Symptoms Of Treatment-resistant Depression Research Articles

Choosing Between Ketamine and Electroconvulsive Therapy for Outpatients With Treatment-Resistant Depression—Advantage Ketamine?

This Viewpoint examines key issues stemming from several recent reports of electroconvulsive therapy (ECT) vs ketamine for improving depressive symptoms in treatment-resistant depression (TRD).

Predictors of Treatment Response in Patients with Treatment-Resistant Depression: Outcomes of a Randomized Trial

Objective: This report aims to compare the effectiveness between electroconvulsive therapy (ECT) and transcranial direct stimulation (tDCS) among patients with treatment-resistant depression (TRD) and the associated factors. Methods: This was a secondary data analysis of a randomized, controlled, open-label trial conducted from 1 July 2018, to 31 December 2018. The dataset of 90 patients included in the study was retrieved from Mendeley Data. Patients with TRD were randomized 1:1 into either receiving ECT or tDCS. A good treatment response was determined as an improvement from the Hamilton Depression (HAM-D) baseline score at a rate of more than or equal to 50% at the end of a 2-week intervention. A mixed-effect logistic regression was performed to explain the hierarchical data structure of predictors to successful treatment outcome. Results: The largest magnitude of change was consistently observed in the ECT treatment arm across both HAM-D score and the clinical global impression severity scale (CGI-S) scale (p < 0.001). Lower baseline HAM-D scores (OR: 0.72, 95% CI: 0.58, 0.92), lower baseline CGI-S scale (OR: 0.30, 95% CI: 0.17, 0.55), and ECT as the choice of treatment modality (OR: 14.0, 95% CI: 5.08, 38.58) independently predicted successful therapy among TRD patients, while modelling with multiple logistic regression determined that low socio-economic status (aOR: 20.01, 95% CI: 1.89, 211.47), ECT (aOR: 31.7, 95% CI: 6.32, 159.0) and a lower baseline CGI-S scale (aOR: 0.18, 95% CI: 0.06, 0.57) were significantly predictive of a positive treatment outcome among patients with TRD. Conclusions: ECT was more effective in alleviating depressive symptoms in TRD as compared to tDCS.

Gender differences in obstructive sleep apnea with comorbid treatment-resistant depression

BackgroundA bidirectional relationship between major depression and obstructive sleep apnea (OSA) has been established, suggesting the possibility of overlapping and compounding disease processes. Depression, however, while more prevalent in women, is a highly heterogeneous disorder and can be difficult to treat regardless of gender. A common overlapping symptom of depression and OSA is fatigue. Gender differences in OSA symptomatology (and fatigue in particular) are also consistently observed. Here, we investigate OSA in specific relation to treatment-resistant depression.MethodsA cross-sectional exploratory design was used to analyse data from 94 patients with treatment-resistant depression from a subspecialist mood disorders outpatient service who had no previous sleep assessment. Participants completed overnight polysomnography and a battery of rating scales assessing mood, sleep, and daytime functioning. Linear regression models determined whether presence of fatigue in treatment-resistant depression predicted OSA severity.ResultsThere was a high prevalence (79%) of previously undiagnosed OSA in our sample of patients with treatment-resistant depression. Treatment-resistant depression was one factor to close the gap in obstructive sleep apnea prevalence between men and women in this group. Presence of OSA measured objectively by the Apnea Hypopnea Index was not associated with episode state (depressed vs. euthymic). Daytime sleepiness scores as measured by the Epworth Sleepiness Scale indicated higher than normal daytime sleepiness with no difference between genders. Men and women in our study reported similar amounts of fatigue as measured by the Profile of Mood States-Fatigue Subscale, however, daytime fatigue (but not sleepiness) predicted OSA severity in women only.ConclusionsWe argue that typical symptoms of treatment-resistant depression may overshadow key symptoms of undetected OSA. Specifically, we found that daytime fatigue may be one factor masking a potentially significant underlying sleep disorder in women only. Comprehensive assessment and screening for sleep apnea in patients with treatment-resistant depression is encouraged, and the importance of investigating severity of fatigue in this population is emphasized.

