Manish K. Jha

Personalized Antidepressant Selection and Pathway to Novel Treatments: Clinical Utility of Targeting Inflammation

Major depressive disorder (MDD) is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to two or more antidepressant treatments. There are no valid clinical markers to personalize currently available antidepressant medications, all of which have similar mechanisms targeting monoamine neurotransmission. The goal of this review is to summarize the recent findings of immune dysfunction in patients with MDD, the utility of inflammatory markers to personalize treatment selection, and the potential of targeting inflammation to develop novel antidepressant treatments. To personalize antidepressant prescription, a c-reactive protein (CRP)-matched treatment assignment can be rapidly implemented in clinical practice with point-of-care fingerstick tests. With this approach, 4.5 patients need to be treated for 1 additional remission as compared to a CRP-mismatched treatment assignment. Anti-cytokine treatments may be effective as novel antidepressants. Monoclonal antibodies against proinflammatory cytokines, such as interleukin 6, interleukin 17, and tumor necrosis factor α, have demonstrated antidepressant effects in patients with chronic inflammatory conditions who report significant depressive symptoms. Additional novel antidepressant strategies targeting inflammation include pharmaceutical agents that block the effect of systemic inflammation on the central nervous system. In conclusion, inflammatory markers offer the potential not only to personalize antidepressant prescription but also to guide the development of novel mechanistically-guided antidepressant treatments.

Improvement in self-reported quality of life with cognitive therapy for recurrent major depressive disorder

BACKGROUND Major depressive disorder (MDD) is common, often recurrent and/or chronic. Theoretically, assessing quality of life (QoL) in addition to the current practice of assessing depressive symptoms has the potential to offer a more comprehensive evaluation of the effects of treatment interventions and course of illness. METHODS Before and after acute-phase cognitive therapy (CT), 492 patients from Continuation Phase Cognitive Therapy Relapse Prevention trial (Jarrett et al., 2013; Jarrett and Thase, 2010) completed the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Inventory of Depressive Symptomatology Self-report (IDS-SR) and Beck Depression Inventory (BDI); clinicians completed Hamilton Rating Scale for Depression-17-items. Repeated measures analysis of variance evaluated the improvement in QoL before/after CT and measured the effect sizes. Change analyses to assess clinical significance (Hageman and Arrindell, 1999) were conducted. RESULTS At the end of acute-phase CT, a repeated measure analysis of variance produced a statistically significant increase in Q-LES-Q scores with effect sizes of 0.48-1.3%; 76.9-91.4% patients reported clinically significant improvement. Yet, only 11-38.2% QoL scores normalized. An analysis of covariance showed that change in depression severity (covariates=IDS-SR, BDI) completely accounted for the improvement in Q-LES-Q scores. LIMITATIONS There were only two time points of observation; clinically significant change analyses lacked matched normal controls; and generalizability is constrained by sampling characteristics. CONCLUSIONS Quality of life improves significantly in patients with recurrent MDD after CT; however, this improvement is completely accounted for by change in depression severity. Normalization of QoL in all patients may require targeted, additional, and/or longer treatment.

Daily activity level improvement with antidepressant medications predicts long-term clinical outcomes in outpatients with major depressive disorder

Background Major depressive disorder (MDD) significantly impacts performance of both work- and nonwork-related routine daily activities. We have shown that work productivity is significantly impaired in employed MDD patients, but the extent of impairments in nonwork-related routine activities and its association with antidepressant treatment outcomes has not been established. Materials and methods Activity impairment was measured using the sixth item of Work Productivity and Activity Impairment Scale in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (n=665). Published norms were used to define activity impairment levels. The relationship between activity impairment and baseline sociodemographic and clinical characteristics was evaluated along with changes in activity impairment and its relationship with other clinical outcomes such as symptom severity, function, and side effect burden. Remission status at 3 and 7 months was predicted based on week 6 activity impairment level. Results Higher psychosocial and cognitive impairments and greater number of comorbid medical conditions were associated with greater activity impairment at baseline. Proportion of participants with severe activity impairment declined from 47.6% at baseline to 18.7% at 3 months, while mean activity impairment decreased from 57.1 at baseline to 32.8 at 3 months. During course of treatment, levels of activity impairment correlated most strongly with psychosocial function among measures of symptom severity, function, quality of life, and side effect burden. No or minimal activity impairment at week 6 was associated with two to three times higher rates of remission at 3 and 7 months as compared to moderate or severe activity impairment levels even after controlling for remission status at week 6 and select baseline variables. Conclusion Depressed patients have high levels of nonwork-related activity impairment at baseline that improves significantly with treatment and independently predicts long-term clinical outcomes. Brief systematic assessment of activity impairment during the course of antidepressant treatment can help inform clinical decision-making.

