Optimal doses of antidepressants in dependence on age: Combined covariate actions in Bayesian network meta-analysis.

Background: The meta-analysis by Furukawa et al. (The Lancet Psychiatry 2019, 6(7)) reported optimal doses for antidepressants in adult major depressive disorder (MDD). The present reanalysis aimed to adjust optimal doses in dependence on age. Methods: Analysis was based on the same dataset by Cipriani et al. (The Lancet 2018, 391(10128)) comparing 21 antidepressants in MDD. Random-effects Bayesian network meta-analysis was implemented to estimate the combined covariate action using restricted cubic splines (RCS). Balanced treatment recommendations were derived for the outcomes efficacy (response), acceptability (dropouts for any reason), and tolerability (dropouts due to adverse events). Findings: The combined covariate action of dose and age suggested agomelatine and escitalopram as the best-balanced antidepressants in terms of efficacy and tolerability that may be escalated until 40 and 60 mg/day fluoxetine equivalents (mg/day FE ), respectively, for ages 30-65 years. Desvenlafaxine, duloxetine, fluoxetine, milnacipran, and vortioxetine may be escalated until 20-40 mg/day FE , whereas bupropion, citalopram, mirtazapine, paroxetine, and venlafaxine may not be given in doses  > 20 mg/day FE . Amitriptyline, clomipramine, fluvoxamine, levomilnacipran, reboxetine, sertraline, and trazodone revealed no relevant balanced benefits and may therefore not be recommended for antidepressant treatment. None of the antidepressants was observed to provide balanced benefits in patients >70 years because of adverse events exceeding efficacy. Interpretation: Findings suggest that the combined covariate action of dose and age provides a better basis for judging antidepressant clinical benefits than considering dose or age separately, and may thus inform decision makers to accurately guide antidepressant dosing recommendations in MDD. Funding: No funding.

Combining threshold analysis and GRADE to assess sensitivity to bias in antidepressant treatment recommendations adjusted for depression severity.

Threshold analysis has recently been proposed to be used in combination with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) in order to assess the sensitivity to plausible bias of treatment recommendations derived from Bayesian network meta-analysis (NMA). Here, it was aimed to apply the combination of threshold analysis and GRADE to judge quantitative and qualitative information on risk of bias in antidepressant treatment recommendations. The analysis was based on the data set provided by Cipriani et al. (The Lancet 2018) comparing 21 antidepressants in adult major depressive disorder (MDD). Primary outcomes were efficacy (response rate) and acceptability (dropout rate) adjusted for the covariate depression severity. The combined approach suggested sensitivity to plausible bias to be largest for antidepressant recommendations top ranked by Cipriani et al., that is, amitriptyline, duloxetine, paroxetine, and venlafaxine in terms of efficacy and agomelatine, escitalopram, paroxetine, and venlafaxine in terms of acceptability. Covariate ranges within which recommendations were most sensitive to plausible bias were very severe depression in terms of efficacy (smallest threshold, ie, the largest sensitivity, around 39 Hamilton Depression Rating Scale [HDRS]) and moderate depression in terms of acceptability (smallest thresholds around 16 and 35 HDRS). This indicates that treatment recommendations within these ranges may likely change if plausible bias adjustments take place. The present findings may support decision makers in judging the sensitivity to plausible bias of current antidepressant treatment recommendations to accurately guide treatment decisions in MDD depending on depression severity.

Psychotropic and neurological medication effects on mitochondrial complex I and IV in rodent models.

Mitochondrial complex I (NADH-dehydrogenase) and complex IV (cytochrome-c-oxidase) are reported to be affected by drugs used to treat psychiatric or neurodegenerative diseases, including antidepressants, antipsychotics, anxiolytics, mood stabilizers, stimulants, antidementia, and antiparkinsonian drugs. We conducted meta-analyses examining the effects of each drug category on complex I and IV. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar were searched for studies published between 1970 and 2018. Of 3105 screened studies, 68 articles covering 53 drugs were included in the meta-analyses. All studies assessed complex I and IV in rodent brain at the level of enzyme activity. Results revealed that selected antidepressants increase or decrease complex I and IV, antipsychotics and stimulants decrease complex I but increase complex IV, whereas anxiolytics, mood stabilizers, antidementia, and antiparkinsonian drugs preserve or even enhance both complex I and IV. Potential contributions to the drug effects were found to be related to the drugs' neurotransmitter receptor profiles with adrenergic (α1B), dopaminergic (D1/2), glutaminergic (NMDA1,3), histaminergic (H1), muscarinic (M1,3), opioid (OP1-3), serotonergic (5-HT2A, 5-HT2C, 5-HT3A) and sigma (σ1) receptors having the greatest effects. The findings are discussed in relation to pharmacological mechanisms of action that might have relevance for clinical and research applications.

Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease.

Complex I (NADH dehydrogenase, NDU) and complex IV (cytochrome-c-oxidase, COX) of the mitochondrial electron transport chain have been implicated in the pathophysiology of major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), as well as in neurodegenerative disorders, such as Alzheimer disease (AD) and Parkinson disease (PD). We conducted meta-analyses comparing complex I and IV in each disorder MDD, BD, SZ, AD, and PD, as well as in normal aging. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar, were searched for studies published between 1980 and 2018. Of 2049 screened studies, 125 articles were eligible for the meta-analyses. Complex I and IV were assessed in peripheral blood, muscle biopsy, or postmortem brain at the level of enzyme activity or subunits. Separate meta-analyses of mood disorder studies, MDD and BD, revealed moderate effect sizes for similar abnormality patterns in the expression of complex I with SZ in frontal cortex, cerebellum and striatum, whereas evidence for complex IV alterations was low. By contrast, the neurodegenerative disorders, AD and PD, showed strong effect sizes for shared deficits in complex I and IV, such as in peripheral blood, frontal cortex, cerebellum, and substantia nigra. Beyond the diseased state, there was an age-related robust decline in both complexes I and IV. In summary, the strongest support for a role for complex I and/or IV deficits, is in the pathophysiology of PD and AD, and evidence is less robust for MDD, BD, or SZ.

Adaptive Value Normalization in the Prefrontal Cortex Is Reduced by Memory Load.

Adaptation facilitates neural representation of a wide range of diverse inputs, including reward values. Adaptive value coding typically relies on contextual information either obtained from the environment or retrieved from and maintained in memory. However, it is unknown whether having to retrieve and maintain context information modulates the brain's capacity for value adaptation. To address this issue, we measured hemodynamic responses of the prefrontal cortex (PFC) in two studies on risky decision-making. In each trial, healthy human subjects chose between a risky and a safe alternative; half of the participants had to remember the risky alternatives, whereas for the other half they were presented visually. The value of safe alternatives varied across trials. PFC responses adapted to contextual risk information, with steeper coding of safe alternative value in lower-risk contexts. Importantly, this adaptation depended on working memory load, such that response functions relating PFC activity to safe values were steeper with presented versus remembered risk. An independent second study replicated the findings of the first study and showed that similar slope reductions also arose when memory maintenance demands were increased with a secondary working memory task. Formal model comparison showed that a divisive normalization model fitted effects of both risk context and working memory demands on PFC activity better than alternative models of value adaptation, and revealed that reduced suppression of background activity was the critical parameter impairing normalization with increased memory maintenance demand. Our findings suggest that mnemonic processes can constrain normalization of neural value representations.

Prefrontal hemodynamic after-effects caused by rebreathing may predict affective states - A multimodal functional near-infrared spectroscopy study.