Tiaoqi Jieyu acupuncture for treatment-resistant depression: a randomized controlled trial

To observe the effect of Tiaoqi Jieyu (regulating qi and relieving depression) acupuncture on the clinical symptoms of treatment-resistant depression (TRD), and to explore the relationship between the acupuncture pain sensitivity and symptom's improvement. A total of 78 patients with TRD were randomly divided into an observation group (39 cases, 3 cases dropped off) and a control group (39 cases, 4 cases dropped off). The patients in the control group were treated with medications according to the treatment plan of psychiatrists (at least one medication was 5-hydroxytryptamine reuptake inhibitor). On the basis of the control group, the patients in the observation group were treated with Tiaoqi Jieyu acupuncture, and Baihui (GV 20), Yintang (GV 24+), Yanglingquan (GB 34), Taichong (LR 3), Hegu (LI 4), Neiguan (PC 6), Yinlingquan (SP 9) and Zusanli (ST 36), etc. were selected. The acupuncture was given three times a week. Both groups were treated for 8 weeks. After 8-week treatment, the response rate of Hamilton depression scale-24 (HAMD-24) score after was evaluated in the two groups. The scores of HAMD-24 and Hamilton anxiety scale (HAMA) were compared between the two groups before treatment, after 4, 8-week treatment and 12 weeks after treatment (follow-up). After the first treatment and 8-week treatment, the visual analogue scale (VAS) score in the observation group was evaluated, and the correlation between VAS score after the first treatment and HAMD-24 score before treatment, between VAS score after the first treatment and the course of disease in the observation group was analyzed, and the correlation between difference of VAS after 8-week treatment and after the first treatment and difference of HAMD-24 score before treatment and after 8-week treatment was analyzed. After 8-week treatment, the response rate of HAMD-24 score in the observation group was 52.8% (19/36), higher than 17.1% (6/35) in the control group (P<0.001). Compared before treatment, the scores of HAMD-24 and HAMA in the two groups were decreased after 4-week treatment, 8-week treatment and in follow-up (P<0.05), and those in the observation group were superior to the control group (P<0.05). After 8-week treatment, the acupuncture pain VAS score in the observation group was (5.28±2.13) points, which was higher than (3.33±1.62) points after the first treatment (P<0.001). There was a negative correlation between VAS score after the first treatment and HAMD-24 score before treatment in the observation group (r =-0.486, P=0.003); there was no correlation between acupuncture pain VAS score after the first treatment and the course of disease in the observation group (P>0.05). After 8-week treatment, there was a positive correlation between the difference of VAS score and the difference of HAMD-24 score in the observation group (r =0.514, P=0.001). Tiaoqi Jieyu acupuncture could improve the depression and anxiety in patients with TRD, and the symptom's improvement is related to the recovery of acupuncture pain sensitivity.

Mindfulness skills and experiential avoidance as therapeutic mechanisms for treatment-resistant depression through mindfulness-based cognitive therapy and lifestyle modification.

The COVID-19 pandemic and consequent physical distancing has made it difficult to provide care for those with Treatment-Resistant Depression (TRD). As a secondary analysis of a clinical trial, the aim of this study was to explore potential mechanisms through which three online-delivered approaches, added to treatment as usual, improve depressive symptoms in TRD patients. The three approaches included (a) Minimal Lifestyle Intervention (MLI), (b) Mindfulness-Based Cognitive Therapy (MBCT), and (c) Lifestyle Modification Program (LMP). Sixty-six participants with TRD completed assessments pre-post intervention (mindfulness skills [FFMQ]; self-compassion [SCS]; and experiential avoidance [AAQ-II]) and pre-intervention to follow-up (depressive symptoms [BDI-II]). Data were analyzed using within-subjects regression models to test mediation. Mindfulness skills mediated the effect of MBCT on depressive symptoms (ab = -4.69, 95% CI = -12.93 to-0.32), whereas the lack of experiential avoidance mediated the effect of LMP on depressive symptoms (ab = -3.22, 95% CI = -7.03 to-0.14). Strengthening mindfulness skills and decreasing experiential avoidance may promote recovery in patients with TRD, MBCT, and LMP have demonstrated that they may help increase mindfulness skills and decrease experiential avoidance, respectively. Future work will need to unpick the components of these interventions to help isolate active ingredients and increase optimization.