Can We Address the Shortage of Psychiatrists in the Correctional Setting with Exposure During Residency Training

Psychiatry residents at the University of Texas Southwestern Medical Center were surveyed to investigate their attitudes towards inmates, towards various aspects of correctional psychiatry and whether rotating at the local jail is associated with these attitudes. The overall opinion towards correctional psychiatry was fairly neutral though significantly more negative than towards inpatient psychiatry. While citing a high need for psychiatrists at correctional facilities, residents reported they are not likely to work there when they complete residency. No statistical differences were found between those residents who had rotated at the local jail and those who had not. Given the severe shortage of mental health providers in correctional facilities it is important to expose residents to this and understand ways to promote correctional psychiatry as a career.

Early normalization of Quality of Life predicts later remission in depression: Findings from the CO-MED trial.

BACKGROUND Although normal Quality of Life (QoL) is the outcome desired by patients, it is unclear if QoL changes early in course of antidepressant treatments are independent of depression severity, and can predict subsequent remission. METHODS The Quality of Life Inventory was obtained repeatedly in the Combining Medications to Enhance Depression Outcomes trial. Mixed model analyses assessed QoL change. Using population-based norms, participants were grouped as very low, low, or normal QoL at week 4, and association with remission was evaluated. RESULTS Overall baseline to week 4 QoL improved significantly (p=0.0015) even after controlling for change in depression severity and baseline variables (gender, age, education, race, ethnicity, income, employment status, anxious features, depression onset before age 18, suicidal ideations, and treatment-arm). At week 4, participants with low and normal QoL had higher unadjusted odds ratio (OR) for remission at 3 months (low QoL OR=2.36, 95% confidence interval (CI)=1.25,4.44; normal QoL OR=2.59, 95% CI=1.53,4.39) and 7 months (low QoL OR=2.07, 95% CI=1.00,4.31; normal QoL OR=3.98, 95% CI=2.06,7.69) compared to those with very low QoL. Remission rates, adjusted for baseline variables, were higher only for participants with normal QoL (3 months OR=2.83, 95% CI=1.42,5.68; 7 months OR=6.10, 95% CI=2.40,15.63). LIMITATIONS Secondary analysis, short period of assessment for QoL change, remission instead of functional recovery as long-term outcome. CONCLUSION Quality of life improves early, independent of depression severity. Normal QoL at week 4 is associated with 2-6 times higher remission rates. Findings support QoL beyond symptomatic change as a potential mediator of remission.

Early improvement in psychosocial function predicts longer-term symptomatic remission in depressed patients

The goal of this study was to evaluate the relationship between early change in psychosocial function independent of depression severity and longer-term symptomatic remission. Participants of Combining Medications to Enhance Depression Outcomes trial were randomly selected for model selection (n = 334) and validation (n = 331). Changes in psychosocial function (Work and Social Adjustment Scale, WSAS) from baseline to week 6 were assessed and two data-driven sub-groups of WSAS change were identified in the randomly selected model selection half. Results of analyses to predict symptomatic remission at 3 and 7 months were validated for these sub-groups in the second half (validation sample). From baseline to week 6, psychosocial function improved significantly even after adjusting for depression severity at each visit and select baseline variables (age, gender, race, ethnicity, education, income, employment, depression onset before age 18, anxious features, and suicidal ideation), treatment-arm, and WSAS score. The WSAS change patterns identified two (early improvement and gradual change) subgroups. After adjusting for baseline variables and remission status at week 6, participants with early improvement in the second half (validation sample) had greater remission rates than those with gradual change at both 3 (3.3 times) and 7 months (2.3 times) following acute treatment initiation. In conclusion, early improvement in psychosocial function provides a clinically meaningful prediction of longer-term symptomatic remission, independent of depression symptom severity.

