The role of outcome expectancy in therapeutic change across psychotherapy versus pharmacotherapy for depression.

BACKGROUND: Patient outcome expectancy - the belief that treatment will lead to an improvement in symptoms - is linked to favourable therapeutic outcomes in major depressive disorder (MDD). The present study extends this literature by investigating the temporal dynamics of expectancy, and by exploring whether expectancy during treatment is linked to differential outcomes across treatment modalities, for both optimistic versus pessimistic expectancy. METHODS: A total of 104 patients with MDD were randomized to receive either cognitive behavioral therapy (CBT) or pharmacotherapy for 16 weeks. Outcome expectancy was measured throughout treatment using the Depression Change Expectancy Scale (DCES). Depression severity was measured using both the Hamilton Depression Rating Scale and Beck Depression Inventory-II. RESULTS: Latent growth curve models supported improvement in expectancy across both treatments. Cross-lagged panel models revealed that both higher optimistic and lower pessimistic expectancy at mid-treatment predicted greater treatment response in pharmacotherapy. For CBT, the associative patterns between expectancy and depression differed as a function of expectancy type; higher optimistic expectancy at pre-treatment and lower pessimistic expectancy at mid-treatment predicted greater treatment response. LIMITATIONS: The sample size limited statistical power and the complexity of models that could be explored. CONCLUSIONS: Results suggest that outcome expectancy improved during treatment for depression. Whether outcome expectancy represents a specific mechanism for the reduction of depression warrants further investigation.

The Effect of Intravenous Citalopram on the Neural Substrates of Obsessive-Compulsive Disorder.

This study investigated the effect of an intravenous serotonin reuptake inhibitor on the neural substrates of obsessive-compulsive disorder (OCD), as intravenous agents may be more effective in treating OCD than conventional oral pharmacotherapy. Eight OCD subjects and eight control subjects received alternate infusions of citalopram and placebo during functional magnetic resonance imaging, in a randomized, symptom-provocation, crossover design. Compared with baseline, OCD subjects displayed significant changes in prefrontal neural activity after the citalopram infusion relative to placebo, and these changes correlated with reductions in subjective anxiety.

The effect of bupropion XL and escitalopram on memory and functional outcomes in adults with major depressive disorder: results from a randomized controlled trial.

Decrements in cognitive function are a common feature of Major Depressive Disorder (MDD), and whether distinct classes of antidepressants differentially affect memory in these individuals has not been sufficiently evaluated. In this study we sought to determine the effect of escitalopram and bupropion XL on memory and psychosocial function. Forty-one individuals (18-50 years) with MDD were enrolled in an 8-week, double-blind, double-dummy, randomized controlled comparative trial of bupropion XL and escitalopram. Thirty-six participants completed pre and post memory assessments. Verbal, non-verbal and working memory were evaluated with a comprehensive neuropsychological battery. Psychosocial function was assessed with the Sheehan Disability Scale and Endicott Work Productivity Scale. Escitalopram and bupropion XL significantly improved immediate as well as delayed verbal and nonverbal memory, global function (all p≤0.001), and work productivity (p=0.045), with no significant between-group differences. Improvement in immediate verbal memory exerted a direct influence on improvement in global function (p=0.006). Treatment with either escitalopram or bupropion XL was associated with improvement in memory and psychosocial function in adults with MDD.

Paroxetine in the treatment of dysthymic disorder without co-morbidities: A double-blind, placebo-controlled, flexible-dose study.

Few published studies have evaluated selective serotonin reuptake inhibitors in dysthymia without current co-morbid major depression. In this 12-week study, 40 dysthymic patients were randomly assigned to either placebo (n=19) or 20-40 mg/day of paroxetine (n=21). At endpoint, the paroxetine group showed significantly greater improvement on the Clinical Global Impression Scale, Beck Depression Inventory, and Quality of Life Enjoyment and Satisfaction Questionnaire (p<0.05), and a trend to superiority over placebo on the Hamilton Depression Rating Scale. Response and remission were significantly higher with paroxetine than placebo (p<0.05). There were no significant differences in drop out rates or frequency of adverse effects, except for excessive sweating (greater with paroxetine, p=0.04). Reporting of multiple side effects was also higher with paroxetine than with placebo (p=0.02). Paroxetine is more effective than placebo in improving symptoms and quality of life in dysthymia, and is generally tolerable.

