Gamma-aminobutyric acid (GABA) dysfunction has been implicated in depression, although research findings remain inconsistent. This may indicate that distinct biological mechanisms underlie different symptom profiles in depressive episodes. Altered GABA function might be especially relevant in cases characterised by psychomotor retardation and vegetative symptoms, which are prominent in melancholia. This study aimed to investigate if such melancholic features are related to GABA levels or GABAA-receptor availability. This was a secondary analysis of data obtained from a randomised controlled trial. Forty-two patients with either bipolar or unipolar depression were assessed before and after a course of repetitive transcranial magnetic stimulation. GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) were measured using a [1H] magnetic resonance spectroscopy MEGA-PRESS sequence. A subset of 28 patients underwent [11C]flumazenil positron emission tomography (PET) to evaluate GABAA-receptor availability in the dACC, basal ganglia, and hypothalamus. Psychomotor retardation was assessed with the expression subscale of the Clinical Assessment Interview for Negative Symptoms. Sleep disturbances were evaluated using components of the Pittsburgh Sleep Quality Index, while appetite loss was measured using an item from the Montgomery-Åsberg Depression Rating Scale – self-rated. The scores were standardised and combined to create composite measures for vegetative and somatic symptoms. Additionally, baseline psychomotor activity was measured using accelerometry. The findings did not establish that psychomotor or vegetative symptoms were associated with GABA levels or GABAA-receptor availability in the frontostriatal pathways or hypothalamus. To better understand the relationship between GABA dysfunction and melancholic features, future studies should ideally focus on patients exhibiting more pronounced psychomotor and vegetative symptoms and examine additional cortical regions.

Negative symptoms are experienced by up to 60

Background Depression is characterized by disturbed emotion processing. Repetitive transcranial magnetic stimulation, and its development intermittent theta- burst stimulation (iTBS), induces brain network changes and is an emerging treatment alternative for depression. In this sham- controlled study, we aimed at studying the effects of iTBS on emotion anticipation and processing in depression. Methods 42 patients with depression were allocated to receive active or sham iTBS treatment. Before treatment (baseline) and four weeks after baseline (follow- up), participants underwent functional magnetic resonance imaging (fMRI) scanning with simultaneous recordings of skin conductance responses (SCR). During scanning, participants were presented to an emotion anticipation and processing paradigm. Behavioral data (symptom ratings and ratings of emotional stimuli) were also collected. Results There were no differences in behavioral, skin conductance or neural activity after active, compared with sham, treatment. However, across groups, SCRs to positive anticipation increased and SCRs to negative processing decreased at follow- up. Additionally, amygdala and right insula reactivity to negative processing, and right amygdala reactivity to positive processing, decreased at follow- up. Increased ACC activity after active treatment to positive anticipation and processing was correlated with decreased anhedonia symptoms. Conclusions Active, compared with sham, iTBS treatment does not affect behavioral, skin conductance or neural activity to emotion anticipation and processing in depression. However, across treatment groups, changes occur with time, perhaps reflecting normalization processes or partial treatment effect of sham iTBS. The ACC seems to be involved in the treatment mechanism of iTBS.

PURPOSE:Repetitive transcranial magnetic stimulation (rTMS) is an evidence‑based intervention for major depressive disorder (MDD) and treatment‑resistant depression (TRD). This study compared the regulatory, organizational, and clinical implementation of rTMS in Sweden and Japan between 2020 and 2024 and assessed alignment with international consensus recommendations. MATERIALS AND METHODS:A cross‑sectional survey was conducted using publicly available information from rTMS‑providing facilities in both countries. Facilities confirming rTMS provision were included. Two investigators independently extracted facility‑level variables into a harmonized template covering service distribution, registry participation, stimulation protocols, device types, practitioner roles, eligibility criteria, reimbursement arrangements, and reported patient counts. Analyses were descriptive; financial variables were summarized to characterize access and were not part of a formal economic evaluation. RESULTS:Both countries primarily used rTMS for MDD/TRD, required psychiatric assessment, and applied similar safety exclusions. Sweden delivered rTMS within a tax‑funded regional system, with 29 centres in 2024 and near‑complete participation in a national registry integrated with electronic health records; intermittent theta‑burst stimulation (iTBS) predominated. Japan had a mixed public-private model with 112 facilities and partial registry participation (62/112). Public insurance in Japan covered only a 10‑Hz left dorsolateral prefrontal cortex protocol, whereas private clinics frequently offered iTBS. Workforce roles, device diversity, and patient co‑payments differed, with greater financial barriers reported in Japan. CONCLUSIONS:Differences in health‑system structure and registry completeness likely explain observed variation. Findings may inform policymakers seeking to optimize neuromodulation services, strengthen monitoring systems, and reduce access inequities.