Validating pre-treatment body mass index as moderator of antidepressant treatment outcomes: Findings from CO-MED trial

BACKGROUND Currently, there are no valid clinical or biological markers to personalize the treatment of depression. Recent evidence suggests that body mass index (BMI) may guide the selection of antidepressant medications with different mechanisms of action. METHODS Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants with BMI measurement (n = 662) were categorized as normal- or underweight (<25), overweight (25-<30), obese I (30-<35), and obese II+ (≥35). Logistic regression analysis with remission as the dependent variable and treatment arm-by-BMI category interaction as the primary independent variable was used to evaluate if BMI differentially predicted response to escitalopram (SSRI) monotherapy, bupropion-escitalopram combination, or venlafaxine-mirtazapine combination, after controlling for gender and baseline depression severity. RESULTS Remission rates among the three treatment arms differed on the basis of pre-treatment BMI (chi-square=12.80, degrees of freedom=6, p = .046). Normal- or under-weight participants were less likely to remit with the bupropion-SSRI combination (26.8%) than SSRI monotherapy (37.3%, number needed to treat or NNT = 9.5) or venlafaxine-mirtazapine combination (44.4%, NNT = 5.7). Conversely, obese II+ participants were more likely to remit with bupropion-SSRI (47.4%) than SSRI monotherapy (28.6%, NNT = 5.3) or venlafaxine-mirtazapine combination (37.7%, NNT = 10.3). Remission rates did not differ among overweight and obese I participants. LIMITATIONS Secondary analysis, higher rates of obesity than the general population. CONCLUSIONS Antidepressant selection in clinical practice can be personalized with BMI measurements. Bupropion-SSRI combination should be avoided in normal- or under-weight depressed outpatients as compared to SSRI monotherapy and venlafaxine-mirtazapine combination and preferred in those with BMI≥35.

COMT val158met polymorphism and molecular alterations in the human dorsolateral prefrontal cortex: Differences in controls and in schizophrenia

The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function. Next, we compared target gene expression profiles in a cohort of control and schizophrenia cases, each characterized by COMT genotype. We find that the COMT val allele in control subjects is associated with significant upregulation of GluN2A and GAD67 mRNA levels compared to met carriers. Comparisons between control and schizophrenia groups reveal that GluN2A, GAD67 and DRD2 are differentially regulated between diagnostic groups in a genotype specific manner. Chronic antipsychotic treatment in rodents did not explain these differences. These data demonstrate an association between COMTval158met genotype and gene expression profile in the DLPFC of controls, possibly adaptations to maintain DLPFC function. In schizophrenia val homozygotes, these adaptations are not seen and could reflect pathophysiologic mechanisms related to the known poorer performance of these subjects on DLPFC-dependent tasks.