Effect of Adjunctive Simvastatin on Depressive Symptoms Among Adults With Treatment-Resistant Depression

Immune-metabolic disturbances have been implicated in the pathophysiology of major depressive disorder and may be more prominent in individuals with treatment-resistant depression (TRD). Preliminary trials suggest that lipid-lowering agents, including statins, may be useful adjunctive treatments for major depressive disorder. However, no adequately powered clinical trials have assessed the antidepressant efficacy of these agents in TRD. To assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD. This 12-week, double-blind, placebo-controlled randomized clinical trial was conducted in 5 centers in Pakistan. The study involved adults (aged 18-75 years) with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) major depressive episode that had failed to respond to at least 2 adequate trials of antidepressants. Participants were enrolled between March 1, 2019, and February 28, 2021; statistical analysis was performed from February 1 to June 15, 2022, using mixed models. Participants were randomized to receive standard care plus 20 mg/d of simvastatin or placebo. The primary outcome was the difference between the 2 groups in change in Montgomery-Åsberg Depression Rating Scale total scores at week 12. Secondary outcomes included changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, and the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. C-reactive protein and plasma lipids were measured at baseline and week 12. A total of 150 participants were randomized to simvastatin (n = 77; median [IQR] age, 40 [30-45] years; 43 [56%] female) or placebo (n = 73; median [IQR] age, 35 [31-41] years; 40 [55%] female). A significant baseline to end point reduction in Montgomery-Åsberg Depression Rating Scale total score was observed in both groups and did not differ significantly between groups (estimated mean difference for simvastatin vs placebo, -0.61; 95% CI, -3.69 to 2.46; P = .70). Similarly, there were no significant group differences in any of the secondary outcomes or evidence for differences in adverse effects between groups. A planned secondary analysis indicated that changes in plasma C-reactive protein and lipids from baseline to end point did not mediate response to simvastatin. In this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care. ClinicalTrials.gov Identifier: NCT03435744.

