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Side effects to antidepressant medications are common and can impact the prognosis of successful treatment outcome in people with major depressive disorder (MDD). However, few studies have investigated the severity of side effects over the course of treatment and their association with treatment outcome. Here we assessed the severity of side effects and the impact of treatment type and anxiety symptoms over the course of treatment, as well as whether side effects were associated with treatment outcome. Participants were N = 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic MDD. Participants were randomised to receive escitalopram, sertraline, or venlafaxine-extended release with equal probability and reassessed at 8 weeks regarding Hamilton Rating Scale Depression (HRSD17) and Quick Inventory of Depressive Symptomatology (QIDS-SR16) remission and response. Severity of side effects were assessed using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale and assessed at day 4 and weeks 2, 4, 6, and 8. Frequency, intensity, and burden of side effects were greatest at week 2, then only frequency and intensity of side effects gradually decreased up to week 6. Treatment type and anxiety symptoms did not impact the severity of side effects. A greater burden—but not frequency or intensity—of side effects was associated with poorer treatment outcome and as early as 4 days post-treatment. Together, this work provides an informative mapping of the progression of side effects throughout the treatment course and their association with treatment outcome. Importantly, the burden of side effects that are present as early as 4 days post-treatment predicts poorer treatment outcome and should be monitored closely. iSPOT-D: Registry name: ClinicalTrials.gov. Registration number: NCT00693849.

Bipolar disorder (BD) is commonly misdiagnosed as major depressive disorder (MDD). This is understandable, as depression often precedes mania and is otherwise indistinguishable in both. It is therefore imperative to identify neural mechanisms that can differentiate the two disorders. Interrogating resting brain neural activity may reveal core distinguishing abnormalities. We adopted an a priori approach, examining three key networks documented in previous mood disorder literature subserving executive function, salience and rumination that may differentiate euthymic BD and MDD patients. Thirty-eight patients with BD, 39 patients with MDD matched for depression severity, and 39 age-gender matched healthy controls, completed resting-state fMRI scans. Seed-based and data-driven Independent Component analyses (ICA) were implemented to examine group differences in resting-state connectivity (pFDR < 0.05). Seed analysis masks were target regions identified from the fronto-parietal (FPN), salience (SN) and default-mode (DMN) networks. Seed-based analyses identified significantly greater connectivity between the subgenual cingulate cortex (DMN) and right dorsolateral prefrontal cortex (FPN) in BD relative to MDD and controls. The ICA analyses also found greater connectivity between the DMN and inferior frontal gyrus, an FPN region in BD relative to MDD. There were also significant group differences across the three networks in both clinical groups relative to controls. Altered DMN–FPN functional connectivity is thought to underlie deficits in the processing, management and regulation of affective stimuli. Our results suggest that connectivity between these networks could potentially distinguish the two disorders and could be a possible trait mechanism in BD persisting even in the absence of symptoms.

Although the cost of poor treatment outcomes of depression is staggering, we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in major depressive disorder (MDD) and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test-retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. A total of 80 MDD outpatients were scanned prior to treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin-norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). A total of 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by ⩾50% symptom improvement on the 17-item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (Cohen's d effect size 0.63 to 0.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward 'normalization' post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR (Cohen's d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyper-reactivity, which progressed to hypo-reactivity rather than normalization post-treatment, and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin-norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments.

When we move our articulator organs to produce overt speech, the brain generates a corollary discharge that acts to suppress the neural and perceptual responses to our speech sounds. Recent research suggests that inner speech – the silent production of words in one's mind – is also accompanied by a corollary discharge. Here, we show that this corollary discharge contains information about the temporal and physical properties of inner speech. In two experiments, participants produced an inner phoneme at a precisely-defined moment in time. An audible phoneme was presented 300 ms before, concurrently with, or 300 ms after participants produced the inner phoneme. We found that producing the inner phoneme attenuated the N1 component of the event-related potential – an index of auditory cortex processing – but only when the inner and audible phonemes occurred concurrently and matched on content. If the audible phoneme was presented before or after the production of the inner phoneme, or if the inner phoneme did not match the content of the audible phoneme, there was no attenuation of the N1. These results suggest that inner speech is accompanied by a temporally-precise and content-specific corollary discharge. We conclude that these results support the notion of a functional equivalence between the neural processes that underlie the production of inner and overt speech, and may provide a platform for identifying inner speech abnormalities in disorders in which they have been putatively associated, such as schizophrenia.

