Substance abuse in patients with bipolar disorder: A systematic review and meta-analysis.

By considering the debilitating outcome of co-occurring of bipolar disorder (BD) and substance abuse, determination of risk factors of substance use disorders (SUD: abuse or dependence of drugs and/or alcohol) is essential to identify the susceptible patients. The purpose of this study was to clarify the major determinant factors of SUD among adults with BD by reviewing the relevant literature. We systematically searched electronic databases including PubMed (MEDLINE), EMBASE, OVID, Cochrane and Scopus for human studies addressing the co-existence of bipolar disorder and SUD. All potential published papers up to September 2016 have been reviewed. The statistical analysis was performed using Comprehensive Meta-analysis version 2. Male gender (Odds ratio: 2.191 (95% CI: 1.121-4.281), P 0.022), number of manic episodes (P: 0.001) and previous history of suicidality (Odds ratio: 1.758 (95% CI: 1.156-2.674), P: 0.008) were associated to SUD in patients with BD. SUD was not related to age, subtype of BD, hospitalization and co-existence of anxiety disorders or psychotic symptoms. SUD affects many aspects of BD regarding clinical course, psychopathology and prognosis. Our study demonstrates that male gender, history of higher number of manic episodes and suicidality are associated to higher susceptibility to SUD. Thus, assignment of more intensive therapeutic interventions should be considered in patients with increased risk of drug abuse to prevent development of SUD.

Two-year outcome of vagus nerve stimulation in treatment-resistant depression.

One of the major goals of antidepressant treatment is a sustained response and remission of depressive symptoms. Some of the previous studies of vagus nerve stimulation (VNS) have suggested antidepressant effects. Our naturalistic study assessed the efficacy and the safety of VNS in 74 European patients with therapy-resistant major depressive disorder. Psychometric measures were obtained after 3, 12, and 24 months of VNS. Mixed-model repeated-measures analysis of variance revealed a significant reduction (P < or = 0.05) at all the 3 time points in the 28-item Hamilton Rating Scale for Depression (HRSD28) score, the primary outcome measure. After 2 years, 53.1% (26/49) of the patients fulfilled the response criteria (> or =50% reduction in the HRSD28 scores from baseline) and 38.9% (19/49) fulfilled the remission criteria (HRSD28 scores < or = 10). The proportion of patients who fulfilled the remission criteria remained constant as the duration of VNS treatment increased. Voice alteration, cough, and pain were the most frequently reported adverse effects. Two patients committed suicide during the study; no other deaths were reported. No statistically significant differences were seen in the number of concomitant antidepressant medications. The results of this 2-year open-label trial suggest a clinical response and a comparatively benign adverse effect profile among patients with treatment-resistant depression.

Differential prediction of first clinical response to serotonergic and noradrenergic antidepressants using the loudness dependence of auditory evoked potentials in patients with major depressive disorder.

OBJECTIVE: Predictors of treatment response to serotonergic versus nonserotonergic, e.g., noradrenergic, antidepressants are of considerable clinical relevance as they could help to reduce the occurrence of patients' receiving weeks or even months of unsuccessful treatment. Several studies show that the response to selective serotonin reuptake inhibitors can be successfully predicted by using the loudness dependence of auditory evoked potentials (LDAEP), which denotes change in the amplitudes in response to different stimulus intensities and is to date one of the best validated indicators of the central serotonergic system. The aim of the current randomized prospective study was to investigate whether or not LDAEP also allows the differential prediction of treatment response to serotonergic versus noradrenergic antidepressants. METHOD: Electrophysiologic recordings were performed on 48 subjects between 1999 and 2001. After exclusions due to artifacts, the study sample consisted of 35 unmedicated inpatients with a DSM-IV or ICD-10 diagnosis of major depressive disorder (mean +/- SD age = 42.5 +/- 10.8 years; 13 male, 22 female; mean +/- SD score of 28.9 +/- 5.7 on the Hamilton Rating Scale for Depression [HAM-D], the primary measure for psychopathology). The patients were then treated for 4 weeks with either the selective serotonin reuptake inhibitor citalopram or the noradrenaline reuptake inhibitor reboxetine. RESULTS: Analysis of variance (F = 5.05, df = 1,31; p = .03) revealed that responders (50% improvement in HAM-D score) to the citalopram treatment were characterized by a strong LDAEP at baseline, and responders to reboxetine were characterized by a weak LDAEP at baseline. Non-responders to citalopram or reboxetine showed the inverse LDAEP characteristics, respectively. CONCLUSION: This study is one of the first to demonstrate differential prediction of response to different classes of antidepressants. Patients at the beginning of an antidepressant treatment who show an initially strong LDAEP have a greater probability of responding to a serotonin-agonist antidepressant, whereas patients with a weak LDAEP will probably benefit more from a nonserotonergic, e.g., noradrenergic, antidepressant. If these results were replicated in a larger sample, this simple electroencephalographic method could be more broadly used in clinical practice to support clinicians in replacing the trial and error method with a more targeted and individualized approach to antidepressant treatment.