Med Check: Alzheimer’s Agitation, Idiopathic Hypersomnia, Depression, and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Alzheimer’s Agitation, Idiopathic Hypersomnia, Depression, and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:4 Jan 2023https://doi.org/10.1176/appi.pn.2023.01.1.5AXS-05 May Delay Relapse of Alzheimer’s AgitationAxsome Therapeutics’ investigational combination drug AXS-05 (45 mg dextromethorphan/105 mg bupropion) may delay relapse of agitation associated with Alzheimer’s disease, the company announced in November.In the phase 3 ACCORD trial, 108 patients with Alzheimer’s disease agitation who had already responded to AXS-05 in a previous, open-label trial either continued treatment with the drug or were switched to placebo for up to 26 weeks. Relapse was defined as a worsening of 10 points or more on the Cohen-Mansfield Agitation Inventory (CMAI) from the time the patients were randomized to either continued treatment or to placebo, a CMAI total score greater than when they entered the study, or hospitalization or other institutionalization because of agitation associated with Alzheimer’s disease.Patients who took AXS-05 had a 3.6-fold lower risk of relapse compared with those who took placebo. During the trial, 7.5% of patients who took the drug experienced a relapse of Alzheimer’s disease agitation, compared with 25.9% of those who took placebo. Serdexmethylphenidate Granted Orphan Drug Status for Idiopathic Hypersomnia The Food and Drug Administration (FDA) has granted orphan drug status to serdexmethylphenidate for the treatment of idiopathic hypersomnia, KemPharm Inc. announced in November. Serdexmethylphenidate is KemPharm’s prodrug of d-methylphenidate.The FDA may grant orphan drug status to investigational therapies that address rare medical diseases or conditions. If the drug later receives FDA approval for treating the disease or condition, the FDA may not approve any other applications to market the same drug for the same indication for seven years, except in limited circumstances.KemPharm will soon begin a phase 2 trial of serdexmethylphenidate in patients with idiopathic hypersomniaand a second trial in patients with narcolepsy.Serdexmethylphenidate is also an active ingredient in Corium’s Azstarys (serdexmethylphenidate and dexmethylphenidate), which the FDA approved in March of 2021 for treating symptoms of attention-deficit/hyperactivity disorder in patients aged 6 years and older. Spravato May Be More Effective Than Quetiapine XR for TRDAn open-label phase 3b trial suggests that Spravato (esketamine nasal spray) may have greater efficacy than quetiapine extended release (XR) for treating symptoms of treatment-resistant depression (TRD) in adults, Janssen Pharmaceutical Companies announced in November. Janssen is the manufacturer of Spravato.In the ESCAPE-TRD trial, 676 patients with TRD were randomized to receive either Spravato or quetiapine XR, both in combination with a continuing selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor, for 32 weeks. At the eighth week, 21.7% of the patients who received Spravato experienced remission of their symptoms, compared with 14.1% of those who took quetiapine. At study’s end, symptoms abated in 55% of patients who took Spravato, compared with 37% of those who took quetiapine FDA to Review IPX203 for Parkinson’s DiseaseIn November, Amneal Pharmaceuticals Inc. announced that the FDA has accepted for review the company’s New Drug Application for IPX203 (carbidopa/levodopa extended release) for the treatment of Parkinson’s disease.In the phase 3 RISE-PD trial, 506 patients who were at least 40 years old when they were diagnosed with Parkinson’s disease were randomized to receive either IPX203 or immediate-release carbidopa/levodopa. All patients had motor fluctuations.The primary endpoint was change from baseline in the daily amount of “Good On” time, defined as the sum of “On” time without dyskinesia and “On” time with non-troublesome dyskinesia. At the twentieth week, those who took IPX203 had an average of roughly half an hour more of “Good On” time compared with those who took immediate-release carbidopa/levodopa.In addition, a study published in the May 2022 Neurology found that 29.7% of patients who took IPX203 were “much improved” or “very much improved,” as evidenced in their scores on the Patient Global Impression of Change, compared with 18.8% of those who took immediate-release carbidopa/levodopa. ■“A Phase 3 Trial of IPX203 vs CD-LD IR in Parkinson’s Disease Patients with Motor Fluctuations (RISE-PD)” ISSUES NewArchived

Impact of Repeated Doses of Subcutaneous Esketamine on Acute Dissociative Symptoms in Treatment-Resistant Depression.

Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects. A retrospective analysis of 394 subcutaneous esketamine injections given to 70 patients with TRD that were administered once a week during a six-week trial in conjunction with oral antidepressant therapy. Doses between 0.5 to 1.0 mg/kg were administered according to the patient's response. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS) 30 and 60 min after every weekly treatment (day 1, 8, 15, 22, 29 and 36). Seventy patients received a total of 394 subcutaneous esketamine injections over six weeks. Over time, the evolution of CADSS scores demonstrated a significant mean difference of CADSS at 60 min post-injection (p = 0.010) throughout the six infusions. The mean CADSS scores at 60 min on day 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics and no interactions between time and combined medication. Our results suggest that repeated subcutaneous esketamine doses are safe and well-tolerated regarding their acute dissociative and psychotomimetic symptoms. Symptoms usually peak at 30 min and decrease at 60 min post-injection, returning to their pretreatment levels at 120 min. Dissociative symptoms do not correlate with antidepressant response.

Cognitive-affective processes and suicidality in response to repetitive transcranial magnetic stimulation for treatment resistant depression

