A review of recent research on cognitive processing indicates that biases in attention, memory, and interpretation, as well as repetitive negative thoughts, are common across emotional disorders, although they vary in form according to type of disorder. Current cognitive models emphasize specific forms of biased processing, such as variations in the focus of attention or habitual interpretative styles that contribute to the risk of developing particular disorders. As well as predicting risk of emotional disorders, new studies haveprovided evidence of a causal relationship between processing bias and vulnerability. Beyond merely demonstrating the existence of biased processing, research is thus beginning to explore the cognitive causes of emotional vulnerability, and their modification.

Cognitive Vulnerability to Emotional Disorders

Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events. 1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of 2 weeks and interfere considerably with work and family relations. On the basis of this broad definition, the lifetime incidence of depression in the United States is more than 12% in men and 20% in women. 2 Some have advocated a much narrower definition of severe depression, which they call melancholia or vital depression. 3 A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depressive disorder overlap, a history of mania defines a distinct illness termed bipolar disorder. 4 Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major depression.

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Major depressive disorder.

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

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Major depressive disorder

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)60046-5.pdf

Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis

Inhibition and impulsivity: Behavioral and neural basis of response control

Context Selective serotonin reuptake inhibitors (SSRIs) are often described as having a delayed onset of effect in the treatment of depression. However, some trials have reported clinical improvement as early as the first week of treatment. Objective To test the alternative hypotheses of delayed vs early onset of antidepressant action with SSRIs in patients with unipolar depression. Data Sources Trials identified by searching CENTRAL, The Cochrane Collaboration database of controlled trials (2005), and the reference lists of identified trials and other systematic reviews. Study Selection Randomized controlled trials of SSRIs vs placebo for the treatment of unipolar depression in adults that reported outcomes for at least 2 time points in the first 4 weeks of treatment (50 trials from >500 citations identified). Trials were excluded if limited to participants older than 65 years or specific comorbidities. Data Extraction Data were extracted on trial design, participant characteristics, and outcomes by a single reviewer. Data Synthesis Pooled estimates of treatment effect on depressive symptom rating scales were calculated for weeks 1 through 6 of treatment. In the primary analysis, the pattern of response seen was tested against alternative models of onset of response. The primary analysis incorporated data from 28 randomized controlled trials (n = 5872). A model of early treatment response best fit the experimental data. Treatment with SSRIs rather than placebo was associated with clinical improvement by the end of the first week of use. A secondary analysis indicated an increased chance of achieving a 50% reduction in Hamilton Depression Rating Scale scores by 1 week (relative risk, 1.64; 95% confidence interval, 1.2-2.25) with SSRI treatment compared with placebo. Conclusions Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use, and the improvement continues at a decreasing rate for at least 6 weeks.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/668229/yoa60024_1217_1223.pdf

Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis.

Importance Alterations in glutamatergic neurotransmission may be fundamental to the pathophysiology of schizophrenia, and the glutamatergic system is a target for novel therapeutic interventions in the disorder. Objective To investigate the nature of brain glutamate alterations in schizophrenia by conducting a meta-analysis of glutamate proton magnetic resonance (MRS) spectroscopy studies. Data Sources The MEDLINE database was searched for studies published from January 1, 1980, to April 1, 2015. Search terms included magnetic resonance spectroscopy , schizophrenia , psychosis , clinical or genetic high risk, and schizoaffective . Inclusion criteria were single voxel 1H-MRS studies reporting glutamate, glutamine or Glx values for a patient or risk group in comparison to a healthy volunteer group. Study Selection Fifty-nine studies were identified, which included 1686 patients and 1451 healthy individuals serving as controls. Data Extraction and Synthesis A random-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently. Effect sizes were determined for glutamate, glutamine, and Glx in brain regions that had been examined in at least 3 different studies. A secondary analysis grouped studies into those examining patients at different stages of illness (high risk, first-episode psychosis, or chronic schizophrenia). Effects of age, antipsychotic dose, and symptom severity were determined using meta-regression. Results In schizophrenia, there were significant elevations in glutamate in the basal ganglia (Hedges g  = 0.63; 95% CI, 0.15-1.11), glutamine in the thalamus ( g  = 0.56; 95% CI, 0.02-1.09), and Glx in the basal ganglia ( g  = 0.39; 95% CI, 0.09-0.70) and medial temporal lobe ( g  = 0.32; 95% CI, 0.12-0.52). No region showed a reduction in glutamate metabolites in schizophrenia. Secondary analyses revealed that elevated medial frontal Glx levels were evident in individuals at high risk for schizophrenia ( g  = 0.26; 95% CI, 0.05-0.46) but not in those with first-episode psychosis or chronic schizophrenia, whereas elevated Glx in the medial temporal lobe was seen with chronic schizophrenia ( g  = 0.40; 95% CI, 0.08-0.71) but not in the high-risk or first-episode groups. Meta-regression found no association with age, symptom severity, or antipsychotic dose. Conclusions and Relevance Schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential.

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Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

OBJECTIVE: Antidepressants that increase serotonin or norepinephrine in the brain are effective in treating depression, but there is no neuropsychological account of how these changes relieve depressive states. Cognitive theories suggest that biases in information processing lead depressed patients to make unrealistically negative judgments about themselves and the world. METHOD: A single dose of the noradrenergic antidepressant reboxetine or placebo was administered to 24 healthy volunteers. Effects on emotional processing were assessed through facial expression recognition, emotional categorization, and emotional memory. RESULTS: On the three measures, reboxetine biased perception toward positive, rather than negative, information in the absence of changes in nonemotional performance or mood. CONCLUSIONS: These results suggest that a single dose of an antidepressant can increase the processing of positively valenced material in nondepressed volunteers. Antidepressants may therefore work in a manner simi...

Toward a neuropsychological theory of antidepressant drug action: increase in positive emotional bias after potentiation of norepinephrine activity.

OBJECTIVE: The authors used magnetic resonance spectroscopy (MRS) to assess the effect of acute administration of the selective serotonin reuptake inhibitor (SSRI) citalopram on cortical levels of γ-aminobutyric acid (GABA). METHOD: Ten healthy volunteers received either intravenous citalopram (10 mg) or saline in a randomized, double-blind, crossover design. The occipital GABA/creatine ratio was measured with a proton MR spectral editing technique. RESULTS: In comparison with saline, citalopram produced a mean increase of 35% in relative brain GABA concentration in the occipital cortex. CONCLUSIONS: These findings extend previous work showing that SSRI treatment increases cortical GABA in depressed patients and suggest that this results from an action of SSRIs on GABA neurons rather than as a secondary consequence of mood improvement.

Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor.

Objective: A previous positron emission tomography (PET) study reported increased serotonin 5-HT 2A receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT 2A receptor ligand [ 11 C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT 2A receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. Method: Cortical 5-HT 2A receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [ 11 C]MDL 100,907 in brain tissue. Results: Relative to the comparison subjects, the recovered depr...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.2006.163.9.1580

Matthew Taylor

Papers

Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis.

Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

Toward a neuropsychological theory of antidepressant drug action: increase in positive emotional bias after potentiation of norepinephrine activity.

Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor.

Increased 5-HT 2A Receptor Binding in Euthymic, Medication-Free Patients Recovered From Depression: A Positron Emission Study With [ 11 C]MDL 100,907