Psychological treatment of depression in inpatients: a systematic review and meta-analysis

Research on psychological treatment of depression in inpatients is not conclusive, with some studies finding clear positive effects and other studies finding no significant benefit compared to usual care or structured pharmacotherapy. The results of a meta-analysis investigating how effective psychological treatment is for depressed inpatients are presented. A systematic search in bibliographical databases resulted in 12 studies with a total of 570 respondents. This set of studies had sufficient statistical power to detect small effect sizes. Psychological treatments had a small (g = 0.29), but statistically significant additional effect on depression compared to usual care and structured pharmacological treatments only. This corresponded with a numbers-needed-to-be-treated of 6.17. Heterogeneity was zero in most analyses, and not significant in all analyses. There was no indication for significant publication bias. Effects were not associated with characteristics of the population, the interventions and the design of the studies. Although the number of studies was small, and the quality of many studies was not optimal, it seems safe to conclude that psychological treatments have a small but robust effect on depression in depressed inpatients. More high-quality research is needed to verify these results.     

Psychotherapy for chronic major depression and dysthymia: A meta-analysis

Although several studies have examined the effects of psychotherapy on chronic depression and dysthymia, no meta-analysis has been conducted to integrate results of these studies. We conducted a meta-analysis of 16 randomized trials examining the effects of psychotherapy on chronic depression and dysthymia. We found that psychotherapy had a small but significant effect (d = 0.23) on depression when compared to control groups. Psychotherapy was significantly less effective than pharmacotherapy in direct comparisons (d = − 0.31), especially SSRIs, but that this finding was wholly attributable to dysthymic patients (the studies examining dysthymia patients were the same studies that examined SSRIs). Combined treatment was more effective than pharmacotherapy alone (d = 0.23) but even more so with respect to psychotherapy alone (d = 0.45), although again this difference may have reflected the greater proportion of dysthymic samples in the latter. No significant differences were found in drop-out rates between psychotherapy and the other conditions. We found indications that at least 18 treatment sessions are needed to realize optimal effects of psychotherapy. We conclude that psychotherapy is effective in the treatment of chronic depression and dysthymia but probably not as effective as pharmacotherapy (particularly the SSRIs).     

HIV-1 Tat neurotoxicity in primary cultures of rat midbrain fetal neurons: Changes in dopamine transporter binding and immunoreactivity

HIV-1 neurotoxic proteins (Tat, gp120) are believed to play a major role in pathogenesis of dementia in a significant portion of the AIDS patient population. Dopaminergic systems appear to be particularly important in HIV-associated dementia. In the current studies, we determined that primary cell cultures prepared from the midbrain of 18-day-old rat fetuses are sensitive to Tat neurotoxicity and investigated the possible effects of Tat on DAT-specific ligand binding and DAT immunoreactivity in rat fetal midbrain cultures. We found that Tat neurotoxicity was associated with a significant decrease in [3H]WIN 35428 binding. Immunostaining of cell cultures with antibodies recognizing the C-end epitope of DAT did not reveal significant changes in DAT immunoreactivity. The results of this study implicate involvement of monoamine transmission systems in HIV-associated dementia.     

Attention‐deficit hyperactivity disorder: A study of association with both the dopamine transporter gene and the dopamine D4 receptor gene

Attention‐deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Several investigations have reported associations between ADHD and both the 7‐repeat allele of the 48 bp VNTR at the DRD4 gene and the 10‐repeat allele of the 40 bp VNTR at the DAT1 gene, but the results have been inconsistent. A sample of 81 Brazilian ADHD children and adolescents and their parents were screened for these DRD4 and DAT1 VNTRs. An excess of the DRD4 7‐repeat allele was observed when both ADHD probands and their parents were compared with an ethnically matched control sample (chi‐square = 11.55, P = 0.03; chi‐square = 12.17, P = 0.03, respectively). However, haplotype relative risk (HRR) analysis showed no preferential transmission of the DRD4 7‐repeat allele. No evidence of association with the DAT1 polymorphism was detected by both approaches. Nevertheless, an interaction effect of both genes on ADHD hyperactive/impulsive dimension was observed (F = 4.68; P = 0.03). These results add to the group of studies that together suggest a small effect of these genes in the susceptibility to ADHD. © 2001 Wiley‐Liss, Inc.     

