Background
Few reports have aimed to describe the mediational effect of cognitive deficits on functional outcomes in major depressive disorder (MDD), and relatively few interventions are demonstrated to mitigate cognitive deficits in MDD.

Methods
Studies enrolling subjects between the ages of 18–65 were selected for review. Bibliographies from identified articles were reviewed to identify additional original reports aligned with our objectives.

Results
Cognitive deficits in MDD are consistent, replicable, nonspecific, and clinically significant. The aggregated estimated effect size of cognitive deficits in MDD is small to medium. Pronounced deficits in executive function (≥1 SD below the normative mean) are evident in ∼20–30% of individuals with MDD). Other replicated abnormalities are in the domains of working memory, attention, and psychomotor processing speed. Mediational studies indicate that cognitive deficits may account for the largest percentage of variance with respect to the link between psychosocial dysfunction (notably workforce performance) and MDD. No conventional antidepressant has been sufficiently studied and/or demonstrated robust procognitive effects in MDD.

Conclusions
Cognitive deficits in MDD are a principal mediator of psychosocial impairment, notably workforce performance. The hazards posed by cognitive deficits in MDD underscore the need to identify a consensus-based neurocognitive battery for research and clinical purposes. Interventions (pharmacological, behavioral, neuromodulatory) that engage multiple physiological systems implicated in cognitive deficits hold promise to reduce, reverse, and prevent cognitive deficits.

Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/wps.20204

Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder

Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.

These guidelines from the British Association for Psychopharmacology address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting, involving experts in schizophrenia and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from the participants and interested parties, and cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. The practice recommendations presented are based on the available evidence to date, and seek to clarify which interventions are of proven benefit. It is hoped that the recommendations will help to inform clinical decision making for practitioners, and perhaps also serve as a source of information for patients and carers. They are accompanied by a more detailed qualitative review of the available evidence. The strength of supporting evidence for each recommendation is rated.

https://journals.sagepub.com/doi/pdf/10.1177/0269881119889296

Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology:

Context Psychotropic medication polypharmacy is common in psychiatric outpatient settings and, in some patient groups, may have increased in recent years. Objective To examine patterns and recent trends in psychotropic polypharmacy among visits to office-based psychiatrists. Design Annual data from the 1996-2006 cross-sectional National Ambulatory Medical Care Surveys were analyzed to examine patterns and trends in psychotropic polypharmacy within nationally representative samples of 13 079 visits to office-based psychiatrists. Setting Office-based psychiatry practices in the United States. Participants Outpatients with mental disorder diagnoses visiting office-based psychiatrists. Main Outcome Measure Number of medications prescribed in each visit and specific medication combinations. Results There was an increase in the number of psychotropic medications prescribed across years; visits with 2 or more medications increased from 42.6% in 1996-1997 to 59.8% in 2005-2006; visits with 3 or more medications increased from 16.9% to 33.2% (both P Conclusions There has been a recent significant increase in polypharmacy involving antidepressant and antipsychotic medications. While some of these combinations are supported by clinical trials, many are of unproven efficacy. These trends put patients at increased risk of drug-drug interactions with uncertain gains for quality of care and clinical outcomes.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/210495/yoa90000_26_36.pdf

National Trends in Psychotropic Medication Polypharmacy in Office-Based Psychiatry

The class of serotonin and norepinephrine reuptake inhibitors (SNRIs) now comprises three medications: venlafaxine, milnacipran, and duloxetine. These drugs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity. Whereas milnacipran blocks 5-HT and norepinephrine reuptake with equal affinity, duloxetine has a 10-fold selectivity for 5-HT and venlafaxine a 30-fold selectivity for 5-HT. All three SNRIs are efficacious in treating a variety of anxiety disorders. There is no evidence for major differences between SNRIs and SSRIs in their efficacy in treating anxiety disorders. In contrast to SSRIs, which are generally ineffective in treating chronic pain, all three SNRIs seem to be helpful in relieving chronic pain associated with and independent of depression. Tolerability of an SNRI at therapeutic doses varies within the class. Although no direct comparative data are available, venlafaxine seems to be the least well-tolerated, combining serotonergic adverse effects (nausea, sexual dysfunction, withdrawal problems) with a dose-dependent cardiovascular phenomenon, principally hypertension. Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity.

SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants.

Recent advances in neuropharmacology and neuroimaging are mapping the topography of symptoms in major depressive disorder (MDD). Different malfunctioning neuronal circuits apparently mediate different symptoms in MDD. Since all patients with MDD do not have the same symptoms, this implies that they may not all have the same malfunctioning circuits. Furthermore, since MDD patients treated with antidepressants commonly experience residual symptoms that prevent them from attaining complete remission, this implies that not all circuits are successfully targeted by treatment in such patients. A new neurobiologically informed treatment strategy for such patients calls for targeting residual symptoms by augmenting antidepressants with agents capable of boosting specific neurotransmitters in the hypothetically malfunctioning circuits. With this approach, the frequently residual symptoms of sleepiness, fatigue, and executive dysfunction can be targeted with bupropion, atomoxetine, modafinil, atypical antipsychotics, and stimulants.

/pdf/brain-circuits-determine-destiny-in-depression-a-novel-196xs0cl0r.pdf

Brain Circuits Determine Destiny in Depression: A Novel Approach to the Psychopharmacology of Wakefulness, Fatigue, and Executive Dysfunction in Major Depressive Disorder.

The atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole have become first-line treatment for schizophrenia because they reduce the positive symptoms of psychosis but do not have a high incidence of extrapyramidal symptoms However, these agents, like other antipsychotics, may take as long as 16 or more weeks to produce a response, and even with prolonged treatment are unlikely to evoke responses greater than 50% improvement in symptoms This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation with other psychotropic drugs, all of which occur commonly in clinical practice This article reviews the current evidence for these increasingly common means of treating schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation To date, there are only two controlled studies of antipsychotic polypharmacy involving an atypical antipsychotic; the rest of the data are uncontrolled trials and case reports that describe a mixture of positive and negative findings One multicenter, double-blind trial shows a faster onset of action when divalproex is added to risperidone or olanzapine than with antipsychotic monotherapy A small double-blind study demonstrates efficacy when lamotrigine is added to clozapine The rest of the data on augmentation with anticonvulsants are uncontrolled, and most report adverse effects With the exception of divalproex, there are currently no compelling data to justify the use of antipsychotic polypharmacy or augmentation Existing evidence suggests that the best treatments for schizophrenia and psychosis may be long-term trials of a sequence of atypical antipsychotic monotherapies at therapeutic doses

A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation.

Stephen M. Stahl is Adjunct Professor of Psychiatry at the University of California at San Diego School of Medicine. He has conducted numerous research projects awarded by the National Institute of Mental Health, the Veterans Administration, and the pharmaceutical industry. The author of more than 400 articles and chapters, Stephen M. Stahl is an internationally recognized clinician, researcher, and teacher in psychiatry with subspecialty expertise in psychopharmacology.

Stahl's essential psychopharmacology : the prescriber's guide

Antidepressants are divided into several classes on the basis of their pharmacologic mechanisms of action, which are thought to be responsible for both their therapeutic actions and their side effect profiles. All classes currently available in the United States affect serotonin, norepinephrine, and/or dopamine neurotransmission. New agents in development also affect neurotransmission of such monoamines and include serotonin-norepinephrine reuptake inhibitors, serotonin-selective agents, selective monoamine oxidase inhibitors, and selective norepinephrine reuptake inhibitors. Treatments with entirely new mechanisms of action are also being studied, including hormone-linked treatments such as estrogen replacement therapy and the steroid antagonist mifepristone (RU-486 or C-1073); novel antagonist peptides such as corticotropin-releasing factor, neurokinins, and injectable pentapeptides; and agents that affect glutamate neurotransmission. The introduction of antidepressants with novel mechanisms of action could potentially revolutionize the treatment of depression.

/pdf/differences-in-mechanism-of-action-between-current-and-1jxu51jju9.pdf

Meghan M. Grady

Papers

SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants.

Brain Circuits Determine Destiny in Depression: A Novel Approach to the Psychopharmacology of Wakefulness, Fatigue, and Executive Dysfunction in Major Depressive Disorder.

A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation.

Stahl's essential psychopharmacology : the prescriber's guide

Differences in Mechanism of Action Between Current and Future Antidepressants