A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders.

OBJECTIVE: To evaluate transcranial magnetic stimulation (TMS) measures of inhibition and excitation in obsessive-compulsive disorder (OCD), major depressive disorder (MDD) and schizophrenia (SCZ). METHODS: Paradigms included: short-interval cortical inhibition (SICI), cortical silent period (CSP), resting motor threshold, intracortical facilitation, and motor evoked potential amplitude. A literature search was performed using PubMed, Ovid Medline, Embase Psychiatry and PsycINFO 1990 through April 2012. RESULTS: A significant Hedge's g was found for decreased SICI (g=0.572, 95% confidence interval [0.179, 0.966], p=0.004), enhanced intracortical facilitation (g=0.446, 95% confidence interval [0.042, 0.849], p=0.030) and decreased CSP (g=-0.466, 95% confidence interval [-0.881, -0.052], p=0.027) within the OCD population. For MDD, significant effect sizes were demonstrated for decreased SICI (g=0.641, 95% confidence interval [0.384, 0.898], p=0.000) and shortened CSP (g=-1.232, 95% confidence interval [-1.530, -0.933], p=0.000). In SCZ, a significant Hedge's g was shown for decreased SICI (g=0.476, 95% confidence interval [0.331, 0.620], p=0.000). CONCLUSION: Inhibitory deficits are a ubiquitous finding across OCD, MDD, SCZ and enhancement of intracortical facilitation is specific to OCD. SIGNIFICANCE: Provides a clear platform from which diagnostic procedures can be developed.

Inhibition of the cortex using transcranial magnetic stimulation in psychiatric populations: current and future directions.

Several lines of evidence suggest that deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission are implicated in the pathophysiology of schizophrenia, bipolar disorder, major depressive disorder and obsessive-compulsive disorder. Cortical inhibition refers to a neurophysiological process, whereby GABA inhibitory interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to measure cortical inhibition, excitability and plasticity in the cortex. These measures were traditionally specific to the motor cortex, which is an important limitation when nonmotor neurophysiological processes are of primary interest. Recently, TMS has been combined with electro encephalography (EEG) to derive such measurements directly from the cortex. This review focuses on neurophysiological studies related to inhibitory and excitatory TMS paradigms, linking dysfunctional GABAergic neurotransmission to disease states. We review evidence that suggests cortical inhibition deficits among psychiatric populations and demonstrate how each disorder has a specific neurophysiological response to treatment. We conclude by discussing the future directions of TMS combined with EEG, demonstrating the potential to identify biological markers of neuropsychiatric disorders.

Pregabalin effects on neural response to emotional faces.

Pregabalin has shown promise in the treatment of anxiety disorders. Previous functional magnetic resonance imaging (fMRI) studies indicate agents used to treat anxiety, e.g., SSRIs and benzodiazepines, attenuate amygdala, insula, and medial prefrontal cortex (mPFC) activation during emotional processing. Our prior study has shown that during anticipation of an emotional stimulus, pregabalin attenuates amygdala and insula activation but increases medial PFC activation. In this study, we examined whether, similar to SSRIs and benzodiazepines, pregabalin attenuates amygdala, insula, and medial PFC during emotional face processing. Sixteen healthy volunteers underwent a double-blind within-subjects fMRI study investigating effects of placebo, 50 mg, and 200 mg pregabalin on neural activation during an emotional face-matching task. Linear mixed model analysis revealed that pregabalin dose-dependently attenuated left amygdala activation during fearful face-matching and left anterior insula activation during angry face-matching. The 50 mg dose exhibited more robust effects than the 200 mg dose in the right anterior insula and ventral ACC. Thus, pregabalin shares some similarity to SSRIs and benzodiazepines in attenuating anger and fear-related insula and amygdala activation during emotional face processing. However, there is evidence that a subclinical 50 mg dose of pregabalin produced more robust and widespread effects on neural responses in this paradigm than the more clinically relevant 200 mg dose. Taken together, pregabalin has a slightly different effect on brain activation as it relates to anticipation and emotional face processing, which may account for its unique characteristic as an agent for the treatment of anxiety disorders.

