Early versions of The Diagnostic and Statistical Manual of Mental Disorders (DSM I and II) did not clearly distinguish between wellness and sickness , or emotional and psychotic disorders . To address these problems, the authors of DSM-III (1980–1987), and its current iteration DSM-IV-TR (2000-), proposed diagnostic categories, which represent mental disorders as present or absent (i.e., categorical variables), using temporal, functional, and symptom-based criteria. This has helped to create a reliable language for naming mental disorders . However, the “splitting” of psychopathology into nearly 400 disorders may have obscured shared biological substrates and specific predictors of response.
In contrast, dimensional models seek to identify underlying factors, which influence phenotypic expression. Across emotional disorders, psychology research has shown that positive affectivity (PA) and negative affectivity (NA), defined as dimensions of emotional temperament, can help to account for the comorbid features of mood and anxiety disorders , and may provide a framework for transdiagnostic treatments . However, PA and NA have only recently become a focus of pharmacological research (possibly related to the historical divide between psychology and psychiatry; the specialized nomenclature surrounding the constructs themselves; and their origin in quantitative methods [such as factor analysis and structural equation modeling; SEM]).
Given the limited efficacy of current pharmacotherapy for major depressive disorder [MDD; Refs. 6–9] and the historical decline in the development of antidepressants , there is increasing clinical urgency to develop more effective treatments. In this article, we will synthesize findings from clinical psychology and affective neuroscience related to the construct of emotional temperament; examine the effects of antidepressants on PA and NA (Table 1); and propose a biobehavioral research paradigm for MDD.
|McCabe et al., 2009 ||Comparison of neural responses to reward-related and aversive stimuli in unmedicated, recovered depressed subjects versus healthy controls.||Unmedicated, recovered depressed patients exhibited reduced response to reward, measured as hypoactivity in the ventral striatum, despite self-reported levels of pleasure similar to healthy controls.||1. Patients with a history of depression may have neural deficits in reward processing.|
2. Deficits may also represent an endophenotype for depression and/or a target for treatment and prevention strategies.
|Gotlib et al., 2010 ||Comparison of neural processing of reward and loss conditions in healthy children with strong genetic loading for depression (high risk) versus healthy children with no family history of depression (low risk).||High risk children showed decreased activity in putamen and left insula during anticipation of reward and increased activity in right insula compared to low risk controls.||1. Abnormal neural processing of reward may be a susceptibility factor for depression.|
|Tang et al., 2009 ||Double-blind, controlled trial of 240 MDD subjects randomized to 16 weeks of cognitive therapy, paroxetine, or 8 weeks of placebo. Placebo completers could then elect to enter into an additional open-label trial of an SSRI.||1. Linear regression analysis: all 3 groups showed improvement in depression over the first 8 weeks, but changes in trait extraversion/neuroticism on the NEO-FI were 4–8 times greater with paroxetine than placebo.|
2. Matching analysis: Paroxetine-treated patients demonstrated 3.5 times greater change in PA and 6.8 times greater change in NA compared to placebo-treated subjects; paroxetine-treated patients had 1.9 times greater improvements in NA relative to PA.
|1. Supports the cause-correction hypothesis.|
2. Partially supports the preferential effects hypothesis.
|Quilty et al., 2010 ||Data from naturalistic and randomized, controlled trials combined in a structural equation modeling analysis comparing MDD patients who received SSRIs with those receiving noradrenergic and dopaminergic reuptake blockers (NDMs) or reversible monoamine oxidase inhibitors (RIMAs).||1. MDD subjects receiving SSRIs exhibited greater trait NA/neuroticism change than those receiving noradrenergic and dopaminergic reuptake blockers (NDMs) and reversible monoamine oxidase inhibitors (RIMAs).|
2. Goodness-of-fit indices favored a mediation rather than complication model.
|1. SSRI induced reduction in NA may mediate depression symptom changes.|
2. SEM may also be a valuable technique for modeling antidepressant effects through the dimension of PA.
|Harmer et al., 2009 ||Double-blind, controlled study of 31 depressed patients and 31 matched healthy controls randomized to a single dose of reboxetine (4 mg) or placebo. Subjects given a battery of emotional processing tasks before and 3 h after administration of treatment.||Depressed patients treated with reboxetine exhibited a reversal in emotional appraisal deficits, including recognition of positive facial expressions, response speed to positive self-relevant personality adjectives, and memory for these positive adjectives compared to placebo.||1. Emotional processing in depressed patients can be modified by the acute administration of an NRI antidepressant in the absence of symptom changes.|
2. Reversal of these emotional processing deficits may provide a key substrate for synergistically combining pharmacological and psychological interventions.