OBJECTIVE:Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to be an effective and well tolerated treatment for depression, and it is being investigated also for other indications. This study presents the Swedish National Quality Register for rTMS (Q-rTMS). The registry comprises epidemiological data, data from standardized rating scales, details on treatment settings, and a registry-specific patient questionnaire. METHODS:A presentation of the Q-rTMS including the types of data collected, the organizational structure of the register, as well as a brief overview of the volume of data accumulated between the registry's inception in 2018 and the end of 2024. RESULTS:As of 2024, the register contained data from a total of 3083 unique individuals and 3842 treatment series, collected from 27 different rTMS providers. The most common indication for rTMS was depression (International Classification of Diseases, Tenth Revision diagnoses (ICD-10): F32-F34, 74.1%) followed by bipolar affective disorder (ICD-10: F31, 14.2%). The average age was 43.2 years, and 56.5% were women. The register included matched pre- and post-treatment data exceeding 60% completeness for the Montgomery-Åsberg Depression Rating Scale-Self Assessment (MADRS-S), the Clinical Global Impression-Severity (CGI-S), and the EuroQol five-dimensional questionnaire (EQ-5D-5L). CONCLUSION:The Q-rTMS combines high coverage with longitudinal documentation of clinically relevant outcome measures and may hence contribute to population-based real-world effectiveness research in rTMS for depression.

BACKGROUND:Schizophrenia-spectrum disorders (SSD) are characterized by structural and functional brain abnormalities, including disrupted functional connectivity within networks such as the salience network. The anterior cingulate cortex (ACC), a core hub of this network, has shown alterations in the major neurotransmitter systems comprising glutamate (Glu) and γ-aminobutyric acid (GABA). While dysfunctional glutamatergic signaling has been proposed as a key mechanism in SSDs, the relationship between anterior cingulate cortex (ACC) functional connectivity, glutamatergic neurotransmission, and clinical symptomatology remains poorly understood. METHODS:Here, we combined resting-state functional MRI to measure functional brain connectivity with proton magnetic resonance spectroscopy to measure Glu and GABA levels in the dorsal ACC of 26 patients with schizophrenia spectrum disorders and 38 healthy controls. RESULTS:Patients showed reduced connectivity within the salience network compared to controls. Across the whole sample, a dorsal ACC-seed showed glutamate-dependent connectivity to several clusters, including right insula, thalamus, and cerebellum. In patients, the averaged connectivity of these clusters was associated with positive symptom severity. CONCLUSIONS:These findings suggest that disrupted glutamatergic modulation of large-scale brain networks may underlie core clinical features in schizophrenia spectrum disorders.

BACKGROUND:Impaired plasticity has been implicated in major depressive disorder (MDD), which is reflected in impaired automatic sensory detection as measured using mismatch negativity (MMN). Intermittent theta-burst stimulation (iTBS) is used to treat MDD and its mechanism of action has been suggested to be plasticity dependent. Thus, we aimed at evaluating MMN as a MDD biomarker and predictor of antidepressant effect of iTBS. METHODS:This study comprised 46 patients with MDD and 64 healthy controls. The participants completed an auditory duration deviant MMN paradigm. In patients, MMN was recorded before and after a two-week intervention of twice-daily stimulation with a prolonged iTBS protocol, or sham, over the dorsomedial prefrontal cortex (DMPFC). Depressive symptoms were assessed with the affective subscale of the Brief Psychiatric Rating Scale (BPRS-affective) and through the self-report version of the Montgomery-Åsberg Depression Rating Scale (MADRS-S). RESULTS:There were no differences in MMN amplitude at baseline between patients and controls, nor any correlations between depressive symptoms and MMN amplitude. MMN amplitude did not change after iTBS. However, in the active iTBS group a larger baseline MMN amplitude correlated significantly with greater reductions of depressive symptoms following iTBS, Δ-MADRS-S (r = 0.48, p = 0.021) and Δ-BPRS-affective (r = 0.46, p = 0.026). No correlation between baseline MMN amplitude and change of depressive symptoms was observed in the sham group. CONCLUSION:Larger MMN amplitudes at baseline were associated with greater improvement in depressive symptoms only after active iTBS over the DMPFC. Indicating potential predictive properties of MMN in DMPFC iTBS in MDD, warranting replication in larger samples.