Evidence for cortical inhibitory and excitatory dysfunction in obsessive compulsive disorder.

Several lines of evidence suggest that obsessive-compulsive disorder (OCD) is associated with an inability to inhibit unwanted intrusive thoughts. The neurophysiological mechanisms mediating such inhibitory deficits include abnormalities in cortical γ-aminobutyric acid (GABA) inhibitory as well as N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms. Molecular evidence suggests that both these neurotransmitter systems are involved in OCD. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to ascertain neurophysiological indices of inhibitory GABA and facilitatory NMDA receptor-mediated mechanisms. In this study, both mechanisms were indexed in 34 patients with OCD (23 unmedicated and 11 medicated) and compared with 34 healthy subjects. Cortical inhibitory and facilitatory neurotransmission was measured using TMS paradigms known as short-interval cortical inhibition (SICI), cortical silent period (CSP), and intracortical facilitation (ICF). Patients with OCD demonstrated significantly shortened CSP (p<0.001, Cohen's d=0.91) and increased ICF (p<0.009, Cohen's d=0.71) compared with healthy subjects. By contrast, there were no significant deficits in SICI. After excluding patients with OCD and comorbid major depressive disorder (MDD) from the analysis, these differences remained significant. Our findings suggest that OCD is associated with dysregulation in cortical inhibitory and facilitatory neurotransmission. Specifically, these findings suggest impairments in GABA(B) receptor-mediated and NMDA receptor-mediated neurotransmission. These findings are consistent with previously published genetic studies implicating GABA(B), and NMDA transporter and receptor genes in OCD. It is posited that dysregulation of such mechanisms may lead to the generation and persistence of intrusive thoughts that form the basis for this disorder.

The pharmacologic treatment of anxiety disorders: a review of progress.

Anxiety disorders, as a group, are among the most common mental health conditions and frequently cause significant functional impairment. Both psychotherapeutic and pharmacologic techniques are recognized to be effective management strategies. This review provides a discussion of the major classes of psychotropic medications investigated in clinical trials of the following anxiety disorders: panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Findings suggest that both selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are useful first-line agents for most of the anxiety disorders, particularly given the frequent comorbidity with mood disorders. Highly serotonergic agents are preferred for obsessive-compulsive disorder. Other antidepressants, such as tricyclic antidepressants or monoamine oxidase inhibitors, are generally reserved as second- and third-line strategies due to tolerability issues. Evidence for other agents, including anticonvulsants and atypical antipsychotics, suggests that they may have an adjunctive role to antidepressants in cases of treatment resistance, while azapirones have been used effectively for generalized anxiety disorder, and a substantial body of evidence supports benzodiazepine use in panic disorder and generalized anxiety disorder. Despite notable advances, many patients with anxiety disorders fail to adequately respond to existing pharmacologic treatments. Increased research attention should be focused on systematizing pharmacologic and combined pharmacologic-psychosocial strategies to address treatment resistance and developing novel treatments for anxiety disorders.

Pharmacotherapy of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a prevalent psychiatric disorder that may result in significant social and occupational debilitation unless symptoms are recognized and treated appropriately. Considerable research effort has been devoted over the last 20 years to developing effective pharmacological treatments for this illness. At this time, the bulk of the agents investigated include antidepressants, anticonvulsants, atypical antipsychotics, benzodiazepines, and antiadrenergic agents. Herein, we review the existing evidence base for these different classes of psychotropics in PTSD. Emphasis is placed on discussion of evidence stemming from randomized placebo-controlled clinical trials wherever possible. A brief description of novel agents that have shown initial promise for PTSD treatment is also provided.

The relationship between testosterone and sexual function in depressed and healthy men.

