Changes in RNA expression levels during antidepressant treatment: a systematic review.

More than a third of patients treated with antidepressants experience treatment resistance. Furthermore, molecular pathways involved in antidepressant effect have yet to be fully understood. Therefore, we performed a systematic review of clinical studies that examined changes in RNA expression levels produced by antidepressant treatment. Literature search was performed through April 2021 for peer-reviewed studies measuring changes in mRNA or non-coding RNA levels before and after antidepressant treatment in human participants following PRISMA guidelines. Thirty-one studies were included in qualitative synthesis. We identified a large amount of heterogeneity between the studies for genes/RNAs measured, antidepressants used, and treatment duration. Of the six RNAs examined by more than one study, expression of the brain-derived neurotrophic factor (BDNF) gene and genes in the inflammation pathway, particularly IL-1ß, were consistently reported to be altered by antidepressant treatment. Limitations of this review include heterogeneity of the studies, possibility of positive publication bias, and risk of false-negative findings secondary to small sample sizes. In conclusion, our systematic review provides an updated synthesis of RNA expression changes produced by antidepressant treatment in human participants, where genes in the BDNF and inflammatory pathways were identified as potential targets of antidepressant effect. Importantly, these findings also highlight the need for replication of the included studies in multiple strong, placebo-controlled studies for the identification of evidence-based markers that can be targeted to improve treatment outcomes.

Weight-gain independent effect of mirtazapine on fasting plasma lipids in healthy men.

Treatment with mirtazapine, a widely prescribed antidepressant, has been linked to weight gain and dyslipidemia. Whether dyslipidemia occurs secondary to increased appetite due to antidepressant treatment, or due to direct pharmacological effects of mirtazapine is unknown. The aim of this analysis is to complement our previously published results of the effect of mirtazapine on metabolism and energy substrate partitioning from a proof-of-concept, open-label clinical study (ClinicalTrials.gov NCT00878540) in 12 healthy males (20-25 years). We report the effect of a seven-day administration of mirtazapine 30 mg per day on weight and lipid metabolism in healthy men under highly standardized conditions with respect to diet, physical activity and day-night-rhythm and under continuous clinical observation. After a 7-day administration of mirtazapine 30 mg, we observed a statistically significant increase in triglyceride levels (mean change + 4.4 mg/dl; 95% CI [- 11.4; 2.6]; p = 0.044) as well as TG/HDL-C ratio (mean change + 0.2; 95% CI [- 0.4; 0.1]; p = 0.019) and a decrease in HDL-cholesterol (mean change - 4.3 mg/dl; 95% CI [2.1; 6.5]; p = 0.004), LDL-cholesterol (mean change - 8.7 mg/dl; 95% CI [3.8; 13.5]; p = 0.008), total cholesterol (mean change - 12.3 mg/dl; 95% CI [5.4; 19.1]; p = 0.005), and non-HDL-C (mean change - 8.0 mg/dl; 95% CI [1.9; 14.0]; p = 0.023). Notably, weight (mean change - 0.6 kg; 95% CI [0.4; 0.8]; p = 0.002) and BMI (mean change - 0.2; 95% CI [0.1; 0.2]; p = 0.002) significantly decreased. No change in waist circumference (mean change - 0.4 cm; 95% CI [- 2.1; 2.9]; p = 0.838) or waist-to-hip-ratio (mean change 0.0; 95% CI [- 0.0; 0.0]; p = 0.814) was observed. This is the first study showing unfavorable changes in lipid metabolism under mirtazapine in healthy individuals despite highly standardized conditions including dietary restriction, and despite the observation of a decrease of weight. Our findings support the hypothesis that mirtazapine has direct pharmacological effects on lipid metabolism. ClinicalTrials.gov: NCT00878540.

Recurrent suicide attempts affect normalization of HPA axis dysregulation after recovery from major depression.

More than 700,000 people worldwide die by suicide every year, and the number of suicide attempts is estimated as 20 times higher, most of them being associated with psychiatric disorders, especially major depression. Knowledge about effective methods for preventing suicide attempts in individuals at high risk for suicide is still scarce. Dysregulation of the neuroendocrine stress response system, i.e., the hypothalamic-pituitary-adrenocortical (HPA) axis, is one of the most consistent neurobiological findings in both major depression and suicidality. While the HPA axis is mostly overactive in depression, individuals with a history of suicide attempts exhibit an attenuated hormonal response to stress. It is unknown, however, whether the HPA axis is constantly attenuated in repeated suicide attempters or whether it regains normal responsivity after recovery from depression. Using the combined dexamethasone suppression/corticotropin-releasing hormone (dex/CRH) test, we assessed HPA axis regulation in acute depression (N = 237) and after recovery with respect to previous suicide attempts. Patients without previous suicide attempts show normalization of the stress hormone response to the second dex/CRH (basal ACTH response and cortisol response) after recovery from acute depression, while patients with multiple previous SA show an increased ACTH response. The change in HPA axis responsivity in patients with only one previous SA lies between the response patterns of the other groups with no change in HPA axis reactivity. Our findings suggest that patients with a history of suicide attempts belong to a subgroup of individuals that exhibit a distinct pattern of stress hormone response during acute depression and after recovery. Future studies may extend our approach by investigating additional psychological stress tasks to gain a broader understanding of the stress pathology of recurrent suicide attempters.