Effect of antiparkinsonian drug himantane on the content of dopamine transporter DAT protein in rat striatum and cultured heochromocytoma PC-12 cells

We studied the effects of antiparkinsonian drug himantane (acute and subchronic administration) on the content of dopamine transporter protein DAT in rat striatum ex vivo and on the content of DTA in cultured PC-12 cells (10⁻⁵–10⁻⁷ M, the preparation was added to the incubation medium once or 7 times). The preparation significantly reduced the content of DAT protein both ex vivo and in vitro. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 3, pp. 300–303, March, 2008     

Striatal dopamine transporter binding correlates with serum BDNF levels in patients with striatal dopaminergic neurodegeneration

Compelling evidence has shown, that neurotrophins responsible for the regulation of neuronal growth, survival, and differentiation are involved in neurodegenerative diseases. Whereas lower serum levels of brain derived neurotrophic factor (BDNF) have been observed in patients with Parkinson's disease, no studies have directly related the degree of striatal neurodegeneration of dopaminergic neurons (DA) with serum BDNF levels. In this study we examined the relationship between striatal neurodegeneration as determined with ¹²³I-PE2I-single photon emission computer tomography (SPECT) and serum BDNF levels in patients with parkinsonism. Twenty-one patients with abnormal in vivo striatal dopamine transporter (DAT) binding as evidenced with [¹²³I]PE2I SPECT brain scanning were included. Samples for serum BDNF levels were collected at the time of the SPECT scanning, and BDNF was measured with enzyme-linked immunosorbent assay (ELISA). The striatal binding potential of non-displaceable [¹²³I]PE2I was calculated. We found a positive correlation between serum BDNF levels and striatal DAT availability (p < 0.01, R² = 0.36). We find that in patients with striatal dopaminergic neurodegeneration serum BDNF levels decrease along with loss in striatal DAT binding.     

5-羟色胺和去甲肾上腺素转运蛋白基因多态性与抑郁症易感性的关联分析

7)之间存在显著性关联.结论 NET-T182C与抑郁症易感性存在关联,NET-T182C和5-HTTLPR均与抑郁症的严重程度存在关联.     

Insertion mutation at the C-terminus of the serotonin transporter disrupts brain serotonin function and emotion-related behaviors in mice

The 5-hydroxytryptamine transporter (5-HTT) regulates 5-hydroxytryptamine (5-HT) neurotransmission by removing 5-HT from the synaptic cleft. Emerging evidence from clinical and genetic studies implicates the 5-HTT in various neuropsychiatric conditions, including anxiety and depression. Here we report that a 5-HTT null mutant mouse line was generated by gene trapping that disrupted the sequence encoding the C-terminus of 5-HTT. This mutation resulted in significant reduction of 5-HTT mRNA and loss of 5-HTT protein. Brain levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid, were markedly decreased in C-terminus 5-HTT -/- mice, while 5-HT uptake or 5-HT content in platelets was absent. Behavioral phenotyping showed that C-terminus 5-HTT -/- mice were normal on a screen for gross behavioral, neurological, and sensory functions. In the tail suspension test for depression-related behavior, C-terminus 5-HTT -/- mice showed increased immobility relative to their +/+ controls. By comparison, a previously generated line of 5-HTT -/- mice lacking exon 2, encoding the N-terminus of the 5-HTT, showed abnormally high immobility in response to repeated, but not acute, exposure to the tail suspension test. In a novel, brightly-lit open field, both C-terminus 5-HTT -/- mice and N-terminus 5-HTT -/- mice displayed decreased center time and reduced locomotor activity compared with their +/+ controls. Both mutant lines buried significantly fewer marbles than their +/+ controls in the marble burying test. These findings further demonstrate the neurobiological functions of the 5-HTT and add to a growing literature linking genetic variation in 5-HTT function with emotional abnormalities.     