Posttraumatic stress disorder (PTSD) is a debilitating condition affecting millions of people worldwide. Existing treatments often fail to address the complexity of its symptoms and functional impairments resulting from severe and prolonged trauma. Electroencephalographic Neurofeedback (NFB) has emerged as a promising treatment that aims to reduce the symptoms of PTSD by modulating brain activity. We conducted a systematic review and meta-analysis of ten clinical trials to answer the question: how effective is NFB in addressing PTSD and other associated symptoms across different trauma populations, and are these improvements related to neurophysiological changes? The review followed the Preferred Reporting Items for Systematic Reviews and Meta analyses guidelines. We considered all published and unpublished randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) involving adults with PTSD as a primary diagnosis without exclusion by type of trauma, co-morbid diagnosis, locality, or sex. Ten controlled studies were included; seven RCTs and three NRSIs with a total number of participants = 293 (128 male). Only RCTs were included in the meta-analysis (215 participants; 88 male). All included studies showed an advantage of NFB over control conditions in reducing symptoms of PTSD, with indications of improvement in symptoms of anxiety and depression and related neurophysiological changes. Meta-analysis of the pooled data shows a significant reduction in PTSD symptoms post-treatment SMD of -1.76 (95% CI -2.69, -0.83), and the mean remission rate was higher in the NFB group (79.3%) compared to the control group (24.4%). However, the studies reviewed were mostly small, with heterogeneous populations and varied quality. The effect of NFB on the symptoms of PTSD was moderate and mechanistic evidence suggested that NFB leads to therapeutic changes in brain functioning. Future research should focus on more rigorous methodological designs, expanded sample size and longer follow-up.

Efference copies refer to internal duplicates of movement-producing neural signals. Their primary function is to predict, and often suppress, the sensory consequences of willed movements. Efference copies have been almost exclusively investigated in the context of overt movements. The current electrophysiological study employed a novel design to show that inner speech – the silent production of words in one’s mind – is also associated with an efference copy. Participants produced an inner phoneme at a precisely specified time, at which an audible phoneme was concurrently presented. The production of the inner phoneme resulted in electrophysiological suppression, but only if the content of the inner phoneme matched the content of the audible phoneme. These results demonstrate that inner speech – a purely mental action – is associated with an efference copy with detailed auditory properties. These findings suggest that inner speech may ultimately reflect a special type of overt speech. As you read this text, the chances are you can hear your own inner voice narrating the words. You may hear your inner voice again when silently considering what to have for lunch, or imagining how a phone conversation this afternoon will play out. Estimates suggest that we spend at least a quarter of our lives listening to our own inner speech. But to what extent does the brain distinguish between inner speech and the sounds we produce when we speak out loud? Listening to a recording of your own voice activates the brain more than hearing yourself speak out loud. This is because when the brain sends instructions to the lips, tongue, and vocal cords telling them to move, it also makes a copy of these instructions. This is known as an efference copy, and it enables regions of the brain that process sounds to predict what they are about to hear. When the actual sounds match those predicted – as when you hear yourself speak out loud – the brain’s sound-processing regions dampen down their responses. But does the inner speech in our heads also generate an efference copy? To find out, Whitford et al. tracked the brain activity of healthy volunteers as they listened to speech sounds through headphones. While listening to the sounds, the volunteers had to produce either the same speech sound or a different speech sound inside their heads. A specific type of brain activity decreased whenever the inner speech sound matched the external speech sound. This decrease did not occur when the two sounds were different. This suggests that the brain produces an efference copy for inner speech similar to that for external speech. These findings could ultimately benefit people who suffer from psychotic symptoms, for example as part of schizophrenia. Symptoms such as hearing voices are thought to reflect problems with producing and interpreting inner speech. The technique that Whitford et al. have developed will enable us to test this long-held but hitherto untestable idea. The results should increase our understanding of these symptoms and may eventually lead to new treatments.