Effects of weariness of life, suicide ideations and suicide attempt on HPA axis regulation in depression.

The neuropathological mechanisms leading to suicidality are still unknown, which, in view of an annual toll of around 1 million completed suicides constitutes an urgent clinical and societal problem. Alterations of stress hormone (ACTH and cortisol, representing the activity of the hypothalamic-pituitary-adrenocortical, HPA axis) regulation has been repeatedly studied in context of suicidality. Following a suicide attempt, stress hormone activity seems to be blunted, while depressed patients with suicidal ideation often present with elevated HPA axis activity. METHODS: We investigated the effects of different forms of suicidality on HPA axis regulation in 568 hospitalized patients of the Munich Antidepressant Response Signature (MARS) project. All patients had a diagnosis of a depressive disorder; 62 patients reported a recent suicide attempt, 192 patients suicide ideation, and 171 patients expressed weariness of life as the weakest form of suicidality, the latter not being analyzed in studies so far. All patients participated in the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test for assessing HPA axis regulation shortly after admission to the hospital. RESULTS: We found an increased ACTH and cortisol response following the dex/CRH-test in patients that were weary of life. In contrast, stress hormone response in suicide attempters and suicide ideators did not differ from non-suicidal patients. Further, repeated suicide attempts in patients' history were associated with more pronounced stress hormone attenuation. CONCLUSION: In this so far largest study analyzing the HPA axis with respect to suicidality, we could not confirm the assumption of a general attenuation of HPA axis response in depressed suicide ideators and attempters. Conversely, HPA axis appears to be influenced by divergent effects of a specific suicidal psychopathology as well as outlasting effects of previous suicide attempts. We discuss these findings in the light of recent concepts of suicidality, pointing to multifactorial effects of acute and predisposing conditions on HPA axis reactivity in depressed patients.

Function and Psychotherapy of Chronic Suicidality in Borderline Personality Disorder: Using the Reinforcement Model of Suicidality.

Although great advancements in evidence-based therapies, chronic suicidal patients with borderline personality disorder (BPD) still challenge our mental health system. While BPD patients continue suffering from distress and aversive emotions, therapists and relatives feel often stunned and helpless when confronted with suicidality resulting in interruption of therapies, repeated presentations to emergency rooms and referrals to hospitals. Reviewing the current knowledge of the functions and background of non-suicidal self-injury, we learned that reinforcement mechanisms play an important role to understand why individuals act in deliberate self-mutilation. While individual motives for non-suicidal self-injury and suicidal behavior including suicidal ideations can differ, the principle mechanisms appear to be transferrable. Elucidating the individual motives and function of suicidal behavior is an important therapeutic step, giving us access to very central maladaptive schemes and false believes that we need to address in order to reduce chronic suicidality in BPD patients. This Perspective article aims to give a better idea of what is behind and what are the differences between non-suicidal self-injury, suicidal ideations and suicide attempts. It further integrates recent developments of behavioral science in a reinforcement model of suicidality that can provide therapists a practical armamentarium in their work with chronic suicidal clients.

Clinical characteristics and treatment outcome in a representative sample of depressed inpatients - findings from the Munich Antidepressant Response Signature (MARS) project.

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.

Polymorphisms in the BDNF and BDNFOS genes are associated with hypothalamus-pituitary axis regulation in major depression.