Rab 11 regulates constitutive dopamine transporter trafficking and function in N2A neuroblastoma cells

The dopamine transporter (DAT) is a crucial regulator of dopaminergic neurotransmission which undergoes constitutive and substrate-mediated trafficking to and from the membrane. Although, considerable research has been done to elucidate the regulation of substrate-stimulated DAT trafficking, less is known about which trafficking proteins are involved in constitutive DAT trafficking. Rab proteins are GTPases known to regulate the trafficking of proteins to and from specific endocytic compartments. Rabs 8 and 11, in particular, are involved in trafficking proteins from intracellular compartments to the plasma membrane. In this study, we sought to determine whether Rabs 8 and 11 would modulate DAT activity and trafficking in N2A neuroblastoma cells. We used Rab mutations known to confer constitutively active or dominant negative activity of these proteins to investigate the role of Rab activity in constitutive DAT trafficking and function. We found that constitutively active Rab 11 upregulates DAT function and surface expression while neither the constitutively active nor the dominant negative mutant of Rab 8 had any effect on DA uptake. Furthermore, immunofluorescence experiments revealed that dominant negative Rab 11 overexpression results in decreased surface DAT indicating a necessary function of Rab 11 in DAT trafficking to the plasma membrane. These data show for the first time a functional role of Rab proteins in the constitutive recycling of DAT to the plasma membrane.     

Association between serotonin transporter gene polymorphism and eating disorders outcome: a 6-year follow-up study

Eating disorder patients show different long-term outcomes, and trait-related alterations of serotonergic function, which might be related with the serotonin transporter (5-HTT) gene. We studied the relationships between 5-HTTLPR polymorphism, eating specific and general psychopathology and the long-term outcome of anorexia nervosa (AN) and bulimia nervosa (BN) patients. We evaluated the distribution of the functional 5-HTTLPR polymorphism in a series of 201 Italian, Caucasian, eating disorder patients (113 with AN and 88 with BN binge/purging (BP subtype) and in 150 Caucasian unrelated controls. Prior to starting an individual cognitive behavior therapy, a clinical assessment was performed by means of the structured clinical interview for DSM-IV axis I disorders and several self-report questionnaires. This assessment was repeated at the end of treatment, 3 years after the end of treatment and 3 years after the first follow-up. Diagnostic changes between AN and BN were frequent (28.3%), and the presence of depressive disorders was associated with a higher rate of diagnostic crossover during the follow-up period. The S-allele of the 5-HTTLPR genotype increases the risk susceptibility for both depressive comorbidity (OR?=?4.23; 95% CI, 1.45-12.37) and diagnostic crossover during the follow-up period in AN patients (OR = 5.04; 95% CI, 1.69-14.98). Logistic regression analyses confirmed these findings, when the interaction between genotype and psychiatric comorbidity as predictors of diagnostic instability in AN patients were taken into account. No significant association was found between 5-HTTLPR genotype and recovery. The S-allele of the 5-HTTLPR genotype increases the risk for depressive disorders comorbidity, and moderates the long-term outcome of anorectic patients.     

Cholesterol and serotonin transporter polymorphism interactions in late-life depression

Background

It has been suggested that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies associations between vascular diseases (coronary artery syndrome or stroke) and depression. This study investigated whether the 5-HTTLPR polymorphism has modifying effects on previously identified associations between cholesterol levels and prevalence/incidence of late-life depression.

Methods

In 732 community residents aged 65+, depression was ascertained (Geriatric Mental State Schedule) at baseline and after 2 years. 5-HTTLPR genotype and lipid levels (total, HDL and LDL cholesterol and triglycerides) were assayed. Covariates were age, sex, education, disability, and cognitive function.

Results

Significant associations between lower baseline HDL cholesterol levels with prevalent and incident depression were also modified by 5-HTTLPR polymorphism, and were only significant in the presence of one or more copies of the s allele.

Conclusion

A more atherogenic lipid profile, as indicated by lower HDL cholesterol is a risk factor for late-life depression and this risk is modified by a gene implicated in serotonin transport.     