Hand-motor dysfunction in depression: characteristics and pharmacological effects.

Motor retardation is a relevant aspect of depression. Kinematic analysis of movements can be applied to explore which type of motor dysfunction is associated with depression and to examine motor side effects of antidepressants. Using this tool, we aimed to investigate fine motor performance in patients suffering from depression and to compare a selective noradrenaline re-uptake inhibitor (NARI) (reboxetine) and a selective serotonin reuptake inhibitor (SSRI) (citalopram) regarding motor side effects after 4 weeks of treatment. In the first study (I), we examined 37 depressed patients and 37 healthy subjects using a digitizing graphic tablet and kinematic analysis of handwriting and rapid drawing movements. Both groups were comparable regarding age, gender distribution, handedness (preponderance of right-handers) and educational level. In the second study (ll), we examined different types of hand movements in 16 depressed patients receiving citalopram (flexible dosage) and 12 depressed patients treated with reboxetine (varying dosage) using the afore-mentioned methods. Both groups were comparable regarding age, gender, handedness and the baseline Hamilton Depression Rating Scale total score. I: Depressed patients performed drawing with significantly less regular velocity than controls (p < 0.001), but normal velocity. Handwriting of depressed patients was abnormally slow (p = 0.04). II: Reboxetine led to a significant improvement of repetitive drawing movements in depression. In contrast, citalopram had no pronounced effects on hand movements in depressed patients. I: Irregular patterns of velocity peaks in depressed patients point to basal ganglia dysfunction and/or deficient activity of the sensorimotor cortex and the supplementary motor area as possible substrates of hand-motor disturbances in depression. II: Computer-aided analysis of hand movements is a sensitive tool for the registration of differential pharmaceutical effects on hand-motor function in depression.

Nocturnal hormone profiles in patients with schizophrenia treated with olanzapine.

Nocturnal hormone profiles were measured in patients with schizophrenia with predominantly negative symptoms both under drug-free baseline conditions and after subchronic administration of the atypical antipsychotic olanzapine, with the aim of characterizing its pharmacological properties on the neuroendocrine level. The following hormones were studied in the sleep laboratory under polysomnographic control: adrenocorticotrophic hormone, cortisol, growth hormone (GH), prolactin, testosterone, and melatonin. Blood samples were taken at regular time intervals over the night, and serum concentrations of the hormones were determined. Ten patients completed the study, two of them were excluded from analysis due to incomplete hormone profiles. The dynamics of baseline nocturnal hormone secretion were similar to the patterns known from healthy subjects. After the treatment period of about 4 weeks, hypothalamic-pituitary-adrenal axis activity was reduced with decreased cortisol plasma levels compared to baseline conditions. Olanzapine induced a moderate prolactin elevation. The characteristic GH peak around sleep onset, clearly present under baseline conditions, was markedly reduced after treatment. Testosterone and melatonin secretion were not significantly altered. In conclusion, although interpretation is difficult in some cases due to interference with indirect effects of olanzapine administration and the consequences of the clinical course of the underlying schizophrenic disorder, the neuroendocrine findings are consistent with the receptor-binding profile of olanzapine where, beside the D(2) antagonism, the antiserotonergic properties are most important.

