic behavior and difficulty in making appropriate choices, whereas functional imaging studies indicate that subjects with unipolar and bipolar depression have abnormal activity in medial and orbital prefrontal areas. Many of these areas also show volume changes and decreased glial number and density in mood-disordered subjects.

Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders.

Disturbances of the serotoninergic neutrotransmitter system have been implicated in the pathogenesis of mood disorders. A functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has been recently reported to be associated with both unipolar and bipolar disorder. In this study, we investigated the possibility that the 5-HTTLPR might be associated with depressive symptomatology in a sample of mood disorder subjects. One hundred and thirty-two psychiatric inpatients affected by major depressive (n = 67) and bipolar (n = 65) disorder (DSM-IV) were assessed at admission by the Hamilton Depression Rating Scale (HAMD-21, divided into Core, Sleep, Activity, Psychic anxiety, Somatic anxiety and Delusion clusters) and were typed using PCR techniques. The only prior treatment permitted was low dose benzodiazepines (<5 mg diazepam or equivalent); no prior (<2 weeks) antidepressant or neuroleptic treatment was allowed. 5-HTTLPR variants were not associated with total depressive symptomatology as measured by HAMD. The short 5-HTTLPR variant was marginally associated with higher psychic anxiety scores (F = 7.11, d.f. = 1,262, P = 0.008). The association was stronger among bipolars and early onset subjects. 5-HTTLPR variants were not associated with the remaining symptom clusters. The upstream regulatory region of the serotonin transporter gene has not, therefore, a major influence on the depressive symptomatology in mood disorder subjects.

Dopamine receptor D 4 gene is associated with delusional symptomatology in mood disorders

Disturbances of the dopaminergic neurotransmitter system have been implicated in the pathogenesis of depressive symptoms. Many studies have, however, failed to detect any association between genetic markers for the dopamine system and mood disorders. A possible reason for this may lie in the definition of phenotype, which is traditionally based on psychiatric diagnosis. In this study, we investigated the possibility that functional variants of the dopamine D 4 receptor (DRD4) gene might be associated with depressive symptomatology in a sample of mood disorder subjects. Seventy-nine inpatients affected by bipolar ( n=37) and major depressive ( n=42) disorder (DSM-IV) were assessed at admission by the Hamilton Depression Rating Scale and were typed for DRD4 variants at the third exon using polymerase chain reaction (PCR) techniques. DRD4 was associated with delusional symptoms ( F=5.56; d.f.=2,145; P=0.005), with DRD4*7 exhibiting higher scores when compared to DRD4*4 ( P=0.006) variants. Polarity of mood disorder did not influence results significantly. The findings are in accordance with our previous report of an association of the DRD4 gene with delusional symptomatology of major psychoses. DRD4*7 should, therefore, be considered a liability factor for delusional symptoms in mood disorders.

Self-esteem in remitted patients with mood disorders is not associated with the dopamine receptor D4 and the serotonin transporter genes

Disturbances of the dopaminergic and serotoninergic neurotransmitter systems have been implicated in the pathogenesis of depressive symptoms. Associations have been reported between markers of the two neurotransmitter systems and the presence of illness or severity of depressive episodes, but no attention has been focused on the periods of remission. The present report focuses on a possible association of self-esteem in remitted mood disorder patients with the functional polymorphism located in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the dopamine receptor D 4 (DRD4). Inpatients ( N=162) affected by bipolar ( n=103) and unipolar ( n=59) disorder (DSM III-R) were assessed by the Self-Esteem Scale (SES, Rosenberg, 1965) and were typed for DRD4 and 5-HTTLPR ( n=58 subjects) variants at the third exon using polymerase chain reaction (PCR) techniques. Neither DRD4 nor 5-HTTLPR variants were associated with SES scores, and consideration of possible stratification effects such as sex and psychiatric diagnosis did not reveal any association either. The serotonin transporter and dopamine receptor D 4 genes do not, therefore, influence self-esteem in remitted mood disorder subjects.

Tyrosine hydroxylase gene associated with depressive symptomatology in mood disorder

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine and norepinephrine. It may be involved in the pathophysiology of psychiatric disorders and positive associations have been reported for TH gene markers in mood disorders. While most replications failed to confirm the initial findings, other papers suggested a potential role of this gene in the etiology of mood disorders. Among the many different reasons for a lack of consistent replications, a critical role is played by the "correct" phenotype identification. Actually, up to now the only classification criteria has been the psychiatric diagnosis, but within the same psychiatric diagnoses the symptomatologic presentation may vary dramatically depending upon severity, presence of psychotic features or other psychopathologic traits. Thus, the aim of our study is to evaluate a possible association for TH gene with symptomatology in a sample of subjects affected by mood disorders. We have developed a phenotype definition based on the observed symptomatology divided into the four factors "Excitement," "Depression," "Delusion," and "Disorganization." Our sample includes 46 mood disorder subjects, investigated by the OPCRIT (operational criteria checklist for psychotic illness) checklist for their symptomatological pattern and typed for TH variants by polymerase chain reaction (PCR) amplification. Depressive factor was associated with TH variants (F = 4.79, df = 4, 87, P = 0.006), with TH*2 subjects presenting lower depressive scores. Subjects with genotype TH*2/2 were the only ones in the sample to report mild depressive episodes. TH variants may be related with depressive symptomatology in subjects affected by mood disorders.