Human herpesvirus 6 and multiple sclerosis: a one-year follow-up study

BACKGROUND: This study was undertaken in order to investigate the possible relation of HHV-6 and EBV in relapsing-remitting MS (RRMS). MATERIALS AND METHODS: A one-year follow up study was performed analysing peripheral blood mononuclear cells and serum samples of 57 patients with RRMS and 57 healthy blood donors (HBD) by a quantitative real time PCR, to detect HHV-6 and EBV. Clinical data (starting age and EDSS increase) were collected. RESULTS: We did not find any statistically significant difference for EBV between RRMS patients and HBD. Regarding HHV-6: i) There was a higher prevalence of HHV-6 in RRMS patients than in controls: 80.7% versus 29.8% respectively. ii) HHV-6 active replication seems to be related to exacerbations. iii) Only variant A was detected among RRMS patients with HHV-6 active replication. iv) Although some difference was found when we compared clinical data in RRMS patients with and without HHV-6 active replication, the results did not reach statistical significance. CONCLUSIONS: A higher HHV-6A frequency of active infection (reactivation or new infection) would lead to a more frequent exposure of HHV-6A antigens to the immune system of RRMS patients; this active replication of HHV-6A seems to be specifically related with the exacerbations in a subset of RRMS patients.     

An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults

Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self‐reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3′UTR and intron 8 of DAT1, the 10‐repeat and 6‐repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7‐repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS‐G and CAARS‐H (DSM‐IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS‐G was also found for the 7‐repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults. © 2015 Wiley Periodicals, Inc.     

Eyeblink conditioning in patients with hereditary ataxia: a one-year follow-up study

Delay eyeblink conditioning was examined in patients with genetically-defined heredoataxias and age-matched control subjects. 24 patients with spinocerebellar ataxia type 6 (SCA6), type 3 (SCA3), and Friedreichs ataxia (FRDA) participated. SCA6 affects primarily the cerebellum, whereas extracerebellar involvement is common in SCA3 and FRDA. Testing was performed in three sessions six months apart. Severity of ataxia was defined based on the International Ataxia Cooperative Rating Scale (ICARS). As expected, cerebellar patients were significantly impaired in eyeblink conditioning compared to controls. Signs of retention and further learning across sessions were present in controls, but not in the cerebellar patients. In addition, findings of disturbed timing of conditioned responses were observed. Both onsets and peaks of the conditioned responses (CRs) occurred significantly earlier in cerebellar patients. Shortened CR responses were most prominent in patients with primarily cerebellar cortical disease (SCA6). In the group of all cerebellar patients, the SCA3 and the FRDA group correlations between learning deficits and clinical findings were weak. Moderate-to-strong correlations were found in the SCA6 patients. There was no significant change, however, in clinical ataxia scores and CR incidence across the three sessions. In summary, impaired learning of conditioned eyeblink responses is a stable finding across multiple sessions in patients with degenerative cerebellar disorders. Eyeblink conditioning may be a useful measure of cerebellar impairment in patients with hereditary ataxias that primarily affect the cerebellum (such as SCA6). In other heredoataxias (such as SCA3 and FRDA), extracerebellar involvement not assessed by ICARS likely contributes to eyeblink conditioning abnormalities.     

Prevalence of depression in menopause: a pilot study

Summary Objective: The objective of this study was to determine whether women in peri-menopause are more likely to have a major mood disorder than those in pre- or postmenopause. Methods: We studied 100 women between the ages of 45 and 65 years old who were seen at four different women's health centers. Using menstrual and when available, laboratory criteria, each subject was determined to be pre-, peri- or postmenopausal. Each subject completed a Beck Depression Inventory (BDI) and provided psychiatric and medical history in a telephone interview. All patients with a BDI score greater than or equal to 10 were invited to have a psychiatric assessment, including a Structured Clinical Interview for DSM-IV Diagnoses (SCID-DSM IV). Results: The women in the perimenopausal group (n = 38) had statistically significant higher BDI scores than those women in the pre-menopausal (n = 17) and postmenopausal (n = 45) groups (p < 0.0001). Of those in the perimenopausal group who scored ≥ 10 and completed the SCID and met criteria for any psychiatric diagnosis, 11 out of 22 met criteria for Major Depressive Disorder, Recurrent. Conclusions: These data suggest that perimenopause may be a associated with recurrence of pre-existing depressive illness. The findings underscore the clinical importance of screening for and treating major depressive illness in women during the menopausal years.     