Brain activity has been shown to be influenced by respiratory behavior. Here, we evaluated whether respiration-induced hypo- or hypercapnia may support differentiation between physiological versus pathological respiratory behavior. In particular, we investigated whether systemic physiological measures could predict the brain's time-frequency hemodynamics after three respiratory challenges (i.e., breath-holding, rebreathing, and hyperventilation) compared to resting-state. Prefrontal hemodynamics were assessed in healthy subjects (N = 27) using functional near-infrared spectroscopy (fNIRS). Systemic physiological measures were assessed in form of heart rate, partial end-tidal carbon dioxide, respiration rate, and saturation of peripheral oxygen. Time-frequency dynamics were quantified using the wavelet transform coherence (i.e., defined here as cortical-systemic coherence). We found that the three respiratory challenges modulated cortical-systemic coherence differently: (1) After rebreathing, cortical-systemic coherence could be predicted from the amplitude of the heart rate (strong negative correlation). (2) After breath-holding, the same observation was made (moderate negative correlation). (3) After hyperventilation, no significant effect was observed. (4) These effects were found only in the frequency range of very low-frequency oscillations. The presented findings highlight a distinct role of rebreathing in predicting cortical-systemic coupling based on heart rate changes, which may represents a measure of affective states in the brain. The applied multimodal assessment of hemodynamic and systemic physiological measures during respiratory challenges may therefore have potential applications in the differentiation between physiological and pathological respiratory behavior.

Brain correlates of verbal fluency in subthreshold psychosis assessed by functional near-infrared spectroscopy.

The prevalence of subthreshold psychotic symptoms in the general population has gained increasing interest as a possible precursor of psychotic disorders. The goal of the present study was to evaluate whether neurobiological features of subthreshold psychotic symptoms can be detected using verbal fluency tasks and functional near-infrared spectroscopy (fNIRS). A large data set was obtained from the Zurich Program for Sustainable Development of Mental Health Services (ZInEP). Based on the SCL-90-R subscales 'Paranoid Ideation' and 'Psychoticism' a total sample of 188 subjects was assigned to four groups with different levels of subthreshold psychotic symptoms. All subjects completed a phonemic and semantic verbal fluency task while fNIRS was recorded over the prefrontal and temporal cortices. Results revealed larger hemodynamic (oxy-hemoglobin) responses to the phonemic and semantic conditions compared to the control condition over prefrontal and temporal cortices. Subjects with high subthreshold psychotic symptoms exhibited significantly reduced hemodynamic responses in both conditions compared to the control group. Further, connectivity between prefrontal and temporal cortices revealed significantly weaker patterns in subjects with high subthreshold psychotic symptoms compared to the control group, possibly indicating less incisive network connections associated with subthreshold psychotic symptoms. The present findings provide evidence that subthreshold forms of psychotic symptoms are associated with reduced hemodynamic responses and connectivity in prefrontal and temporal cortices during verbal fluency that can be identified using fNIRS.

Time-frequency dynamics of the sum of intra- and extracerebral hemodynamic functional connectivity during resting-state and respiratory challenges assessed by multimodal functional near-infrared spectroscopy.

Monitoring respiratory processes is important for evaluating neuroimaging data, given their influence on time-frequency dynamics of intra- and extracerebral hemodynamics. Here we investigated the time-frequency dynamics of the sum of intra- and extracerebral hemodynamic functional connectivity states during hypo- and hypercapnia by using three different respiratory challenge tasks (i.e., hyperventilation, breath-holding, and rebreathing) compared to resting-state. The sum of intra- and extracerebral hemodynamic responses were assessed using functional near-infrared spectroscopy (fNIRS) within two regions of interest (i.e., the dorsolateral and the medial prefrontal cortex). Time-frequency fNIRS analysis was performed based on wavelet transform coherence to quantify functional connectivity in terms of positive and negative phase-coupling within each region of interest. Physiological measures were assessed in the form of partial end-tidal carbon dioxide, heart rate, arterial tissue oxygen saturation, and respiration rate. We found that the three respiration challenges modulated time-frequency dynamics differently with respect to resting-state: 1) Hyperventilation and breath-holding exhibited inverse patterns of positive and negative phase-coupling. 2) In contrast, rebreathing had no significant effect. 3) Low-frequency oscillations contributed to a greater extent to time-frequency dynamics compared to high-frequency oscillations. The results highlight that there exist distinct differences in time-frequency dynamics of the sum of intra- and extracerebral functional connectivity not only between hypo- (hyperventilation) and hypercapnia but also between different states of hypercapnia (breath-holding versus rebreathing). This suggests that a multimodal assessment of intra-/extracerebral and systemic physiological changes during respiratory challenges compared to resting-state may have potential use in the differentiation between physiological and pathological respiratory behavior accompanied by the psycho-physiological state of a human.