Lakshmi N. Ravindran

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 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.

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 Hedges 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 Hedges 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.

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.

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, Cohens d=0.91) and increased ICF (p<0.009, Cohens 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 GABAB receptor-mediated and NMDA receptor-mediated neurotransmission. These findings are consistent with previously published genetic studies implicating GABAB, 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.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder Section 5. Complementary and Alternative Medicine Treatments

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Complementary and Alternative Medicine Treatments” is the fifth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 12 questions for 2 broad categories of complementary and alternative medicine (CAM) interventions: 1) physical and meditative treatments (light therapy, sleep deprivation, exercise, yoga, and acupuncture) and 2) natural health products (St. John’s wort, omega-3 fatty acids; S-adenosyl-L-methionine [SAM-e], dehydroepiandrosterone, folate, Crocus sativus, and others). Recommendations were based on available data on efficacy, tolerability, and safety. Conclusions: For MDD of mild to moderate severity, exercise, light therapy, St. John’s wort, omega-3 fatty acids, SAM-e, and yoga are recommended as first- or second-line treatments. Adjunctive exercise and adjunctive St. John’s wort are second-line recommendations for moderate to severe MDD. Other physical treatments and natural health products have less evidence but may be considered as third-line treatments. CAM treatments are generally well tolerated. Caveats include methodological limitations of studies and paucity of data on long-term outcomes and drug interactions.

Pregabalin Influences Insula and Amygdala Activation During Anticipation of Emotional Images

Pregabalin (PGB) has shown potential as an anxiolytic for treatment of generalized and social anxiety disorder. PGB binds to voltage-dependent calcium channels, leading to upregulation of GABA inhibitory activity and reduction in the release of various neurotransmitters. Previous functional magnetic resonance imaging (fMRI) studies indicate that selective serotonin reuptake inhibitors and benzodiazepines attenuate amygdala, insula, and medial prefrontal cortex activation during anticipation and emotional processing in healthy controls. The aim of this study was to examine whether acute PGB administration would attenuate activation in these regions during emotional anticipation. In this double-blind, placebo-controlled, randomized crossover study, 16 healthy controls completed a paradigm involving anticipation of negative and positive affective images during fMRI approximately 1 h after administration of placebo, 50, or 200 mg PGB. Linear mixed model analysis revealed that PGB was associated with (1) decreases in left amygdala and anterior insula activation and (2) increases in anterior cingulate (ACC) activation, during anticipation of positive and negative stimuli. There was also a region of the anterior amygdala in which PGB dose was associated with increased activation during anticipation of negative and decreased activation during anticipation of positive stimuli. Attenuation of amygdala and insula activation during anticipatory or emotional processing may represent a common regional brain mechanism for anxiolytics across drug classes. PGB induced increases in ACC activation could be a unique effect related to top–down modulation of affective processing. These results provide further support for the viability of using pharmaco-fMRI to determine the anxiolytic potential of pharmacologic agents.

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.

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 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.