Training Psychiatry Residents at Correctional Facilities

To the Editor: We read the recently published article “General Psychiatric Residents and Corrections: Moving Forensic Education Beyond the Classroom” [1] with great interest. As the author elegantly puts it, there is an epidemic of psychiatric disorders in correctional facilities. These facilities have now become the largest mental health providers in several counties and states in the USA. Given that the prevalence of mental illness is five times greater than general population [1], the shortage of psychiatrists in correctional settings has reached crisis proportions [2]. In our review of the National Health Provider Scarcity Area (HPSA) database in 2011, we identified 457 correctional facilities in the USA that had over 250 inmates and an inmates-per-year-to-full-time-psychiatrist ratio greater than 2,000:1 [3]. Most psychiatry residency programs are located 3–4 miles from the nearest correctional facility [3] and are uniquely situated to serve this vulnerable population. In 2009, the Department of Psychiatry at the University of Texas SouthwesternMedical Center started collaborating with the Dallas County to train residents at the Lew Sterrett Justice Center. During this month-long mandatory rotation, residents work as members of interdisciplinary teams that provide psychiatric care to approximately 7,000 inmates [3]. Our residents deliver this care on different levels ranging from psychiatric evaluation to inpatient-level care to intensive crisis management (continuous behavioral observation) to outpatient-level medication management and consultation with other medical services. In addition to gaining valuable clinicaland systemsbased-learning experiences, residents also have opportunities to observe forensic evaluations and court hearings. In our limited experience, exposure to the correctional setting has led to an increase in the number of residents opting to work with patients in the criminal justice system. In the last 5 years, one chief resident has started working at the Lew Sterrett Justice Center and four residents have joined the maximum security forensic state hospital of Texas. We disagree with the author that most psychiatry residency programs do not provide clinical training in correctional facilities. In 2010, we conducted an online survey (https://www. surveymonkey.com/s/NYFXJPZ) of 201 institutions through the American Association of Psychiatric Residency Training email listserv. Of the 95 respondents among 492 individuals surveyed, 30 % reported having a mandatory rotation and 25 % reported having an elective rotation at a correctional facility [4]. Training directors were mostly positive in their opinion about rotation at correctional settings, and a majority felt that more residents will choose to work at correctional facilities if they rotate there. Free text responses from training directors provided further details about the barriers to training residents in correctional facilities. Some commonly reported barriers were safety/security concerns, lack of funding, poor learning environment at correctional facilities, lack of room in the schedule, distance from the training program, lack of availability of residents, and lack of interest [4]. The use of listserv as compared to direct email to training directors [5] likely resulted in a low response rate. We welcome this growing awareness of inadequate mental health services for patients in the criminal justice system and fully agree with the author that more training programs should train their residents in correctional settings. The collaboration between academic institutions and correctional facilities will increase the opportunities for scholarly work and lead to the development of innovative strategies to address this urgent public health concern. M. K. Jha (*) : C. S. North :A. M. Brenner (*) University of Texas Southwestern Medical Center, Dallas, TX, USA e-mail: manishjha2201@yahoo.com e-mail: adam.brenner@utsouthwestern.edu

Association of T and non-T cell cytokines with anhedonia: Role of gender differences

OBJECTIVE Among individual depressive symptoms, anhedonia has been reliably associated with activation of the innate immune response. However, it is unclear whether this association extends to T cell cytokines and if gender differentially affects this association. METHOD Concentrations of T (IL-17, T-helper (Th) 1- and Th2-) and non-T cell cytokines were measured in plasma using the Bioplex Pro™ human cytokine multiplex kit in Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants who provided plasma at baseline (n = 166). Anhedonia was measured with three items of the clinician-rated Inventory of Depressive Symptomatology and depression severity (minus anhedonia item) was measured with Quick Inventory of Depression Severity Self-Report version (modified-QIDS-SR). Separate generalized linear models for anhedonia and modified-QIDS-SR as dependent variables were conducted with IL-17, Th1-, Th2-, and non-T cell- cytokines as primary independent variables and gender, body mass index (BMI), and age as covariates. Exploratory analyses included gender-by-biomarker interactions. RESULTS Higher levels of IL-17 (p = 0.032), Th1- (p = 0.002), Th2-(p = 0.001) and non-T-(p = 0.009) cell markers were associated with greater severity of anhedonia controlling for BMI, age, and gender. Gender also had a significant main effect on anhedonia, however, there was a significant gender by immune marker interaction only for IL-17 (p = 0.050). Anhedonia severity increased with higher IL-17 in males (r = 0.42, p = 0.003) but not in females (r = 0.09, p = 0.336). Only non-T cell markers were associated with the modified-QIDS-SR, and there were no significant gender-specific associations with this variable. CONCLUSIONS T and non-T cell-related inflammatory markers were associated with greater severity of anhedonia, while gender moderated the association of IL-17 with anhedonia in patients with major depressive disorder.