Distinct Effects of Major Affective Disorder Diagnoses and Suicidal Symptom Severity on Inhibitory Control Function and Proinflammatory Cytokines: Single-Site Analysis of 800 Adolescents and Adults.

BACKGROUND: Inhibitory control function and proinflammatory cytokines play a role in the pathomechanisms underlying major affective disorders and suicidal behavior. However, the distinct or interactive effects of major affective disorders and suicidal symptom severity on inhibitory control function and proinflammatory cytokines remain unclear. METHODS: This study included 287 patients with bipolar disorder, 344 with major depressive disorder, and 169 healthy controls. We categorized the participants into three groups on the basis of Montgomery-Åsberg Depression Rating Scale (MADRS) item 10 (suicidal symptoms) score: 0, 2 or 3, and ≥4. The participants completed the go/no-go task and the measurements for C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) levels. RESULTS: Errors in the go/no-go task were associated with suicidality (p = .040), regardless of the severity of suicidal symptoms and diagnosis. An elevated CRP level was especially associated with MADRS item 10 score ≥ 4 (p = 0.001). Increased TNF-α level could distinguish bipolar disorder from major depressive disorder (p < .001). DISCUSSION: Our study indicated the distinct effects of major affective disorder diagnosis and suicide symptom severity on inhibitory control function and CRP and TNF-α levels. Importantly, individuals with the poorest inhibitory control function and highest CRP levels had more severe suicidal symptoms.

Longitudinal study on all-cause and suicide mortality among individuals with attention deficit hyperactivity disorder.

BACKGROUND: Previous research has linked attention deficit hyperactivity disorder (ADHD) with an increased risk of all-cause mortality, primarily owing to unnatural causes such as accidents and suicides. This increase may be attributable to the co-occurrence of major psychiatric disorders, including schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), autism spectrum disorder (ASD), anxiety disorders, substance use disorders (SUDs), and personality disorders (PDs). This study examined the all-cause and specific-cause mortality rates in individuals with ADHD and the influence of psychiatric comorbidities. METHODS: Between 2003 and 2017, 1.17 million individuals were enrolled in the study, of which 233,886 received a diagnosis of ADHD from the Taiwan's National Health Insurance Research Database. A 1:4 sex- and birth year-matched control group without ADHD was also included. Hazard ratios (HRs) for mortality rates were estimated between groups after adjusting for demographic data. RESULTS: During the follow-up period, 781 individuals with ADHD died. The HR for all-cause mortality was 1.45 (95% confidence interval [CI]: 1.30-1.61), largely owing to unnatural causes, particularly suicide. Suicide rates were particularly high in individuals with ADHD and psychiatric comorbidities: the HRs for suicide were 47.06 in ADHD with SUDs (95% CI: 6.12-361.99), 32.02 in ADHD with SCZ (7.99-128.29), 23.60 in ADHD with PDs (7.27-76.66), 10.11 in ADHD with anxiety disorders (5.74-17.82), 9.30 in ADHD with BD (4.48-19.33), 8.36 in ADHD with MDD (5.66-12.35), and 6.42 in ADHD with ASD (1.83-22.53) relative to ADHD only. DISCUSSION: ADHD was associated with increased mortality rates, primarily owing to suicide. The presence of major psychiatric comorbidities was associated with a further increase in suicide mortality risk.

Psychiatric rehabilitation and cognitive deficit for treatment-resistant depression.

Patients with TRD often experience persistent impairment of affective, psychosocial, and cognitive function, which impedes their recovery. The continuation of pharmacotherapy for patients with TRD remains the cornerstone of functional recovery. Cognitive dysfunction is prevalent in patients with MDD and may make patients' depressive symptoms and psychosocial functioning worse, even in the remitted stage of illness. Deficits can manifest not only in specific cognitive domains but also in global cognitive function, which may reflect underlying persistent pathophysiological changes. Compared with nontreatment-resistant patients with MDD, patients with TRD exhibit greater subjective and objective cognitive impairment, which possibly contributes to a greater adverse impact on daily functioning. Cognitive and psychosocial remission should be a goal in treating MDD. How to appropriately and individualized perform pharmacological intervention, psychotherapy, neuromodulation, cognitive remediation or other rehabilitation treatment programs is a critical step to achieve our goal. Integrating multiple interventions that engage multiple physiological systems with a multidisciplinary team warrants increased attention, and personalized therapeutic programs may facilitate the complete restoration of patients' everyday functioning.