Depression is a debilitating mental health disorder that affects a significant portion of the adolescent population, and 20

During the first year following electroconvulsive therapy (ECT) for major depressive disorder (MDD) there is a large risk of relapse. Previous studies have shown favourable results for lithium after ECT for MDD. However, lithium is infrequently prescribed after ECT. While some evidence exists for other pharmacological strategies such as TCAs and TCA-lithium combinations, comparative data remain limited. The aim of this study was to explore pharmacological treatments after ECT for MDD and analyse their association with relapse following response to ECT for MDD. We hypothesized that lithium would be associated with a lower risk of relapse. We conducted a nationwide cohort study using data from Swedish registers. Patients 18 years or older with MDD who received ECT 2013-2019 and responded distinctly to ECT were followed for a year. Specified drugs dispensed up to four weeks after the ECT series were considered the exposure. Relapse was defined as psychiatric hospitalisation, renewed ECT, intentional self-harm, or death by suicide. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using Cox models controlled for several potential confounders. The study population included 2 858 patients with distinct response to ECT. The most common psychiatric drugs dispensed after ECT were antipsychotics (39.7%), mirtazapine (38.0%), and selective serotonin reuptake inhibitors (SSRI) (35.9%). There was a statistically non-significant lower risk of relapse associated with lithium (aHR 0.86, 95% CI 0.69-1.07, p = 0.17). Antipsychotics were associated with a greater risk of relapse (aHR 1.17, 95% CI 1.05-1.31, p = 0.006). For other pharmacological treatments there were no associations with risk of relapse.

BACKGROUND:Depression is characterized by disturbed emotion processing, with aberrant neural and physiological responses to emotional stimuli. Here, we applied an emotion anticipation and processing paradigm to investigate brain neural and electrodermal reactivities in patients with depression compared with healthy controls. METHODS:The study included 42 patients (27 females) and 44 healthy controls (21 females). Subjects underwent functional magnetic resonance imaging with simultaneous measurement of electrodermal activity. During scanning, red or green color cues were presented, followed by pictures of negative or positive valence, respectively. Behavioral valence and arousal ratings of the picture stimuli were conducted after scanning. Anhedonia was assessed through a semi-structured interview in both subject groups. RESULTS:Patients perceived positive pictures as less positive than controls did. Positive anticipation (i.e., green color cues) elicited stronger activations in the anterior cingulate cortex and the right insula in patients than in healthy controls, indicating salience network disturbances. An exploratory analysis of all regions in the Automated Anatomical Labeling Atlas 2 found significant differences in activity to positive anticipation between groups in several brain regions involved in cognition and emotion processing. Positive and negative anticipation elicited stronger electrodermal responses in healthy controls. However, electrodermal reactivity to negative pictures was higher in patients than in controls. CONCLUSIONS:Ongoing depression affects emotion anticipation and processing at the behavioral, neural, and physiological levels. These findings contribute to increased understanding of the disorder.

Gamma-aminobutyric acid (GABA) and glutamate are implicated in the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS), though findings from magnetic resonance spectroscopy (MRS) are inconsistent. Furthermore, the relationship between GABAA-receptor availability and rTMS outcomes remains largely unexplored. In this study, GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) were measured using a 1H-MRS MEGA-PRESS sequence in 42 patients with bipolar or unipolar depression, both before and after a sham-controlled, double-blind clinical trial involving intermittent theta-burst stimulation (iTBS) over the dorsomedial prefrontal cortex. A subset of 28 patients also underwent [11C]flumazenil positron emission tomography (PET) to measure whole-brain GABAA-receptor availability and mean receptor availability in the nucleus accumbens and dACC. Depressive symptoms were assessed using the self-rated Montgomery Åsberg Depression Rating Scale (MADRS-S). The results indicated no significant changes in neurotransmitter levels or GABAA-receptor availability post-iTBS in either the active or sham conditions. However, changes in MADRS-S scores after active iTBS were positively correlated with changes in GABA levels in the dACC (r(13) = 0.54, p = 0.04) and baseline GABAA-receptor availability in the nucleus accumbens (r(11) = 0.66, p = 0.02). These correlations were absent in the sham group. The findings suggest that a reduction in GABA within targeted frontostriatal circuits can be part of the antidepressant mechanism of iTBS, challenging previous research. Additionally, they indicate a potential predictive role for frontostriatal GABAA-receptor availability in the treatment of depression using dorsomedial prefrontal iTBS.