BackgroundRepetitive transcranial magnetic stimulation (rTMS) can elicit 45–55 % response rates and may alleviate suicidality symptoms in treatment resistant depression (TRD). Blunted anticipatory reward sensitivity and negatively biased self-referential processing may predict trajectories of depressive and suicidality symptoms in rTMS for TRD and be modulated during treatment. MethodsFifty-five individuals with TRD received four weeks of low-frequency rTMS applied to the right dorsolateral prefrontal cortex (LFR-rTMS) and were followed until 17 weeks post-baseline. Participants completed behavioral measures of anticipatory reward sensitivity and self-referential processing at baseline and five weeks post-baseline (approximately one-week post-treatment). We examined whether baseline anticipatory reward sensitivity and self-referential processing predicted trajectories of depressive and suicidality symptoms from baseline to follow-up and whether these cognitive-affective variables showed change from baseline to week five. ResultsAnticipatory reward sensitivity and negative self-referential encoding at baseline were associated with higher overall depressive symptoms and suicidality from baseline to 17 weeks post-baseline. At week five, participants self-attributed a higher number of positive traits and a lower number of negative traits and had a lesser tendency to remember negative relative to positive traits they had self-attributed, compared to baseline. LimitationsThe specificity of these results to LFR-rTMS is unknown in the absence of a comparison group, and our relatively small sample size precluded the interpretation of null results. ConclusionsBaseline blunted anticipatory reward sensitivity and negative biases in self-referential processing may be risk factors for higher depressive symptoms and suicidality during and after LFR-rTMS, and LFR-rTMS may modulate self-referential processing.

High-frequency rTMS in the treatment of depressive symptoms in schizophrenia: a neurophysiological profile of respondents and nonresponders

IntroductionDepressive symptoms in schizophrenia have a high prevalence – up to 20-60 %, at the different illness stages. Non-pharmacological treatment, namely rTMS, seems like a promising approach that lacks side-effects typical for antidepressants. RTMS is widely applied in the treatment of depression, however the studies within schizophrenia domain are still rather fewObjectivesThe aim was to examine a potential of neurophysiological data for prediction of the effects of rTMS in the treatment of patients with schizophrenia with depressive symptomsMethods20 male patients with schizophrenia (F20.004, F20.014, F20.414, ICD–10) were examined at the stage of incomplete remission with predominance of prolonged (more than 6 months) treatment resistant depressive symptoms. An examination (clinical and neurophysiological (oddball ERP and EEG) fragments)) was repeated twice - before and after a course of 10 Hz rTMS (left DLPC, 2000 pulses per session, 15 sessions).ResultsPoor outcome was associated with initially higher coherence in alpha and lower - in beta1 EEG bands. The amplitudes of non-target N100 and mismatch negativity didn’t differ the groups of responders and nonrespondersConclusionsThe disturbances within brain networks of beta1 and alpha generators merit attention as potential neurophysiological markers with predictive value in rTMS treatment of patients with schizophrenia with depressive symptoms.DisclosureNo significant relationships.

Changes in the metabolites of cerebrospinal fluid induced by rTMS in treatment-resistant depression: A pilot study

Repetitive transcranial magnetic stimulation (rTMS) improves depressive symptoms in treatment-resistant depression (TRD). This study aimed to analyze changes in cerebrospinal fluid (CSF) metabolites in patients with TRD after rTMS. Five patients with TRD were enrolled in a high frequency (10-Hz) rTMS study. The concentration of 72 CSF metabolites were measured at baseline and at the end of the 6-week rTMS treatment. rTMS significantly increased CSF niacinamide, kynurenine, and creatinine levels and significantly decreased CSF cystine levels, but not the levels of the other 68 CSF metabolites. This is the first CSF metabolomics study on patients with TRD who underwent rTMS.

A comparative study of the effect of electroconvulsive therapy and transcranial direct current stimulation in the treatment of persons suffering from treatment-resistant depression.