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study.

BACKGROUND: Prolonged intermittent theta-burst stimulation (iTBS) is effective for major depressive disorder (MDD). However, whether longer piTBS treatment in a single session could have antidepressant efficacy remains elusive. Therefore, this double-blind, randomized, sham-controlled study aimed to investigate the antidepressant efficacy of 2 daily piTBS sessions for treating MDD patients with a history of poor responses to at least 1 adequate antidepressant trial in the current episode. METHODS: All patients received 2 uninterrupted sessions per day for 10 weekdays (i.e., 2 weeks; a total of 20 sessions). Seventy-two patients were recruited and 1:1:1 randomly assigned to one of three groups: piTBS (piTBSx2), 10-Hz rTMS (rTMSx2), or sham treatment (shamx2, randomly assigned to piTBS or rTMS). 10-Hz rTMS group was included as an active comparison group to enhance assay sensitivity. RESULTS: piTBSx2 group had significantly more responders at week 2 than shamx2 group, but it did not yield better antidepressant effects regarding the %depression changes. The changes of antidepressant scores were not different among the three groups at week 1 (-26.2% vs. -23.3% vs. -22.%) or at week 2 (-34.1% vs. -37.1% vs. -30.1%). Longer treatment duration did not result in stronger placebo effects [sham(piTBS)x2: - 31.7% vs. sham(rTMS)x2: - 26.7%]. CONCLUSION: The present sham-controlled study confirmed that piTBS is an effective antidepressant option, but found no evidence to support that longer piTBS treatment duration resulted in more rapid or better antidepressant effects. A high placebo effect was observed, but longer treatment duration of brain stimulation was not linearly associated with stronger placebo effects.

Cortical inhibition function is associated with baseline suicidal symptoms and post-ketamine suicidal symptom reduction among patients with treatment-resistant depression and strong suicidal ideation.

BACKGROUND: Whether cortical excitation and inhibition functions differ between patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI) and healthy subjects and whether 0.5 mg/kg ketamine infusion can modulate cortical excitation and inhibition functions among patients with TRD-SI remain unclear. METHODS: A total of 29 patients with TRD-SI and 35 age- and sex-matched healthy controls were assessed using paired-pulse transcranial magnetic stimulation. The patients were randomly assigned to receive either a single 0.5-mg/kg ketamine or 0.045-mg/kg midazolam infusion. Depressive and suicidal symptoms were assessed at baseline and 240 min after infusion. Intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI), all of which reflect cortical excitability and inhibition functions, were measured at the same time points. RESULTS: The patients with TRD-SI had lower ICF (p < 0.001) estimates (worse cortical excitatory function) and higher SICI (p = 0.032) and LICI (p < 0.001) estimates (worse cortical inhibitory function) compared with the control group. Higher SICI estimates at baseline were associated with greater baseline suicidal symptoms. No differences were found in the SICI, ICF, and LICI estimates at 240 min after the infusion between the two groups. Low-dose ketamine did not alter the cortical excitation and inhibition functions of the patients with TRD-SI. However, decreased SICI estimates (greater cortical inhibition function) were related to the reduction of suicidal symptoms. DISCUSSION: Dysfunction of cortical excitation and inhibition may play a crucial role in the pathomechanisms of TRD and suicidal symptoms. However, we found a lack of predictive ability of the baseline cortical excitation and inhibition parameters on the antidepressant and antisuicidal effect of low-dose ketamine infusion.

Antidepressant effects of prolonged intermittent theta-burst stimulation monotherapy at the bilateral dorsomedial prefrontal cortex for medication and standard transcranial magnetic stimulation-resistant major depression: a three arm, randomized, double blind, sham-controlled pilot study.