PURPOSE:Negative symptoms are commonly regarded as a symptom dimension belonging to schizophrenia spectrum disorders but are also present in depression. The recently developed Clinical Assessment Interview for Negative Symptoms (CAINS) has shown to be reliable and valid. A corresponding self-report questionnaire has also been developed, named the Motivation and Pleasure Scale - Self Report (MAP-SR). The purpose was to evaluate the psychometric properties of the Swedish version of the MAP-SR in patients with either schizophrenia or depression. MATERIALS AND METHODS:The MAP-SR was translated to Swedish. Participants were 33 patients with schizophrenia spectrum disorders and 52 patients with a depressive disorder and they completed the MAP-SR, the CAINS and other measures assessing adjacent psychopathology, functioning and cognition. RESULTS:The internal consistency for the MAP-SR was adequate in both groups (schizophrenia spectrum α = .93, depressive disorder α = .82). Furthermore, the MAP-SR had a large correlation to the motivation and pleasure subscale of the CAINS in patients with schizophrenia disorders (r = -0.75, p < .001), however among patients with depression this correlation was medium-to-large (r = -0.48, p < 0.001). CONCLUSIONS:Findings suggest that the Swedish version of the MAP-SR shows promise as a useful measure of motivation and pleasure, especially in patients with schizophrenia spectrum disorders. Furthermore, results also suggest that the MAP-SR does not assess negative symptoms specifically, but that there is an overlap between depressive and negative symptoms.

OBJECTIVES:Electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) are both effective in treating depression. Although rTMS induces fewer adverse effects, its effectiveness relative to ECT is not well established. The aim of this study was to investigate the treatment outcomes of ECT and rTMS in patients who have received both interventions.METHODS:This was a register-based observational crossover study in patients with depression who had undergone ECT and rTMS in Sweden between 2012 and 2021. Primary outcome was reduction in the Montgomery-Åsberg Depression Rating Scale-Self-report (MADRS-S) score. Secondary outcome was response defined as a 50% or greater decrease in the MADRS-S score. Subgroup analyses were performed to identify factors that predicted differential responses between rTMS and ECT. Continuous and categorical variables were analyzed using paired-samples t tests and McNemar tests, respectively.RESULTS:In total, 138 patients across 19 hospitals were included. The MADRS-S score after ECT and rTMS was reduced by 15.0 and 5.6 ( P = 0.0001) points, respectively. Response rates to ECT and rTMS were 38% and 15% ( P = 0.0001), respectively. Electroconvulsive therapy was superior across all subgroups classified according to age and severity of depression.CONCLUSIONS:Our results suggest that ECT is more effective than rTMS in treating depression among patients who have received both interventions. Age and baseline depression severity did not predict who would similarly benefit from rTMS and ECT.