AIM: Men with Major Depressive Disorder (MDD) report high rates of sexual dysfunction, as do healthy males with low levels of testosterone. The objective of this study is to evaluate the effects of depression and low testosterone across various domains of sexual function. METHODS: Untreated depressed males (N = 44) and age-matched healthy controls (N = 50) had blood samples drawn to determine morning levels of total testosterone (TT) and bioavailable testosterone (BT). In addition, questionnaires regarding depressive symptoms as well as sexual function were administered. MAIN OUTCOME MEASURES: Sexual function outcomes were measured using the Sex Effects (SexFX) Scale and depression severity was assessed with the Hamilton Rating Scale for Depression-17 item (HAMD-17). RESULTS: Using TT criteria, 27.9% of men were categorically defined as hypogonadal compared to 19.3% using BT criteria. Within both TT and BT hypogonadal groups, men with MDD had lower scores on all domains of sexual function compared to healthy controls with hypogonadism. Testosterone levels interacted with MDD status to affect orgasm and desire, although not arousal. Multiple linear regression analyses revealed that depression status was the main factor influencing sexual function. Hypogonadal status was not a predictor of sexual function in this sample, although age did play a minor role in the domain of arousal. CONCLUSION: While testosterone levels appear to influence sexual function, specifically orgasm, the presence of MDD appears to be a stronger factor and has high predictive value for sexual outcomes.

Levetiracetam in generalized social anxiety disorder: a double-blind, randomized controlled trial.

OBJECTIVE: This multicenter, double-blind, placebo-controlled, 2-arm, parallel-group study was carried out to determine the effectiveness and safety of the novel anticonvulsant levetiracetam for the treatment of generalized social anxiety disorder (GSAD). METHOD: After a 1-week, single-blind, placebo run-in period, 217 adult outpatients meeting DSM-IV criteria for social anxiety disorder, generalized type, were randomly assigned (1:1) to 12 weeks of double-blind treatment with either levetiracetam (n = 111) or placebo (n = 106). Participants were required to have scores of >or= 60 on the Liebowitz Social Anxiety Scale (LSAS) and a total score of or= 30% reduction in LSAS score) were similar with 41.3% (levetiracetam) and 46.6% (placebo). No significant between-group differences were found on secondary outcome measures, which included changes in Sheehan Disability Scale, Clinical Global Impression of Change, and HDRS scores. CONCLUSIONS: Although well-tolerated, levetiracetam failed to separate from placebo in this trial for the treatment of moderate to severe GSAD.

A randomized controlled trial of atomoxetine in generalized social anxiety disorder.

The current mainstays of social anxiety disorder pharmacotherapy are serotonergic agents, with less known about the efficacy of more noradrenergic drugs. Atomoxetine (ATM), a highly selective norepinephrine reuptake inhibitor, is currently approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). We describe the first controlled trial of ATM with respect to efficacy and tolerability in adults with the generalized subtype of social anxiety disorder (GSAD) without comorbid ADHD. Twenty-seven outpatients with clinically prevailing diagnoses of GSAD by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were randomized in a 1:1 ratio to 10 weeks of double-blind flexible-dose treatment with either ATM 40-100 mg per day (n = 14) or placebo (n = 13). Primary efficacy outcome was score at end point on the Liebowitz Social Anxiety Scale in the intention-to-treat sample. There were no significant group differences in patients completing the study (ATM, 79%; placebo, 77%). Whereas ATM was well tolerated, there were no significant differences in clinical efficacy between ATM and placebo for GSAD. There were few responders overall (ATM, 21%; placebo, 33%), but proportions were similar in each group (chi [1, 26] = 0.47; P = 0.67). Analysis of variance with repeated measures on the Liebowitz Social Anxiety Scale was performed to detect any differential change in social anxiety symptoms between groups. A significant time effect was found (F = 8.71; P = 0.007), but the time-by-treatment interaction was nonsignificant (F = 0.013; P = 0.91). Although the small sample size limits confidence in the reported results, the comparable, and low, response rates for ATM and placebo suggest that in the absence of comorbid ADHD, ATM is unlikely to be an effective agent for the treatment of GSAD.

Obsessive-compulsive spectrum disorders: a review of the evidence-based treatments.