Little is known about the structural brain changes that occur over the first few years of schizophrenia, or how these changes differ from those associated with healthy brain development in adolescence and early adulthood. In this study, we aimed to identify regional differences in grey matter (GM) volume between patients with first-episode schizophrenia (FES) and matched healthy controls, both at the time of the patients' first psychotic episode (baseline condition) and 2–3 years subsequently (follow-up condition). Forty-one patients with FES and 47 matched healthy controls underwent a T1-weighted structural MRI scan. Of these participants, 25 FES patients and 26 controls returned 2–3 years later for a follow-up scan. Voxel-based morphometry in SPM2 was used to identify the regions of GM difference between the groups in the baseline condition, while tensor-based morphometry was used to identify the longitudinal change within subject over the follow-up interval. The FES patients exhibited widespread GM reductions in the frontal, parietal, and temporal cortices and cerebellum in the baseline condition, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES subjects were observed to lose considerably more GM over the follow-up interval than the controls, especially in the parietal and temporal cortices. We argue that the progressive GM atrophy we have found to be associated with the onset of schizophrenia arises from a dysfunction in the dramatic period of healthy brain development typically associated with adolescence.

Auditory-verbal hallucinations (AVH)-the experience of hearing voices in the absence of auditory stimulation-are a cardinal psychotic feature of schizophrenia-spectrum disorders. It has long been suggested that some AVH may reflect the misperception of inner speech as external voices due to a failure of corollary-discharge-related mechanisms. We aimed to test this hypothesis with an electrophysiological marker of inner speech. Participants produced an inner syllable at a precisely specified time, when an audible syllable was concurrently presented. The inner syllable either matched or mismatched the content of the audible syllable. In the passive condition, participants did not produce an inner syllable. We compared the amplitude of the N1, P2, and P3-components of the auditory-evoked potential between: (1) schizophrenia-spectrum patients with current AVH (SZAVH+, n = 55), (2) schizophrenia-spectrum patients without current AVH (SZAVH-, n = 44), (3) healthy controls (HC, n = 43). The HC group showed reduced N1-amplitude in the Match condition (relative to Passive and Mismatch), replicating our previous results. In contrast, the SZAVH+ group showed the opposite effect: enhanced N1-amplitude in the Match condition (relative to Passive and Mismatch). The SZAVH- group showed reductions in the Mismatch condition (relative to Passive and Match). This study provides empirical support for the theory that AVH are related to abnormalities in the normative suppressive mechanisms associated with inner speech. This phenomenon of \"inner speaking-induced suppression\" may have utility as a biomarker for schizophrenia-spectrum disorders generally, and may index a tendency for AVH specifically at more extreme levels of abnormality.

Auditory verbal hallucinations (AVH) are hypothesized to result from failures in corollary discharge mechanisms to correctly predict self-initiated inner speech. However, the role of motor preparation in inner speech, during which sensorimotor predictions are formed, remains unclear. This study aimed to test the hypothesis by examining the relationship between AVH and an electrophysiological marker of action preparation: the contingent negative variation (CNV). Participants completed an electroencephalographic paradigm. In the Active condition, they imagined an inner syllable at a cued moment coinciding with the presentation of an audible syllable. In the Passive condition, participants passively listened to audible syllables. The amplitude of the late CNV preceding inner speech production was compared with that associated with passive listening across 3 groups: (1) schizophrenia spectrum patients with current AVH (SZAVH+, n = 58), (2) schizophrenia spectrum patients without current AVH (SZAVH-, n = 50), and (3) healthy controls (HC, n = 49). The HC group showed a more negative late CNV in the Active condition compared with the Passive condition. In contrast, the SZAVH+ and SZAVH- groups showed positive-going slow cortical potentials in both conditions, with less positivity in the Active condition in the former. This pattern significantly predicted AVH status. These findings provide evidence of motor preparation dysfunction during inner speech in schizophrenia spectrum disorders. The distinct pattern of deficits observed in hallucinators may reflect imprecise corollary discharges theorized to underlie some AVH. Premovement neural indices may provide a novel window into abnormalities in prediction formation.

Schizophrenia is a debilitating disorder of unknown cause. There is increasing momentum to consider functional dysconnectivity as an endophenotype of schizophrenia, and in particular, how it relates to cognition as a core feature of the disorder. Here, the authors review the conceptual models of functional dysconnectivity in schizophrenia to date, the evidence they are based on and some of the limitations of these models. The authors then propose 'neural synchrony' as a potential mechanism for functional dysconnectivity and review the current state of evidence for a link between neural synchrony and cognition in schizophrenia across behavioral, physiological, brain imaging, neurochemical and neurogenetic units of enquiry. The authors conclude by outlining the unmet needs in this field and give an outlook on how to fill these gaps.