The dorsomedial prefrontal cortex (DMPFC) plays a pivotal role in depression and anxiosomatic symptom modulation. However, DMPFC stimulation using a double-cone coil has demonstrated inconsistent results for antidepressant efficacy. No study thus far has investigated the antidepressant and anti-anxiosomatic effects of prolonged intermittent theta-burst stimulation (piTBS) bilaterally over DMPFC. Furthermore, head-to-head comparisons of antidepressant effects between standard iTBS and piTBS warrant investigation. This double-blind, randomized, sham-controlled trial recruited 34 patients with highly treatment-resistant depression (TRD) unresponsive to antidepressants and standard repetitive transcranial magnetic stimulation (rTMS)/piTBS. These patients were randomly assigned to one of three monotherapy groups (standard iTBS, piTBS, or sham), with treatment administered bilaterally over the DMPFC twice per day for 3 weeks. The primary outcome was the overall changes of 17-item Hamilton Depression Rating Scale (HDRS-17) over 3-weeks intervention. The changes in Depression and Somatic Symptoms Scale (DSSS) as the secondary outcome and the anxiosomatic cluster symptoms as rated by HDRS-17 as the post-hoc outcome were measured. Multivariable generalized estimating equation analysis was performed. Although no differences in overall HDRS-17 changes between three groups were found, the antidepressant efficacy based on DSSS was higher in piTBS than in iTBS and sham at week 3 (group effect,p = 0.003, post-hoc: piTBS > iTBS, p = 0.002; piTBS > sham, p = 0.038). In post-hoc analyses, piTBS had more alleviation in anxiosomatic symptoms than iTBS (group effect, p = 0.002; post-hoc, p = 0.001). This first randomized sham-controlled study directly compared piTBS and iTBS targeting the DMPFC using a figure-of-8 coil and found piTBS may fail to demonstrate a significant antidepressant effect on overall depressive symptoms, but piTBS seems superior in alleviating anxiosomatic symptoms, even in depressed patients with high treatment resistance. This Trial registration (Registration number: NCT04037592). URL: https://clinicaltrials.gov/ct2/show/NCT04037592 .

Frontal asymmetry as a core feature of major depression: a functional near-infrared spectroscopy study.

BACKGROUND: Frontal asymmetry plays a major role in depression. However, patients with treatment-resistant depression (TRD) have widespread hypofrontality. We investigated whether patients with TRD have a characteristic frontal activation pattern in functional near-infrared spectroscopy (fNIRS) findings and how the frontal cortex responds to different levels of cognitive tasks. METHODS: We enrolled 27 right-handed patients with TRD, 27 patients without TRD and 27 healthy controls. We used multichannel fNIRS to evaluate activation of the bilateral dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC) and left motor area in response to 3 tasks: finger tapping, a low cognitive-load motor task; verbal fluency, a moderate cognitive-load task; and a dual task involving simultaneous finger tapping and verbal fluency, a high cognitive-load task. RESULTS: We found significant between-group differences in left DLPFC activation for all 3 tasks. The healthy controls had cortical activation in the left motor area during finger tapping and the bilateral frontal cortex during the dual task. However, patients without TRD had right VLPFC activation during finger tapping and left DLPFC activation during the dual task. Patients with TRD had bilateral DLPFC activation during finger tapping but exhibited increased bilateral VLPFC and left motor area activation during verbal fluency and increased left motor area activation during the dual task. In healthy controls and patients without TRD, we found that the right VLPFC was positively correlated with depression severity. LIMITATIONS: Our cohort included only patients with late-onset depression. CONCLUSION: We found different patterns of abnormal frontal activation between patients with and without TRD. In patients without TRD, the right prefrontal cortex (PFC) was recruited during simple motor tasks. However, in patients with TRD, the bilateral PFC was recruited during simple tasks and motor cortical resources were used compensatorily during PFC-demanding complex cognitive tasks.