Differential effects of reboxetine and citalopram on hand-motor function in patients suffering from major depression.

RATIONALE: Motor dysfunctions might be a more common side effect of serotonergic than noradrenergic antidepressants. However, the effects of antidepressants on motor function in depression have rarely been analyzed systematically. Computerized methods allow the objective registration of drug-induced motor dysfunction and were applied in this study. OBJECTIVES: To examine the effects of a selective noradrenaline re-uptake inhibitor (NARI) (reboxetine) and a selective serotonin re-uptake inhibitor (SSRI) (citalopram) on hand-motor function in patients with major depression. METHODS: Different types of hand movements (drawing of circles and handwriting probes) were recorded and analyzed in 16 acutely depressed inpatients receiving citalopram (30-60 mg/day) and 12 acutely depressed inpatients treated with reboxetine (4-8 mg/day), using a digitizing tablet for the analysis of movement dynamics. Both groups were comparable regarding mean age (42-43 years), gender, handedness (preponderance of right-handers) and the mean baseline HAMD score (about 27). Five kinematical parameters reflecting velocity, regularity and degree of automation of hand movements have been computed. RESULTS: Reboxetine had significantly more favorable effects on fine motor function (increased velocity of rapid hand movements) in depressed patients than citalopram. These differences became obvious when patients conducted more complex tasks and are not explained by differential antidepressant effects. CONCLUSIONS: Our findings are in line with the hypothesis that SSRI tend to have small, but more pronounced negative effects on motor function than NARI.

Heart rate variability during sleep in patients with schizophrenia treated with olanzapine.

Cardiac adverse events in patients treated with atypical antipsychotics have gained increasing interest in recent years. In the present study, heart rate variability (HRV), which is a sensitive parameter reflecting central autonomic cardiac control, was investigated during treatment with olanzapine. Ten physically healthy male patients with schizophrenia, who displayed predominantly negative symptoms, were studied in the sleep laboratory under drug-free baseline conditions and after 4 weeks of olanzapine medication. HRV was assessed during different sleep stages both in the time and frequency domains. Only slight changes in HRV were shown during treatment, and appeared to be independent of sleep stages. Spectral analysis indicated a slight shift of the sympathovagal balance in favour of the sympathetic tone, which was consistent with an elevation of heart rate in the time domain; total HRV was not altered. These changes are in accordance with olanzapine's receptor profile exerting anticholinergic and anti-adrenergic properties. In conclusion, taken together with findings from previous studies demonstrating that olanzapine does not cause clinically significant changes of the QTc interval, the present results are consistent with the known cardiac safety profile of olanzapine.

Identification of a naturally occurring polymorphism in the promoter region of the norepinephrine transporter and analysis in major depression.

Disturbances in the noradrenergic neurotransmission system have been implicated in the etiology of mood disorders. The norepinephrine transporter (NET) is a main target of antidepressant action and was shown to be dysregulated in major depression. Despite the clinical and physiological significance of NET gene regulation, little is known about the transcriptional control mechanisms governing its expression. Since it is well established that affective disorders have a genetic component with many genes of small effect contributing to the genetic susceptibility of depression, the NET gene is an interesting candidate gene for affective disorders. In a search for polymorphisms or mutations in the 5' flanging region of the NET gene we sequenced approximately 1000 bp upstream of the first codon in the NET gene promoter in 100 patients with major depression and 100 healthy controls. We identified a so far unknown T --> C polymorphism 182 bp upstream of the start codon in a transcriptional relevant region. In a case control association study we investigated the newly identified T-182C polymorphism and an already known G1287A polymorphism in exon 9 of the NET gene in a sample of 193 patients with major depression and 136 healthy, non-related controls. No statistical significant differences between patients and controls were found for any of the analyzed polymorphisms, either in the genotype distribution or in the allele frequencies. Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of major depression.