Newer generation antidepressants and withdrawal effects: reconsidering the role of antidepressants and helping patients to stop

In England, the prescribing of antidepressants, primarily the newer generation antidepressant classes, has steadily increased over recent years. There is ongoing debate about how the efficacy of these drugs is viewed, their place in therapy and the harms associated with stopping them. Much of the evidence of their efficacy comes from short-term placebo-controlled trials which tend not to include outcomes that are of greatest relevance to patients, such as social functioning or quality of life, but rather restrict outcomes narrowly to symptom measures. On such measures these studies do not demonstrate clinically significant differences from placebo for depression. A range of adverse effects are also recognised, often greater in naturalistic studies of long-term antidepressants users than those measured in short-term efficacy studies, including emotional numbing, sexual difficulties, fatigue and weight gain. There is increasing recognition that withdrawal symptoms from antidepressants are common and that these symptoms can be severe and long-lasting in some patients. Recent guidance on how to stop antidepressants in a tolerable way has been presented by the Royal College of Psychiatrists. We believe that increasing awareness about the difficulty that some patients have in stopping antidepressants should lead to more cautious prescribing practice, with antidepressants given to fewer patients and for shorter periods of time. This article discusses the perceived benefits and harms of antidepressant use.

Changes in cognitive and behavioral control after lamotrigine and intensive dialectical behavioral therapy for severe, multi-impulsive bulimia nervosa: an fMRI case study

Purpose Adults with bulimia nervosa (BN) and co-occurring emotional dysregulation and multiple impulsive behaviors are less responsive to existing interventions. Initial data suggest that the combination of Dialectical Behavior Therapy (DBT) and a mood stabilizer, lamotrigine, significantly reduces symptoms of affective and behavioral dysregulation in these patients. Identifying candidate neurobiological mechanisms of change for this novel treatment combination may help guide future randomized controlled trials and inform new and targeted treatment development. Here, we examined neurocognitive and symptom changes in a female patient with BN and severe affective and behavioral dysregulation who received DBT and lamotrigine. Methods Go/no-go task performance data and resting-state functional MRI scans were acquired before the initiation of lamotrigine (after 6 weeks in an intensive DBT program), and again after reaching and maintaining a stable dose of lamotrigine. The patient completed a battery of symptom measures biweekly for 18 weeks over the course of treatment. Results After lamotrigine initiation, the patient made fewer errors on a response inhibition task and showed increased and new connectivity within frontoparietal and frontolimbic networks involved in behavioral and affective control. Accompanying this symptom improvement, the patient reported marked reductions in bulimic symptoms, behavioral dysregulation, and reactivity to negative affect, along with increases in DBT skills use. Conclusion Improved response inhibition and cognitive control network connectivity should be further investigated as neurocognitive mechanisms of change with combined DBT and lamotrigine for eating disorders. Longitudinal, controlled trials integrating neuroimaging and symptom measures are needed to fully evaluate the effects of this treatment. Level of Evidence IV: Evidence obtained from multiple time series with or without the intervention, such as case studies.

Assessment of HiTOP Constructs Across the Population: A Commentary on the HiTOP Measure Development Project

The set of articles in this issue demonstrates the promise of the HiTOP collaborative effort in advancing a viable alternative dimensional taxonomy of psychopathology. Besides transcending the limitations of our current taxonomic system and categorical diagnoses, the potential contributions of HiTOP should extend to also critically examining long-standing notions of psychopathology and mental wellness, evaluating the ability of symptom measures to capture the various manifestations of disorder in the population, and questioning the emphasis on predominant Western cultural norms as a basis for our definitions of psychopathology and their measurement. This commentary addresses the extent to which the implementation of the measurement studies featured in the special issue centered these goals, drawing on the work of scholars from within and outside the fields of psychiatry and clinical psychology, some who have taken a critical view of these fields. The hope is that we work to challenge some basic assumptions and increase self-reflection, with an eye toward reducing bias and mental health disparities.

Ketamine-assisted psychotherapy for trauma-exposed patients in an outpatient setting: A clinical chart review study

Trauma exposure across the lifespan produces risks for posttraumatic stress disorder (PTSD), depression, anxiety, as well as global disability in functioning. This retrospective clinical chart review is the first of its kind to assess the utility of sublingual ketamine-assisted body-centered psychotherapy in trauma-exposed patients in a real world clinic setting. De-identified clinical records data on self-reported symptom measures were retrospectively analyzed for patients (N = 18; M age = 45.22, SD = 12.90) entering ketamine-assisted psychotherapy treatment in an outpatient clinic between 2018 and 2020. Patients who completed six sessions of ketamine therapy reported meaningful (e.g., medium effect size) improvements in PTSD symptoms (P = 0.058; d = −0.48) and global disability in functioning (P = 0.050; d = −0.52) and statistically significant and meaningful improvements in depression (P = 0.019; d = −0.53). There were no improvements in anxiety symptoms. Sublingual ketamine-assisted psychotherapy was associated with heterogenous clinical utility among patients with trauma-exposure in an outpatient setting. This study was underpowered and unrepresentative of the population of ketamine patients in the United States. Replication of these findings is needed with larger and more diverse patient samples.