Immunophenotypic studies on atypical lymphocytes in psychiatric patients

By using phase-contrast microscopy combined with a fluorescent staining technique, the frequency of blast-type atypical lymphocytes (BTALs) appearing in peripheral blood and the phenotypic expression of their surface antigens were studied in 24 patients with schizophrenia, 16 with mood disorder and 14 healthy controls. BTALs were classified as being stimulated or activated cells, morphologically characterized by their large size, dark cytoplasm, a hollow perinuclear containing a few granules and finely dispersed chromatin structures with a few evident nucleoli. A significantly higher number of BTALs were found in the schizophrenic patients compared with healthy control subjects or patients with mood disorder. Further, there was a significant difference in the frequency of BTALs between patients with mood disorder and healthy control subjects. No significant difference in the frequency of BTALs was found between the schizophrenic patients with and without medication. Immunostaining of BTALs revealed that these cells consisted of B, T and non-B, non-T cell subpopulations. Contrary to our expectations, the T cell was only one third of the BTAL population. HLA-DR and CD38 were expressed on most BTALs (>70%), while CD25, an early activation marker of T cells was rarely found on BTALs (<0.3%). The differences in activated lymphocyte populations which appeared as morphologically atypical in the circulation among some psychiatric patients and infectious or autoimmune diseases are discussed. This is the first report on populations of BTALs.

GABAA alpha-1 subunit gene not associated with depressive symptomatology in mood disorders.

Considerable evidence implicates the neurotransmitter gamma-aminobutyric acid (GABA) in the biochemical pathophysiology of mood disorders. In this study, we investigated the possibility that the gene for the gamma-aminobutyric acid type A (GABAA) receptor alpha-1 subunit (GABRA1) might be associated with depressive symptomatology in a sample of mood disorder subjects. Sixty-seven inpatients affected by unipolar (n = 37) and bipolar (n = 30) disorder (DSMIV) were assessed at admission by the Hamilton depression rating scale (HAMD) and were typed using polymerase chain reaction (PCR) techniques. GABRA1 variants were not associated with depressive symptomatology, and consideration of possible stratification effects such as sex, psychiatric diagnosis and illness severity did not reveal any association either. GABAA alpha-1 subunit gene is not, therefore, associated with depressive symptomatology in mood disorder subjects.

A SEVERE TEST OF INTERPERSONAL THEORY OF DEPRESSION AMONG CRIMINAL DEFENDANTS

We attempted to place Coyne's (1976) interpersonal theory of depression in grave danger of refutation among a highly specialized psychiatric sample (76 criminal defendants referred for psychiatric evaluation). We assessed whether mood-disordered subjects scored lower on an index of social contact than nondepressed subjects. Consistent with interpersonal theory, depressed subjects obtained lower scores on the social contact measure than nondepressed subjects — to our knowledge, the first results to support the diagnostic specificity component of Coyne's theory among a clinical sample. Number of co-morbid diagnoses was not significantly related to social contact. It appears that Coyne's theory possesses explanatory power, even when subjected to a relatively severe empirical test.

Depressed Subjects Have Decreased rCBF Activation During Facial Emotion Recognition

AbstractDepressed subjects have deficits in facialemotion recognition that resemble the deficits found in persons with focal right hemisphere brain damage. To locate the brain regions responsible for this problem, the authors imaged regional cerebral blood flow (rCBF) with H2O15 positron emission tomography in 10 mood-disordered patients, as well as in 10 age- and sex-matched healthy comparison subjects, while the subjects matched photographs for facial emotion or, as a control, facial identity. While matching faces for emotion, mood-disordered subjects had decreased rCBF activation bilaterally in their temporal lobes, as well as in the right insula, compared with healthy comparison subjects. Abnormal function of limbic and paraiimbic regions may partially explain the facial emotion-recognition deficits previously noted in depressed subjects.

Blunted left cingulate activation in mood disorder subjects during a response interference task (the Stroop)

Functional neuroimaging studies have found abnormal anterior cingulate activity in depressed subjects, and other studies have shown that the cingulate gyrus becomes active in healthy subjects during interference tasks. The authors hypothesized that subjects with mood disorder might show blunted cingulate activation during the standard Stroop interference task or during a modified version involving sadness-laden words. In contrast to 11 age- and sex-matched healthy control subjects who activated the left cingulate during the standard Stroop, 11 mood-disordered subjects activated the right anterior cingulate gyrus only slightly and instead showed increased activity in the left dorsolateral prefrontal and visual cortex. This study supports theories of blunted limbic and paralimbic activation and abnormal cingulate activity in depression and adds to the growing knowledge of the functional neuroanatomy of depression.