Efficacy of non-invasive brain stimulation interventions in reducing smoking frequency in patients with nicotine dependence: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Nicotine is a highly addictive substance in tobacco products that dysregulates several neurotransmitters in the brain and impairs executive function. Non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are promising treatments for nicotine dependence. We investigated the efficacy and acceptability of NIBS in managing smoking cessation through a systematic review and network meta-analysis (NMA). METHODS: We conducted a systematic review to identify randomized controlled trials (RCTs) that investigated the efficacy of NIBS for smoking cessation. All pairwise meta-analyses and NMA procedures were conducted using random-effects and frequentist models. The co-primary outcomes were (1) the change in number of cigarettes smoked per day (change in frequency of smoking) in patients with nicotine dependence after NIBS and (2) acceptability (the dropout rate). The effect sizes for co-primary outcomes of change in frequency of smoking and acceptability were assessed according to standardized mean difference (SMD) and odds ratio, respectively. RESULTS: Twelve RCTs with 710 participants (mean age: 44.2 years, 31.2% female) were included. Compared with the sham control, 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) was associated with the largest changes in smoking frequency [SMD = -1.22, 95% confidence interval (95% CI) = -1.77 to -0.66]. The 2-mA bifrontal tDCS (SMD = -0.97, 95% CI = -1.32 to -0.62) and 10-Hz deep rTMS over the bilateral DLPFC with cue provocation (SMD = -0.77, 95% CI = -1.20 to -0.34) were associated with a significantly larger decrease in smoking frequency versus the sham. None of the investigated NIBSs was associated with dropout rates significantly different from those of the sham control groups. CONCLUSION: Prefrontal non-invasive brain stimulation interventions appear to reduce the number of cigarettes smoked with good acceptability.

Efficacy and tolerability of theta-burst stimulation for major depression: A systematic review and meta-analysis.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is the current treatment option for major depression (MD). Theta-burst stimulation (TBS), a variation of rTMS, affords a short stimulation duration, low stimulation pulse intensity, and possibility to improve rTMS efficiency. This systematic review and meta-analysis examined the studies on efficacy and tolerability of TBS in patients with MD. METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the literature from 1990 until May 24, 2020, and performed a random-effects meta-analysis by including response and remission rates of depression and dropout rates as main outcome measures. RESULTS: In total, 10 studies including 6 randomized controlled trials (RCTs; n = 294) and 4 uncontrolled clinical trials (non-RCTs; n = 297) were included. The overall effect size of response rate and remission rates were 0.38 (95% confidence interval [CI]: 0.29-0.48) and 0.20 (95% CI: 0.13-0.29), respectively. Notably, the TBS group showed favorable efficacy without major adverse events. CONCLUSIONS: TBS treatment was more efficient in terms of time and energy than the standard rTMS was. Our meta-analysis provided evidence that the application of TBS to the dorsolateral prefrontal cortex is associated with significant antidepressant effects along with favorable tolerability.

Antidepressant Efficacy of Prolonged Intermittent Theta Burst Stimulation Monotherapy for Recurrent Depression and Comparison of Methods for Coil Positioning: A Randomized, Double-Blind, Sham-Controlled Study.

BACKGROUND: Prolonged intermittent theta burst stimulation (piTBS) with triple doses of the standard protocol is an updated form of repetitive transcranial magnetic stimulation, and it is an effective add-on intervention for major depressive disorder. In the present study, our objective was to investigate the antidepressant efficacy of piTBS monotherapy. Efficacy between the standard 5-cm method and magnetic resonance imaging (MRI)-guided coil positioning to the left dorsolateral prefrontal cortex method was also compared. METHODS: In the present double-blind, randomized, sham-controlled trial, 105 patients with recurrent depression who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode were assigned randomly to one of three groups: piTBS monotherapy (n = 35), repetitive transcranial magnetic stimulation monotherapy (n = 35), or sham stimulation (n = 35). The acute treatment period was 2 weeks. Half of the patients were randomized to MRI navigation in each group. RESULTS: No serious adverse events were observed. The piTBS group exhibited significantly greater decreases in depression scores than the sham group at week 2 (-40.0% vs. -13.9%; p < .001 after correcting for multiple comparisons by Bonferroni [effect size (Cohen's d) = 1.12]), and the odds ratio for responses was high. The MRI navigation method (-32.4%) did not yield better antidepressant effects than the standard method (-40.6%). Brain stimulation and 17-item Hamilton Depression Rating Scale changes in the first week were the most important variables for predicting antidepressant responses. CONCLUSIONS: Left prefrontal piTBS monotherapy is effective for the treatment of recurrent depression, and the MRI-guided method of coil targeting is not better than the standard method.