Major depression is a stress-related disorder with robust clinical and preclinical data implicating that both, dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) axis and of the neurotrophin system of the brain are involved in the pathophysiology. Genetic variations within the brain-derived neurotrophic factor (BDNF) gene region, a major representative of the brain neurotrophins, are suggested to influence response to antidepressant treatment. Specifically, we recently identified two BDNF single nucleotide polymorphisms (SNP), rs2049046 and rs11030094, as associated with antidepressant treatment response in a large pharmacogenetic study of hospitalized patients. We now analyzed these two SNPs in a sub-sample for their association with HPA axis dysregulation using the combined dexamethasone suppression/corticotropin releasing hormone challenge (dex/CRH) test at hospital admission (N = 266) and at discharge (N = 190). Rs11030094, located 3' outside the coding region of BDNF, is also located in an intron of BDNFOS coding for a functional antagonist of BDNF. We further included the non-synonymous Val66Met (rs6265) polymorphism in our analysis, for which - albeit being extensively studied - conflicting results in respect to its role in antidepressant treatment response have been reported. Similar to the previous analysis, rs2049046 and rs11030094 showed a significant effect on antidepressant response. In a gene-dose dependent manner, we found significant lower cortisol responses to the dex/CRH test at discharge in carriers of the respective SNP alleles ('T' of rs2049046 and 'G' of rs11030094) that were associated with antidepressant response (beneficial alleles). These genetic effects on HPA axis regulation were independent of age, sex, medication and depressive symptomatology. Although not reaching statistical significance, the same direction of effect was observed for cortisol at admission, as well as the ACTH response at admission and discharge. An interaction analysis of both SNPs revealed highest cortisol levels in subjects that were non-carriers of both beneficial alleles. The Val66Met (rs6265) was neither associated with antidepressant response nor with HPA axis regulation. Our findings provide further evidence for an interaction of the HPA axis and the neurotrophin system in major depression. This study stresses the importance investigating BDNF variants beyond the extensively studied Val66Met polymorphism. In-depth analyses of both pathophysiologically relevant systems may point to possible new targets for pharmaceutical intervention and precision medicine of major depression in the future.

Effect of mirtazapine on metabolism and energy substrate partitioning in healthy men.

BACKGROUND: Weight gain and metabolic changes during treatment with antidepressant drugs have emerged as an important concern, particularly in long-term treatment. It is still a matter of ongoing debate whether weight gain and metabolic perturbations with antidepressant use are the consequence of increased appetite and weight gain, respectively, or represents direct pharmacological effects of the drug on metabolism. METHODS: We therefore conducted a proof-of-concept, open-label clinical trial, hypothesizing that in exceptionally healthy men no change of metabolic parameters would occur under mirtazapine, when environmental factors such as nutrition, sleep, and physical exercise were controlled and kept constant. Over a 3-week preparation phase, 10 healthy, young men were attuned to a standardized diet adjusted to their individual caloric need, to a regular sleep/wake cycle and moderate exercise. Continuing this protocol, we administered 30 mg mirtazapine daily for 7 days. RESULTS: While no significant weight gain or changes in resting energy expenditure were observed under these conditions, hunger and appetite for sweets increased with mirtazapine, accompanied by a shift in energy substrate partitioning towards carbohydrate substrate preference as assessed by indirect calorimetry. Furthermore, with mirtazapine, insulin and C-peptide release increased in response to a standardized meal. CONCLUSION: Our findings provide important insights into weight-independent metabolic changes associated with mirtazapine and allow a better understanding of the long-term metabolic effects observed in patients treated with antidepressant drugs. CLINICALTRIALS: gov NCT00878540. FUNDING: Nothing to declare.

Successful treatment of tardive lingual dystonia with botulinum toxin: case report and review of the literature.

Tardive dyskinesia (TD) is a dreaded side effect of antipsychotic medication. Recommended treatments for TD may provide reliable improvement but can be, in turn, associated with additional adverse reactions. Recently, several reports have suggested that botulinum toxin A (BTX-A) injection in affected muscles may significantly improve TD. Here, we report a case of severe tongue protrusion dystonia secondary to an antipsychotic medication in a young man. Several approaches including clozapine, amisulpride, aripiprazole, ziprasidone, tiapride and clonazepam failed to improve the symptoms. Injection of 50 U of BTX-A (Dysport, Ipsen, Ettlingen, Germany) into each genioglossal muscle dramatically improved tongue protrusion within few days with a sustained effect. If reasonable precautions are taken, the application seems to be well tolerated with only minor side effects. A review of the literature that is part of this article adverts BTX-A injection as a potential beneficial approach of various kinds of TD.

Possible associations of NTRK2 polymorphisms with antidepressant treatment outcome: findings from an extended tag SNP approach.

BACKGROUND: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. METHODS: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. RESULTS: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (Pcorr  = .018, Pcorr  = .015 and Pcorr  = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. CONCLUSIONS/LIMITATIONS: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies.

Glucose metabolism and antidepressant medication.