OBJECTIVE: To provide a review of the evidence-based treatments for obsessive-compulsive spectrum disorders (OCSD), a group of conditions related to obsessive-compulsive disorder (OCD) by phenomenological and etiological similarities, the morbidity of which is increasingly recognized. METHOD: Literature relating to the following disorders: body dysmorphic disorder, hypochondriasis, trichotillomania, onychophagia, psychogenic excoriation, compulsive buying, kleptomania, and pathological gambling, and published between January 1965 and October 2007, was found using PubMed. Included in this review were 107 treatment reports. RESULTS: Serotonin reuptake inhibitors (SRIs) have shown benefits as first-line, short-term treatments for body dysmorphic disorder, hypochondriasis, onychophagia, and psychogenic excoriation, with some benefits in trichotillomania, pathological gambling, and compulsive buying. There are also suggested benefits for several atypical antipsychotics in disorders with a high degree of impulsivity, including trichotillomania and pathological gambling, and to a lesser extent, kleptomania and psychogenic excoriation. Cognitive-behavioural interventions have generally shown evidence for use as first-line treatment across the spectrum, with some variability in degree of benefit. CONCLUSIONS: As in OCD, several conditions in the proposed OCSD benefit from SRIs and (or) cognitive-behavioural interventions. However, the treatment literature is generally limited, and more randomized controlled trials (RCTs) are needed to evaluate individual and combination treatments, for short-term use and as maintenance.

Pharmacotherapy of PTSD: premises, principles, and priorities.

Post-traumatic stress disorder (PTSD) is a prevalent anxiety disorder that results in multiple disabling symptoms. Research into the underlying neurobiology has implicated dysregulation in multiple neurotransmitter systems including norepinephrine, serotonin, and glutamate as well as the hypothalamic-pituitary axis. Understanding how these biological systems interact with each other and how they may affect key neural structures, such as the amygdala, hippocampus, and prefrontal cortex, to produce post-traumatic symptoms is critical for the development of effective pharmacological treatments. We briefly discuss the proposed biological dysfunctions underlying PTSD and how agents that target these dysfunctions may be utilized in PTSD. We then provide a review of the different pharmacological agents that have been investigated in PTSD. These drugs include: antidepressants, anti-adrenergic agents, anticonvulsants, benzodiazepines, atypical antipsychotics, and novel agents.

Yoga in the treatment of mood and anxiety disorders: A review.

BACKGROUND: Patient use of complementary and alternative treatments, including yoga, to manage mood and anxiety disorders, has been well documented. Despite research interest, there are few recent reviews of the evidence of the benefit of yoga in these conditions. METHOD: The PubMed, Medline and PsycInfo databases were searched for literature published up to July 2008, relating to yoga and depressive and anxiety disorders. RESULTS: The paucity of reported studies and several methodological constraints limit data interpretation. In depressive disorders, yoga may be comparable to medication and the combination superior to medication alone. There is reasonable evidence for its use as second-line monotherapy or augmentation to medication in mild to moderate major depression and dysthymia, with early evidence of benefit in more severe depression. In anxiety disorders, yoga may be superior to medication for a subgroup of patients, but its benefits in specific conditions are still largely unknown. Second-line monotherapy is indicated in performance or test anxiety, but only preliminary evidence exists for obsessive-compulsive disorder and post-traumatic stress disorder. Yoga appears to be superior to no treatment and progressive relaxation for both depression and anxiety, and may benefit mood and anxiety symptoms associated with medical illness. It shows good safety and tolerability in short-term treatment. CONCLUSION: Reasonable evidence supports the benefit of yoga in specific depressive disorders. The evidence is still preliminary in anxiety disorders. Given its patient appeal and the promising findings thus far, further research on yoga in these conditions is encouraged.

Lamotrigine in the treatment of recurrent brief depression.

Recurrent brief depression is a well-recognized subtype of depressive illness with brief episodes of depression alternating with periods of euthymia. The symptoms are often severe, with frequent association to suicidal ideation. Literature suggests frequent nonresponse to first-line antidepressants. Lamotrigine is an anticonvulsant with antidepressant properties, and reported effectiveness in bipolar depression. We report on two patients with recurrent brief depression, nonresponsive to selective serotonin reuptake inhibitors and venlafaxine, and who responded to therapeutic doses of lamotrigine.