|Murphy et al., 2009 ||Double-blind study of 26 healthy volunteers randomized to a single dose of citalopram (20 mg) or placebo. 3 h after administration subjects performed an fMRI block design task which measured neural response to backwardly masked and unmasked presentations of fearful, neutral, and happy facial expressions.||Subjects treated with citalopram demonstrated a significantly reduced amygdala response to fearful facial expressions compared to placebo.||1. Emotional processing in healthy controls can be modified by the acute administration of an SSRI antidepressant.|
2. Early modification of emotional appraisal may represent a functional mechanism for the delayed, clinical effects of SSRI antidepressants.
|Knutson et al., 1998 ||Double-blind, controlled trial of 51 healthy participants randomized to a fixed dose of paroxetine (20 mg/day) or placebo over a 4-week period.||1. Ratings of NA on the PANAS decreased significantly in the paroxetine group compared to placebo. The bulk of these changes occurred within the first week.|
2. No significant changes in PA were detected in either the paroxetine or the placebo group.
|1. First randomized, controlled study to find that SSRIs may reduce NA in healthy participants.|
2. Absence of SSRI-induced improvement in PA is consistent with animal and human studies indicating SSRIs may not be effective for anergic symptoms in a subgroup of MDD patients
|McCabe et al, 2010 ||Randomized, controlled study of 45 healthy participants randomized to 7 days of treatment with citalopram, reboxetine, or placebo. Neural responses to rewarding (sight and/or avor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) assessed with fMRI.||1. Citalopram reduced neural processing of rewarding stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex and aversive stimuli in the lateral orbitofrontal cortex.|
2. Reboxetine, increased neural responses to reward within the medial orbitofrontal cortex, and had weaker effects on neural processing of aversive stimuli.
|1. First study to demonstrate that SSRIs diminish the neural processing of both rewarding and aversive stimuli.|
2. May also help to explain the often-reported emotional flattening effect of SSRIs.
|Taneja et al., 2007 ||Double-blind, crossover trial of 12 healthy individuals randomized to modafinil (400 mg) versus placebo, with 4-day washout period between phases.||1. Ratings of PA on the PANAS increased significantly in the modafinil group compared to placebo.|
2. Ratings of NA also increased in the modafinil group compared to placebo.
|1. First study to demonstrate that a pro-dopaminergic agent may increase PA and NA in healthy individuals.|
2. May help to understand potential for improved mood and worsened anxiety in patients with depression.
|Tomarken et al., 2004 ||Double-blind, controlled trial of 10 depressed patients and 9 matched healthy controls randomized to 300 mg/day of bupropion SR versus placebo. Subjects previously in the bupropion group had their dose increased to 400/day during a second 6-week phase, and subjects previously in the placebo group were titrated to 300 mg/day.||1. Bupropion produced significantly greater improvement in PA deficits (MASQ) compared to placebo.|
2. Placebo had weaker effects on PA than on other symptom or dimensional measures.
|1. Suggests specific catecholaminergic effects on PA in MDD and supports previous studies relating dopaminergic dysfunction in depression to impairments in reward processing.|
2. Dose/duration effect of buproprion corroborates other studies suggesting targeted treatment of low PA in depression should be sequenced in conjunction with, or after stabilization of high NA.
3. Given the weak placebo effects on PA deficits, dimensional ratings may provide a more generative metric for separating antidepressant and placebo effects.
|Dichter et al., 2005 ||Double-blind, controlled trial of 20 outpatients with MDD randomized to fixed doses of venlafaxine XR 225 mg/day, or paroxetine 30 mg/day, over 12 weeks.||1. Both agents produced similar amounts of improvement in NA (MASQ) and depression severity.||1. Did not support the hypothesis that antidepressants with different mechanisms have preferential effects on PA or NA.|
2. Venlafaxine did not separate from paroxetine on ratings of PA.
|Knutson et al., 2004 ||Within-subject, double-blind, placebo controlled study of 8 healthy volunteers to assess the effects of oral dextroamphetamine (AMPH) on neural processing of incentives. Subjects were scanned during a monetary incentive delay task, which separates anticipatory and consummatory incentive processing.||1. Healthy subjects receiving AMPH demonstrated increased positive arousal for anticipating gain and avoiding loss, as measured by increased cue-related excitement and changes in ventral striatum (VS) activity.|
2. AMPH subjects displayed increased right NAcc activation during loss anticipation.
|1. These data are consistent with the “incentive salience” model of dopamine function (103), which posits that dopamine predominantly mediates “incentive” (how much work the organism will do in relation to the reward value assigned) and “salience” (how attractive a stimulus is to an organism).|
2. Suggests a neural mechanism for how increased positive arousal may facilitate reframing of potential losses as potential gains.