Adrenergic Attenuation of Immune Activity is Associated with Anhedonia in Adolescents

While inflammation has been implicated in the manifestation of psychiatric symptoms, the role of immune attenuation via sympathetic modulation in psychopathology remains unclear. Here, this study aimed to assess β2-agonist clenbuterol (CBL) as a promising agent to model adrenergic-induced immune response following ex vivo immune activation with lipopolysaccharide (LPS). Relationships between CBL-modulated cytokine levels and symptom measures were then explored. Adolescents were evaluated with semi-structure interviews and self-reported depression, anxiety, and anhedonia levels. Fasting whole-blood samples were collected and stimulated with LPS in the presence and absence of CBL for 6 hours, with supernatants being subjected to Luminex multiplex assay for 41 cytokines. Cytokine levels between conditions were compared using Bonferroni-corrected nonparametric tests. Exploratory factor analysis reduced 41 cytokines into fewer factors in each experimental condition, and their relationships with psychiatric symptoms were examined with Spearman correlations controlling for age, sex, and BMI. Data from 130 participants (15.25 ± 2.16 years old, 59% female) were analyzed. 10 cytokines were significantly affected by CBL treatment compared to LPS alone. LPS+CBL factor 3 significantly correlated with both anticipatory (rho = -0.39, p = 7.4 × 10-5) and consummatory anhedonia (rho = -0.36, p = 3.3 × 10-4), and these correlations remained significant when controlling additionally for depression. There were no significant associations between immune factors with depression or anxiety severity. Findings support our hypothesis that clenbuterol attenuates inflammatory effects thought to underlie psychiatric conditions in youth. Using a data-driven analytic method, distinctive relationships between CBL-affected cytokines and dimensional anhedonia were reported, further elucidating the role of β2-agonism in adolescent affective symptomatology.

Lurasidone in the long-term treatment of Japanese patients with bipolar I disorder: a 52 week open label study

Background The current study evaluated the long-term (52 week) safety and impact on symptom measures of lurasidone (with or without lithium or valproate) for the treatment of bipolar I disorder in Japanese patients. Methods Bipolar patients for this open-label flexibly dosed lurasidone (20–120 mg/day) study were recruited from those with a recent/current depressive episode who completed an initial 6 week, double-blind, placebo-controlled, lurasidone study (depressed group), and those with a recent/current manic, hypomanic, or mixed episode (non-depressed group) who agreed to enroll directly into the long-term study. Measures of adverse events and safety included treatment-emergent adverse events, vital signs, body weight, ECG, laboratory tests, and measures of suicidality and extrapyramidal symptoms. Symptom measures included Montgomery Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Results The most common adverse events associated with lurasidone were akathisia (30.7%), nasopharyngitis (26.6%), nausea (12.1%), and somnolence (12.1%). Minimal changes in lipids and measures of glycemic control occurred. Mean change in body weight was + 1.0 kg in the non-depressed group and − 0.8 kg in the depressed group. MADRS total scores declined by a mean (SD) of 2.0 (14.7) points from long-term baseline to endpoint in the depressed group who had received placebo in the prior 6 week trial. The depressed group that had received lurasidone during the prior 6 week study maintained their depressive symptom improvements. For the non-depressed group, YMRS total scores decreased over time. Limitations No control group was included, treatment was open-label, and 49.7% of patients completed the 52 week study. Conclusions Long-term treatment with lurasidone 20–120 mg/day for Japanese patients with bipolar disorder maintained improvements in depressive symptoms for depressed patients who were treated in a prior 6 week trial and led to improvements in manic symptoms among a newly recruited subgroup of patients with a recent/current manic, hypomanic, or mixed episode. Few changes in weight or metabolic parameters were evident. Clinical trial registration: JapicCTI-132319, clinicaltrials.gov—NCT01986114.

Dysregulation of threat neurociruitry during fear extinction: the role of anhedonia

Dimensional models of anxiety and depression highlight common and distinct symptom clusters that are thought to reflect disruptions in underlying functional processes. The current study investigated how functioning of threat neurocircuitry relates to symptom dimensions of anxiety and depression. Participants were aged 18–19 years (n = 229, 158 female) and were selected to ensure a range of scores on symptom measures. Symptom dimensions of “General Distress” (common to anxiety disorders and depression), “Fears” (more specific to anxiety disorders), and “Anhedonia-apprehension” (more specific to depression) were evaluated. Participants underwent functional magnetic resonance imaging during a Pavlovian fear conditioning paradigm. Multilevel modeling analyses estimated relationships between symptom dimensions and activation in threat neural circuitry. Exploratory whole brain analyses were also conducted. Threat-related neural activity was not associated with General Distress or Fears. Anhedonia-apprehension was associated with activation of bilateral amygdala, anterior insula and dACC during late extinction. We found no evidence to support an association between symptom dimensions of General Distress or Fears with threat circuitry activation in a large sample of young adults. We did, however, find that the symptom dimension of Anhedonia-apprehension was significantly associated with threat-related neural activation during fear extinction. This effect requires replication in future work but may reflect anhedonic impairments in learning when contingencies are altered, possibly linked to the rewarding relief of an unexpectedly absent threat.

Health Anxiety Predicts the Perceived Dangerousness of COVID-19 over and above Intrusive Illness-Related Thoughts, Contamination Symptoms, and State and Trait Negative Affect

This study sought to evaluate the specificity of health anxiety, relative to other forms of psychopathology, in perceptions of COVID-19 as dangerous. Measures of health anxiety, COVID-19 perceived dangerousness, negative affect, anxiety, depression, stress, contamination-related obsessions and compulsions, and intrusive illness-related thoughts were administered online to 742 community individuals during the Italian national lockdown. Results showed that, after controlling for demographic variables and other internalizing problems, health anxiety was the single most important factor associated with the perceived dangerousness of COVID-19. Moreover, a comparison between the current sample’s scores on various symptom measures and scores from prepandemic Italian samples revealed that, whereas other internalizing symptoms increased by a large or very large magnitude during the pandemic, levels of health anxiety and negative affect increased by a medium amount. This result may indicate that health anxiety is relatively trait-like, increasing the likelihood that our correlational data support the model of health anxiety as a vulnerability rather than an outcome. Together, these results indicate that health anxiety may be a specific risk factor for COVID-related maladjustment and support the distinction of health anxiety from other psychological problems.