Antidepressant-resistant depression is characterized by reduced short- and long-interval cortical inhibition.

BACKGROUND: Major depressive disorder (MDD) is highly heterogeneous and can be classified as treatment-resistant depression (TRD) or antidepressant-responsive depression (non-TRD) based on patients' responses to antidepressant treatment. Methods for distinguishing between TRD and non-TRD are critical clinical concerns. Deficits of cortical inhibition (CI) have been reported to play an influential role in the pathophysiology of MDD. Whether TRD patients' CI is more impaired than that of non-TRD patients remains unclear. METHODS: Paired-pulse transcranial magnetic stimulation (ppTMS) was used to measure cortical inhibitory function including GABAA- and GABAB-receptor-related CI and cortical excitatory function including glutamate-receptor-related intracortical facilitation (ICF). We recruited 36 healthy controls (HC) and 36 patients with MDD (non-TRD, n = 16; TRD, n = 20). All participants received evaluations for depression severity and ppTMS examinations. Non-TRD patients received an additional ppTMS examination after 3 months of treatment with the SSRI escitalopram. RESULTS: Patients with TRD exhibited reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI), as shown by abnormally higher estimates, than those with non-TRD or HC (F = 11.030, p < 0.001; F = 10.309, p < 0.001, respectively). After an adequate trial of escitalopram treatment, the LICI of non-TRD reduced significantly (t = - 3.628, p < 0.001), whereas the ICF remained lower than that of HC and showed no difference from pretreatment non-TRD. CONCLUSIONS: TRD was characterized by relatively reduced CI, including both GABAA- and GABAB-receptor-mediated neurons while non-TRD preserved partial CI. In non-TRD, SSRIs may mainly modulate GABAB-receptor-related LICI. Our findings revealed distinguishable features of CI in antidepressant-resistant and responsive major depression.

Repeated Low-Grade Infections Predict Antidepressant-Resistant Depression: A Nationwide Population-Based Cohort Study.

BACKGROUND: The relationship between severe inflammation and clinical depression in the context of major medical illnesses has been addressed, but the relationship between inflammation caused by mild infections and clinical depression is unclear. We aimed to examine whether a history of repeated low-grade infections (RLGI) in medically healthy subjects (MHS) could increase their vulnerability to major depressive disorder (MDD) (ICD-9-CM) and whether RLGI could be associated with higher resistance to antidepressants in those developing MDD. METHOD: A nationwide, population-based cohort study (January 1996 to December 2011) was conducted for MHS with and without a history of RLGI. The rates of MDD during an up to 8-year follow-up period were compared between the 2 groups in 2 independent cohorts. The stratified responses to adequate antidepressant trials, including easy-to-treat (ETT) and difficult-to-treat (DTT) responses, were also compared in the MDD patients. RESULTS: During the follow-up, the 2 cohorts consistently revealed that the RLGI(+) (ie, high-inflammation; n = 727) group had a significantly higher chance of developing MDD over time than the RLGI(-) (ie, low-inflammation; n = 443) group: Cox proportional hazards regression models showed that the hazard ratio associated with a history of RLGI was 1.369 to 1.911 (P < .001), after adjusting for confounding factors. The RLGI(+) group was consistently associated with a higher likelihood of DTT responses than was the RLGI(-) group (Cohort-2002: 11.5% vs 7.6%; Cohort-2004: 11.8% vs 4.3%; P < .05 by Wald χ² tests in both cohorts). CONCLUSIONS: This is the first large-scale retrospective cohort study to report a reliable temporal association between a history of RLGI and subsequent diagnosis of MDD and poor responses to antidepressants in 2 independent cohorts. Our data support the view that repeated mild infections play a role in the pathophysiology of MDD and antidepressant-resistant depression.