Second messenger/signal transduction pathways in major mood disorders: Moving from membrane to mechanism of action, part II: bipolar disorder

The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [γ-aminobutyric acid (GABA), glutamate] receptors at the plasma membrane. Although the activation and inhibition of these receptors acutely alter local neurotransmitter levels, their neuropsychiatric effects are not immediately observed. This time lag implicates intracellular neuroplasticity as primary in the mechanism of action of antidepressants and mood stabilizers. The modulation of intracellular second messenger/signal transduction cascades affects neurotrophic pathways that are both necessary and sufficient for monoaminergic and amino acid–based treatments. In this review, we will discuss the evidence in support of intracellular mediators in the pathophysiology and treatment of preclinical models of despair and major depressive disorder (MDD). More specifically, we will focus on the following pathways: cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3β, and NFκB/ΔFosB. We will also discuss recent discoveries with rapidly acting antidepressants, which activate the mammalian target of rapamycin (mTOR) and release of inhibition on local translation via elongation factor stimulation. Throughout this discourse, we will highlight potential intracellular targets for therapeutic intervention. Finally, future clinical implications are discussed

Which came first, delusions or hallucinations? An exploration of clinical differences among patients with first-episode psychosis based on patterns of emergence of positive symptoms.

Remarkably little is known about patterns of emergence of specific symptoms in the early course of nonaffective psychotic disorders. Some 159 well-characterized first-episode psychosis patients were categorized into those with: (1) delusions only (n=29, 18.2%); (2) delusions that emerged at least one month before hallucinations (n=31, 19.5%); (3) hallucinations that began at least one month before delusions (n=26, 16.4%); and (4) delusions and hallucinations that emerged concomitantly, within the same month (n=73, 45.9%). These four groups were compared across a number of clinical features, including duration of untreated psychosis, symptom severity, insight, and functioning, while controlling for potential confounders. Patients with delusions and hallucinations emerging within the same month had a shorter duration of untreated psychosis than those in whom one psychotic symptom emerged greater than one month before the other. The delusions-only group had significantly less severe positive, negative, and general psychopathology symptom scores, as well as better social and occupational functioning. Replication and further elucidation of specific patterns of symptom emergence would deepen the field’s understanding of early-course phenomenology, and may inform efforts to improve upon nosology, prognostication, and treatment selection

Major depression is not associated with blunting of aversive responses; evidence for enhanced anxious anticipation.

According to the emotion-context insensitivity (ECI) hypothesis, major depressive disorder (MDD) is associated with a diminished ability to react emotionally to positive stimuli and with blunting of defensive responses to threat. That defensive responses are blunted in MDD seems inconsistent with the conceptualization and diagnostic nosology of MDD. The present study tested the ECI hypothesis in MDD using a threat of shock paradigm. Twenty-eight patients with MDD (35.5±10.4 years) were compared with 28 controls (35.1±7.4 years). Participants were exposed to three conditions: no shock, predictable shock, and unpredictable shock. Startle magnitude was used to assess defensive responses. Inconsistent with the ECI hypothesis, startle potentiation to predictable and unpredictable shock was not reduced in the MDD group. Rather, MDD patients showed elevated startle throughout testing as well as increased contextual anxiety during the placement of the shock electrodes and in the predictable condition. A regression analysis indicated that illness duration and Beck depression inventory scores explained 37% (p<.005) of the variance in patients' startle reactivity. MDD is not associated with emotional blunting but rather enhanced defensive reactivity during anticipation of harm. These results do not support a strong version of the ECI hypothesis. Understanding the nature of stimuli or situations that lead to blunted or enhanced defensive reactivity will provide better insight into dysfunctional emotional experience in MDD

Mean (sem) Retrospective subjective ratings of fear and anxiety.

<p>Mean (sem) Retrospective subjective ratings of fear and anxiety.</p

Startle response during NPU (raw scores).

<p>Startle magnitudes (raw scores) in the controls and patients with major depressive disorder (MDD) during the habituation procedures and during the no shock (N), predictable shock (P), and unpredictable shock (U) condition in the threat procedures. Error bars are SEM.</p

Correlation (probability) between illness duration, trait anxiety, and BDI, and startle reactivity in the MDD patients.

*<p>Average of ITI startle magnitudes in the no-shock, predictable, and unpredictable condition.</p

Schematic representation of sequences of stimulus presentation during each condition in one block of the NPU-threat test.

<p>The upper part of the figure represents a complete block, including two P (predictable), two U (unpredictable) and three N (no shock) conditions (order UNPNPNU as shown or PNUNUNP). The lower part shows each condition, including cues (8-s duration), startle probes presented during cues (grey arrow pointing up) or during cue-free periods (dark arrow pointing up), and shocks. Adapted from reference 31.</p

Biomarkers in mood disorders research: developing new and improved therapeutics

Background Recently, surrogate neurobiological biomarkers that correlate with target engagement and therapeutic response have been developed and tested in early phase studies of mood disorders. Objective The identification of biomarkers could help develop personalized psychiatric treatments that may impact public health. Methods These biomarkers, which are associated with clinical response post-treatment, can be directly validated using multimodal approaches including genetic tools, proteomics/metabolomics, peripheral measures, neuroimaging, biostatistical predictors, and clinical predictors. Results To date, early phase biomarker studies have sought to identify measures that can serve as “biosignatures”, or biological patterns of clinical response. These studies have also sought to identify clinical predictors and surrogate outcomes associated with pathophysiological domains consistently described in the National Institute of Mental Health’s (NIMH) new Research Domain Criteria (RDoC). Using the N-methyl-D-aspartate (NMDA) antagonist ketamine as an example, we identified changes in several domains (clinical, cognitive, and neurophysiological) that predicted ketamine’s rapid and sustained antidepressant effects in individuals with treatment-resistant major depressive disorder (MDD) or bipolar depression. Discussion These approaches may ultimately provide clues into the neurobiology of psychiatric disorders and may have enormous impact Backon the development of novel therapeutics