Personality and the serotonin transporter gene: Associations in a longitudinal population-based study

Associations between the promoter polymorphism of the serotonin transporter gene (5-HTTLPR) and anxiety-related personality traits in healthy adult subjects have been inconsistent. We assessed personality in participants of the Estonian Children Personality Behaviour and Health Study, using parental reports and self-reports. In the younger cohort, according to parental assessments at ages 9 and 15, children homozygous for the S allele had significantly higher scores of Neuroticism and lower scores of Openness, Agreeableness and Conscientiousness. Parental assessment of the older cohort at ages 15 and 18 did not yield any genotype effect on personality; however, interaction of cohort and genotype was not significant. According to self-reports, SS homozygotes had higher Neuroticism at age 15 but not at age 18. Thus, homozygocity for the S allele of the 5-HTTLPR is related to anxiety-related personality traits in general population, but this is easier to detect before adolescence.     

Desipramine induced changes in the norepinephrine transporter, α- and γ-synuclein in the hippocampus,amygdala and striatum

The high incidence of depression in Parkinson's disease (PD) has been well documented in the clinic; however, the underlying molecular mechanisms of these overlapping pathologies remain elusive. Using a rodent model of depression, the Wistar-Kyoto (WKY) rat, we previously demonstrated that in the frontal cortex the altered expression and protein interactions of α- and γ-synuclein (α-Syn, γ-Syn) were associated with dysregulated trafficking of the norepinephrine transporter (NET). Chronic treatment with desipramine (DMI), a NET-selective antidepressant, caused a disappearance of depressive-like behavior that was accompanied by a change in α-Syn and γ-Syn expression and their trafficking of NET. Using this same model, we examined the expression of NET, α-Syn and γ-Syn in the hippocampus, amygdale, brainstem, and striatum, all regions implicated in the development or maintenance of depression or PD pathology. Following chronic treatment with DMI, we observed a significant decrease in NET in the hippocampus, amygdala, and brainstem; decrease in γ-Syn in the hippocampus and amygdala; and, increase in α-Syn in the hippocampus and amygdala. Unexpectedly, we observed a significant decrease in α-Syn expression in the striatum of the WKY following chronic DMI treatment. The altered expression of NET, α-Syn and γ-Syn in different brain suggest that DMI's ability to improve depressive-like behavior in a rodent is associated with region-specific changes in the regulation of NET by α- and γ-Syn.     

Bipolar disorder and the serotonin transporter gene: a family-based association study

BACKGROUND: The human serotonin transporter gene (5-HTT) is a strong candidate for involvement in the pathogenesis of mood disorders. Two common polymorphisms have been identified in the gene: a VNTR in intron 2 and a functional deletion/insertion in the promoter region. In previous studies we proposed that allele 12 of the VNTR might increase susceptibility for bipolar disorder. METHODS: We have genotyped 122 parent-offspring trios of British Caucasian origin where the proband had DSM-IV Bipolar I disorder (BPI). The results were analysed with the transmission/ disequilibrium test (TDT), which examines whether particular alleles are preferentially transmitted from heterozygous parents to affected offspring. RESULTS: The 12 repeat in the VNTR in intron 2 was transmitted 72 times and not transmitted 56 times (chi2 = 2.0, 1 df, P = 0.16). If we exclude 24 families in which the proband was a case in our published case-control studies (Collier et al. 1996a; Rees et al. 1997), the excess transmission of allele 12 reaches conventional levels of statistical significance: chi2 = 3.85, 1 df, P < 0.05. The deletion/insertion polymorphism in the promoter region was not associated with BPI: 66 parents transmitted the inserted (L) allele and 59 parents transmitted the deleted (S) allele (chi2 = 0.39, 1 df, P = 0.53). CONCLUSIONS: The 12 repeat of the VNTR in intron 2 of the serotonin transporter gene might be a susceptibility factor in bipolar affective disorder. The genetic effect, if true, is likely to be small, and requires confirmation in further studies using parental controls.