Background:About 20%–30% of persons with major depression are said to have treatment-resistant depression (TRD) when they do not respond to antidepressants. These people continue to suffer in life and have poor quality of life. Although electroconvulsive therapy (ECT) is the most successful option in treating TRD, many people refuse ECT due to various reasons (stigma, the cost involved, and medical complications). Various studies combine treatment options such as psychotherapy, repetitive trans magnetic stimulation, ketamine, and transcranial direct current stimulation (tDCS) in an attempt to reduce symptoms for those people suffering from TRD. This study aims to compare the effectiveness of ECT and tDCS in TRD.Subjects and Methods:A total of 90 persons suffering from TRD were selected for the study. 46 persons received 6 ECTs and 44 persons received 10 sessions of tDCS. Treatment response was measured using baseline and postassessment scores of Hamilton depression rating scale and clinical global impression. The scores were used to determine the effectiveness of ECT in comparison to tDCS in TRD.Statistical Analysis:The mean ± standard deviation was analyzed and paired t-test was used to find the significance of treatment outcome in a group at a 95% confidence interval.Results:ECT was found to be more effective than tDCS in the reduction of depressive symptoms. tDCS showed a significant reduction in depressive symptoms (P < 0.001). ECT has yet again been proven to be effective in the treatment of TRD.Conclusion and Discussion:tDCS is effective in reducing depressive symptoms in persons suffering from TRD. However, ECT is superior in decreasing depressive symptoms in TRD when compared to tDCS.

Perspectives on Excited Delirium and Ketamine

Perspectives on Excited Delirium and Ketamine

Psilocybin may be effective for treatment-resistant depression

The largest trial to date of the psychedelic drug psilocybin has shown that, alongside psychological support, a single 25mg dose may improve the symptoms of treatment-resistant depression. The phase II study, published in the New England Journal of Medicine on 3 November 2022, was conducted across 22 sites in 10 countries, including the UK, between […]

Psilocybin: a psychedelic alternative to antidepressants?

In November 2022, the largest trial to date of the psychedelic drug, psilocybin, showed that — alongside psychological support — a single 25mg dose could improve the symptoms of treatment-resistant depression for up to 12 weeks. Previous studies have suggested an antidepressant mechanism for psilocybin therapy and have shown that psilocybin is at least as […]

Low-dose ketamine infusion for treating subjective cognitive, somatic, and affective depression symptoms of treatment-resistant depression.

Whether the antidepressant effects of low-dose ketamine infusion and the therapeutic impact of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism vary across different depression symptom domains, namely affective, cognitive, and somatic, remains unclear. We-reanalyzed the data of Adjunctive Ketamine Study of Taiwanese Patients with Treatment-Resistant Depression (TRD). A total of 71 patients with TRD were randomized to three infusion groups: 0.5 and 0.2mg/kg ketamine groups and the normal saline placebo group. The Beck Depression Inventory-II (BDI-II) was used to obtain self-reported scores prior to infusion and 240min after infusion and sequentially on days 3, 7, and 14 after infusion. The three-factor model of cognitive, somatic, and affective depressive symptoms that is based on the BDI-II and proposed by Beck et al. was applied in the current study. The Val66Met BDNF polymorphism was genotyped. Ketamine infusion exerted rapid and sustained antidepressant effects on the affective (p=0.014) and cognitive (p=0.005) depression symptom domains but not on the somatic (p=0.085) depression symptom domain. Only patients with TRD harboring any Val allele at the BDNF rs6265 polymorphism were more likely to respond (p=0.011) to low-dose ketamine infusion. Additional studies should elucidate different mechanisms underlying the effects of ketamine infusion on cognitive, affective, and somatic depression symptom domains in patients with TRD.

A Watershed Infarct Case Presenting Treatment Resistant Depressive Symptoms.

A Watershed Infarct Case Presenting Treatment Resistant Depressive Symptoms.

Ketamine Treatment for Depression in Patients With a History of Psychosis or Current Psychotic Symptoms: A Systematic Review.

Objective: Ketamine shows rapid and robust antidepressant effects in clinical studies. Psychotic features are an exclusion criterion in most ketamine treatment studies based on the assumption that psychosis will increase with ketamine administration. As patients with treatment-resistant depression (TRD) often have psychotic features, and treatment-resistant depressive symptoms are also common in patients with schizophrenia, the aim of this systematic review is to determine whether this assumption holds true. Data Sources: The literature was searched for data on ketamine treatment for depression or negative symptomatology in patients with a history of psychosis or current psychotic symptoms (PubMed/MEDLINE) from inception to March 2020 without date or language restrictions. The following terms were used: ketamine and psychosis, psychotic or schizo*. A filter for human studies was applied. Study Selection: A total of 482 articles were identified; 473 articles were excluded because they did not report on the effect of ketamine treatment in patients with a history of psychosis or current psychotic symptoms. Data Extraction: The remaining 9 articles were reviewed. Results: Nine reports of pilot studies and case reports with a total of 41 patients have been published. These studies suggest that short-term ketamine treatment for depression and even negative symptoms in patients with a history of psychosis or current psychotic features can be both safe and effective, as side effects were mild and self-limiting. Conclusions: The currently available literature does not support the assumption that ketamine will exacerbate psychotic symptoms in predisposed patients. Data, however, are limited, and further trials are needed in this patient group.