Mood disorders: rural/urban differences in prevalence, health care utilization, and disability in Ontario

This study examines whether rural Ontario differs from urban Ontario in mood disorder prevalence, health service use and concomitant disability. An epidemiologic community survey of 9953 individuals was conducted, with rural/urban status defined by population-density-related criteria. Overall, Ontario prevalence rates for depression, manic episode, and dysthymia were similar to previous studies, but rural rates were unexpectedly no different from urban ones. Nearly half of mood disorder subjects used no services, and one-third reported significant disability. Rural individuals with mood disorders were similar to their urban counterparts in service use and disability.

CSF CGRP correlates with neuropeptides in controls but not affective illness

Neuropeptide Y is an abundant peptide in the brain present in high concentrations in the pituitary, hypothalamus, and limbic system. Previous studies have reported decreased cerebrospinal fluid (CSF) NPY-like immunoreactivity (NPY-LI) in depressed subjects. Increased synthesis and tissue concentrations of NPY have been found in distinct brain regions following electroconvulsive and lithium treatment. Also, in animal models, decreased NPY transmission has been linked to anxiety-related behaviors. To further explore the potential role of NPY in mood disorders, we measured CSF NPY-LI in 33 medication-free, mood-disordered subjects (10 BPI, 13 BPII, 10 UP) and 20 healthy controls. Six patients were also studied after they were on steady-state carbamazepine (CBZ), a drug known to alter norepinephrine which has been reported to coexist with NPY. CSF NPY-LI did not significantly vary as a function of diagnosis, gender, or age and showed no consistent association to severity of rated mood on the day of lumbar puncture; however, NPY-LI was significantly lower in the patients on CBZ (n ffi 6, 108 pmol/l mean, SD 32.3) than during their medication-free state (n ffi 6, 133 pmol/l mean, SD 27.4) (paired t test, t ffi 3.6, df ffi 5, p = 0.01 ). Treatment with CBZ resulted in significantly decreased CSF concentrations on NPY-LI which are not likely due to changes in mood. Further examination of the mechanism of CBZ's effects on NPY, as well as its implications for alterations in mood and anxiety, is encouraged.

A family study of anxiety disorders: familial transmission and relationship to mood disorder and psychoactive substance use disorder

The prevalence of mental disorders in 76 first-degree relatives (parents and nontwin siblings) of 33 subjects with anxiety disorder was compared with the prevalence of mental disorders in 45 first-degree relatives of 20 subjects with mood disorder and 13 first-degree relatives of 6 subjects with psychoactive substance use disorder. All subjects were personally interviewed with the Structured Clinical Interview for DSM-III-R Axis I (SCID I). Interrater reliability was high for most diagnoses. Significantly more first-degree relatives of subjects with anxiety disorder had panic disorder and generalized anxiety disorder compared with relatives of probands with mood disorder. Significantly more female than male relatives of anxiety subjects suffered from anxiety disorders; there were no gender differences in the prevalence of anxiety disorders in relatives of mood and psychoactive substance use disorder (PSUD) subjects. The combination of anxiety and mood disorder was overrepresented in first-degree relatives of subjects with the same type of comorbidity. In relatives of subjects with mixed anxiety and psychoactive substance use disorder, but no mood disorder, there was an overrepresentation of PSUD; mainly alcohol abuse or dependence.

CSF neuroactive steroids in affective disorders: Pregnenolone, progesterone, and DBI

Recently several steroid compounds have been discovered to act as neuromodulators in diverse central nervous system (CNS) functions. We wondered if neuroactive steroids might be involved in affective illness or in the mode of action of mood-regulating medications such as carbamazepine. Levels of the neuroactive steroids prenenolone and progesterone, as well as the neuropeptide diazepam binding inhibitor (DBI) (known to promote steroidogenesis), were analyzed from cerebrospinal fluid (CSF) obtained by lumbar puncture (LP) from 27 medication-free subjects with affective illness and 10 healthy volunteers. Mood-disordered subjects who were clinically depressed at the time of the LP had lower CSF pregnenolone (n = 9, 0.16 ng/ml) compared with euthymic volunteers (n = 10, 0.35 ng/ml; p < 0.01). In addition, pregnenolone was lower in all affectively ill subjects (n = 26, 0.21 ng/ml), regardless of mood state on the LP day, than healthy volunteers ( p < 0.05). No differences were found for progesterone or DBI levels by mood state or diagnosis. Progesterone, pregnenolone, and DBI did not change significantly or consistently in affectively ill subjects after treatment with carbamazepine. CSF pregnenolone is decreased in subjects with affective illness, particularly during episodes of active depression. Further research into the role of neuroactive steroids in mood regulation is warranted.