Altered cortical excitability is reported in schizophrenia and depression, but findings are inconsistent. Prefrontal repetitive transcranial magnetic stimulation (TMS) induces short-term motor cortex excitability changes in healthy individuals, but its effect in schizophrenia and depression remains unexplored. Prefrontal intermittent theta burst stimulation (iTBS) improves negative symptoms in depression. Cortical excitability is a suggested biomarker for prefrontal iTBS response. We investigated if prefrontal iTBS affects motor cortex excitability in schizophrenia or depression. Secondary aims were to examine motor cortex excitability as a predictor of iTBS effect on negative symptoms in depression and to compare excitability between groups with schizophrenia, depression and healthy controls. TMS indices of cortical excitability - resting motor threshold, short-interval intracortical inhibition, intracortical facilitation and long-interval intracortical inhibition (LICI) - were pooled from previous studies, including an RCT evaluating iTBS for negative symptoms. The dataset comprised 44 patients with schizophrenia, 52 with depression, and 62 healthy controls. Regression models indicated no effect of active versus sham iTBS on any TMS index (all p ≥ .61). No baseline TMS index predicted negative symptom changes after iTBS in depression (all p ≥ .44). Patients with schizophrenia exhibited more pronounced LICI inhibition than the other groups (Mann-Whitney U = 1670, p < .001). LICI correlated with antipsychotic dose (Spearman's ρ = -0.28, p = .04). Prefrontal iTBS does not modify cortical excitability in schizophrenia or depression, nor does cortical excitability predict prefrontal iTBS effects on negative symptoms. The more pronounced LICI inhibition in schizophrenia may be related to the illness or medication.

There is growing evidence suggesting that immunological mechanisms play a significant role in the development of psychiatric symptoms in certain patient subgroups. However, the relationship between clinical red flags for suspected autoimmune psychiatric disease and signs of central nervous system (CNS) pathology (e.g., routine cerebrospinal fluid (CSF) alterations, CNS damage markers, neurophysiological or neuroimaging findings) has received limited attention. Here, we aimed to describe the prevalence and distribution of potential CNS pathologies in psychiatric patients in relation to clinical red flags for autoimmune psychiatric disease and psychiatric symptoms. CSF routine findings and CNS damage markers; neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP) and total Tau (t-Tau), in CSF from 127 patients with psychiatric disease preselected for suspected immunological involvement were related to recently proposed clinical red flags, psychiatric features, and MRI and EEG findings. Twenty-one percent had abnormal routine CSF findings and 27% had elevated levels of CNS damage markers. Six percent had anti-neuronal antibodies in serum and 2% had these antibodies in the CSF. Sixty-six percent of patients examined with MRI (n = 88) had alterations, mostly atrophy or nonspecific white matter lesions. Twenty-seven percent of patients with EEG recordings (n = 70) had abnormal findings. Elevated NfL levels were associated with comorbid autoimmunity and affective dysregulation symptoms. Elevated t-Tau was associated with catatonia and higher ratings of agitation/hyperactivity. Elevated GFAP was associated with acute onset, atypical presentation, infectious prodrome, tics, depressive/anxiety symptom ratings and overall greater psychiatric symptom burden. In conclusion, preselection based on suspected autoimmune psychiatric disease identifies a population with a high prevalence of CSF alterations suggesting CNS pathology. Future studies should examine the value of these markers in predicting treatment responses.

BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) is a rapidly emerging treatment for depression, but outcome prediction is still a challenge. This study aimed to identify predictors of response to rTMS among baseline clinical factors and early symptomatic improvements. METHODS:This cohort study comprised 136 patients with a unipolar or bipolar depressive episode referred for clinical intermittent theta-burst stimulation or right-sided 1 Hz rTMS at the Uppsala Brain Stimulation Unit. The co-primary outcomes used for logistic regression were response, defined as ≥50 % reduction of Montgomery and Åsberg Depression Rating Scale Self-assessment (MADRS-S) total score, and 1-2 points on the Clinical Global Impression Improvement (CGI-I) scale. Early improvement was defined as ≥20 % reduction in the MADRS-S total score, or ≥ 1 point reduction in each MADRS-S item, after two weeks of treatment. RESULTS:The response rates were 21 % for MADRS-S and 45 % for CGI-I. A depressive episode >24 months had lower odds for MADRS-S response compared to ≤12 months. Early improvement of the MADRS-S total score predicted CGI-I response (95 % CI = 1.35-9.47, p = 0.011), Initiative6 predicted MADRS-S response (95 % CI = 1.08-9.05, p = 0.035), and Emotional involvement7 predicted CGI-I response (95 % CI = 1.03-8.66, p = 0.044). LIMITATIONS:No adjustment for concurrent medication. CONCLUSIONS:A depressive episode ≤12 months and early improvement in overall depressive symptoms, as well as the individual items, Initiative6 and Emotional involvement7, predicted subsequent rTMS response in a naturalistic sample of depressed patients. This could facilitate the early identification of patients who will benefit from further rTMS sessions.