The changes in kynurenine metabolites induced by rTMS in treatment-resistant depression: A pilot study

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that is considered a valuable and promising technique for improving depressive symptoms in treatment-resistant depression (TRD). However, the exact mechanism by which rTMS ameliorates depressive symptoms remains to be clarified. ObjectiveThe aim of the present study was to analyzed the changes in metabolites of patients with TRD in the rTMS treatment, especially focusing on the kynurenine (KYN) pathway. MethodsThirteen participants with TRD were enrolled in a high-frequency (10 Hz) rTMS study. Cognitive function, depressive symptoms and the concentration of plasma tryptophan (TRP) metabolites were measured at baseline and at the endpoint of rTMS treatment. ResultsrTMS treatment significantly improved depressive symptom scores and some subscales of cognitive dysfunction. The present study has demonstrated that rTMS treatment significantly increased plasma TRP levels and significantly decreased plasma serotonin levels, while plasma KYN and kynurenic acid level as well as KYN/TRP ratio remained unchanged. ConclusionsThis is the first metabolomic study of patients with TRD undergoing rTMS treatment. To validate the present results, it is necessary to increase the number of cases including controls, use a sample of cerebrospinal fluid, and measure blood concentration over time in the course of rTMS treatment.

Infralimbic cortical glutamate output is necessary for the neural and behavioral consequences of chronic stress

Exposure to prolonged stress is a major risk-factor for psychiatric disorders such as generalized anxiety and major depressive disorder. Human imaging studies have identified structural and functional abnormalities in the prefrontal cortex of subjects with depression and anxiety disorders, particularly Brodmann's area 25 (BA25). Further, deep brain stimulation of BA25 reduces symptoms of treatment-resistant depression. The rat homolog of BA25 is the infralimbic cortex (IL), which is critical for cognitive appraisal, executive function, and physiological stress reactivity. Previous studies indicate that the IL undergoes stress-induced changes in excitatory/inhibitory balance culminating in reduced activity of glutamate output neurons. However, the regulatory role of IL glutamate output in mood-related behaviors after chronic variable stress (CVS) is unknown. Here, we utilized a lentiviral-packaged small-interfering RNA to reduce translation of vesicular glutamate transporter 1 (vGluT1 siRNA), thereby constraining IL glutamate output. This viral-mediated gene transfer was used in conjunction with a quantitative anatomical analysis of cells expressing the stable immediate-early gene product FosB/ΔFosB, which accumulates in response to repeated neural activation. Through assessment of FosB/ΔFosB-expressing neurons across the frontal lobe in adult male rats, we mapped regions altered by chronic stress and determined the coordinating role of the IL in frontal cortical plasticity. Specifically, CVS-exposed rats had increased density of FosB/ΔFosB-expressing cells in the IL and decreased density in the insula. The latter effect was dependent on IL glutamate output. Next, we examined the interaction of CVS and reduced IL glutamate output in behavioral assays examining coping, anxiety-like behavior, associative learning, and nociception. IL glutamate knockdown decreased immobility during the forced swim test compared to GFP controls, both in rats exposed to CVS as well as rats without previous stress exposure. Further, vGluT1 siRNA prevented CVS-induced avoidance behaviors, while also reducing risk aversion and passive coping. Ultimately, this study identifies the necessity of IL glutamatergic output for regulating frontal cortical neural activity and behavior following chronic stress. These findings also highlight how disruption of excitatory/inhibitory balance within specific frontal cortical cell populations may impact neurobehavioral adaptation and lead to stress-related disorders.