Impaired glucose tolerance is observed in depressed patients, and patients suffering from depression have an increased risk to develop diabetes mellitus. In depressed and diabetic patients, studies have shown both a beneficial effect of antidepressants on glucose homeostasis and the opposite. This review aims to structure the conflicting data and focuses on the question, which effect specific antidepressants have on glucose homeostasis. We therefore performed a systematic review of all available studies referenced in Medline from 1960 to 2011. We included antidepressant agents indexed in the Anatomical Therapeutic Chemical (ATC) classification system of the WHO in 2011 and searched for studies investigating their effects on glucose metabolism in clinical samples as well as in healthy subjects. Of 876 studies screened we included 66. Most studies had small sample sizes and lacked a placebo group limiting conclusions about antidepressant effects on glucose tolerance. However, some evidence points to beneficial effects on glucose homeostasis of hydrazine-type monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). In case of SSRIs, the effect is more pronounced in diabetic patients or patients with comorbid depression and diabetes mellitus. Noradrenegic substances (and possibly also dualacting antidepressants), in contrast, may deteriorate glucose tolerance. They can be used in depressed patients when favorable effects on mood outweigh adverse metabolic effects, but in depressed diabetics this can be at the expense of worsening of glycemic control. The effects of other antidepressants, like bupropione, mirtazapine or newer agents, require further investigation before reliable conclusions can be made. The synthesis of the findings is discussed in light of the specific pharmacodynamic properties of the antidepressants as well as the pathophysiological changes in depression and impaired glucose homeostasis, including animal studies.

Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment.

Single-nucleotide polymorphisms (SNPs) in the FKBP5, GRIK4, and HTR2A genes have been shown to be associated with response to citalopram treatment in the STAR(*)D sample, but only associations with FKBP5 have so far been tested in the Munich Antidepressant Response Signature (MARS) project. Response and remission of depressive symptoms after 5 weeks of antidepressant treatment were tested against 82 GRIK4 and 37 HTR2A SNPs. Association analysis was conducted in about 300 depressed patients from the MARS project, 10% of whom had bipolar disorder. The most predictive SNPs from these two genes and rs1360780 in FKBP5 were then genotyped in a total of 387 German depressed in-patients to analyze potential additive and interactive effects of these variants. We could not replicate previous findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study in our sample. Although not statistically significant, the effect for the best GRIK4 SNP of STAR(*)D (rs1954787, p=0.076, p(corrected)=0.98) seemed to be in the same direction. On the other hand, the nominally significant association with the top HTR2A SNPs of STAR(*)D (rs7997012, allelic, p=0.043, p(corrected)=0.62) was with the opposite risk allele. The GRIK4 SNP (rs12800734, genotypic, p=0.0019, p(corrected)=0.12) and the HTR2A SNP (rs17288723, genotypic, p=0.0011, p(corrected)=0.02), which showed the strongest association with remission in our sample, had not been reported previously. Associations across all genetic markers within the GRIK4 (genotypic, p=0.022) or HTR2A (genotypic, p=0.012) locus using the Fisher's product method (FPM) were also significant. In all 374 patients, the best predictive model included a main effect for GRIK4 rs12800734 and two significant interactions between GRIK4 rs12800734 and FKBP5 rs1360780, and GRIK4 rs12800734 and HTR2A rs17288723. This three SNP model explained 13.1% of the variance for remission after 5 weeks (p=0.00051 for the model). Analyzing a sub-sample of 194 patients, plasma ACTH (p=0.002) and cortisol (p=0.021) responses of rs12800734 GG (GRIK4) carriers, who also showed favorable treatment response, were significantly lower in the second combined dexamethasone (dex)/corticotrophin-releasing hormone (CRH) test before discharge compared with the other two genotype groups. Despite large differences in ethnicity and design compared with the STAR(*)D study, our results from the MARS study further support both independent and interactive involvement of GRIK4, HTR2A and FKBP5 in antidepressant treatment response.

A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression.

CONTEXT: The efficacy of antidepressant drug treatment in depression is unsatisfactory; 1 in 3 patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome. OBJECTIVE: To identify genetic and clinical determinants of antidepressant drug treatment outcome in depression. DESIGN: Genomewide pharmacogenetic association study with 2 independent replication samples. SETTING: We performed a genomewide association study in patients from the Munich Antidepressant Response Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single-nucleotide polymorphisms highly related to outcome in both genomewide association studies was genotyped in a sample of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. PARTICIPANTS: A total of 339 inpatients with a depressive episode (MARS sample), a further 361 inpatients with depression (German replication sample), and 832 outpatients with major depression (STAR*D sample). MAIN OUTCOME MEASURES: We generated a multilocus genetic variable that described the individual number of alleles of the selected single nucleotide polymorphisms associated with beneficial treatment outcome in the MARS sample ("response" alleles) to evaluate additive genetic effects on antidepressant drug treatment outcome. RESULTS: Multilocus analysis revealed a significant contribution of a binary variable that categorized patients as carriers of a high vs low number of response alleles in the prediction of antidepressant drug treatment outcome in both samples (MARS and STAR*D). In addition, we observed that patients with a comorbid anxiety disorder combined with a low number of response alleles showed the least favorable outcome. CONCLUSION: These results demonstrate the importance of multiple genetic factors combined with clinical features in the prediction of antidepressant drug treatment outcome, which underscores the multifactorial nature of this trait.