Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options.

Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.

Transcranial Photobiomodulation For The Management Of Depression: Current Perspectives.

Major depressive disorder (MDD) is a prevalent condition associated with high rates of disability, as well as suicidal ideation and behavior. Current treatments for MDD have significant limitations in efficacy and side effect burden. FDA-approved devices for MDD are burdensome (due to repeated in-office procedures) and are most suitable for severely ill subjects. There is a critical need for device-based treatments in MDD that are efficacious, well-tolerated, and easy to use. In this paper, we review a novel neuromodulation strategy, transcranial photobiomodulation (t-PBM) with near-infrared light (NIR). The scope of our review includes the known biological mechanisms of t-PBM, as well as its efficacy in animal models of depression and in patients with MDD. Theoretically, t-PBM penetrates into the cerebral cortex, stimulating the mitochondrial respiratory chain, and also significantly increases cerebral blood flow. Animal and human studies, using a variety of t-PBM settings and experimental models, suggest that t-PBM may have significant efficacy and good tolerability in MDD. In aggregate, these data support the need for large confirmatory studies for t-PBM as a novel, likely safe, and easy-to-administer antidepressant treatment.

Reported Side Effects, Weight and Blood Pressure, After Repeated Sessions of Transcranial Photobiomodulation.

Background: Transcranial photobiomodulation (t-PBM) consists in the delivery of near-infrared light (NIR) to the scalp, directed to cortical areas of the brain. NIR t-PBM recently emerged as a potential therapy for depression, although safety of repeated treatments has not been adequately explored. Objective: This study assessed incidence of side effects, including weight and blood pressure changes, during repeated sessions of NIR t-PBM using a light-emitting diode source. Methods: We performed a secondary analysis of a double-blind clinical trial on t-PBM for major depressive disorder. Eighteen individuals received NIR t-PBM (n = 9) or sham (n = 9) twice weekly for 8 weeks. Side effects were assessed using the Systematic Assessment for Treatment-Emergent Effects-Specific Inquiry. In 14 individuals (nNIR = 6 vs. nsham = 8), body weight and systemic blood pressure were recorded at baseline and end-point. Results: More subjects in the NIR t-PBM group experienced side effects compared to sham, but only a trend for statistical significance was observed (χ2 = 3.60; df = 1; p = 0.058). The rate of side effects described by participants as "severe" in intensity was low and similar between the treatment groups (χ2 = 0.4; df = 1; p = 0.53), with no serious adverse events. Most side effects resolved during the study and treatment interruption were not required. Changes in weight and systolic blood pressure across groups were neither significant nor approached significance. In the NIR t-PBM group, diastolic blood pressure increased and reached statistical-however not clinical-significance (5.67 ± 7.26 vs. -6.13 ± 6.88; z = -2.40, p = 0.016). Conclusions: This small-sample, exploratory study indicates repeated sessions of NIR t-PBM might be associated with treatment-emergent side effects. The systemic metabolic and hemodynamic profile of repeated t-PBM appeared benign. Future studies with larger samples and longer follow-up are needed to more accurately determine the side-effect profile and safety of NIR t-PBM.

Effects of transcranial photobiomodulation with near-infrared light on sexual dysfunction.

OBJECTIVES: Transcranial photobiomodulation (t-PBM) consists of the delivery of near-infrared (NIR) or red light to the scalp designed to penetrate to subjacent cortical areas of the brain. NIR t-PBM has recently emerged as a potential therapy for brain disorders. This study assessed the efficacy of repeated sessions of NIR t-PBM on sexual dysfunction. METHODS: We performed a secondary analysis of a double-blind clinical trial on t-PBM for major depressive disorder (MDD). Twenty individuals received NIR t-PBM (n = 9) or sham therapy (n = 11) twice a week for 8 weeks. Sexual desire, arousal, and orgasm were assessed using the Systematic Assessment for Treatment-Emergent Effects-Specific Inquiry (SAFTEE-SI). RESULTS: The mean improvement in sexual function (decrease in SAFTEE sex total score) in subjects receiving t-PBM in NIR-mode was significantly greater than in subjects receiving sham-mode in the whole sample (NIR [n = 9] -2.55 ± 1.88 vs. sham [n = 11] -0.45 ± 1.21; z = 2.548, P = 0.011]) and in the completers (NIR [n = 5] -3.4 ± 1.95 vs. sham [n = 7] -0.14 ± 1.21; z = 2.576, P = 0.010]). CONCLUSION: This exploratory study with a small sample size indicates that repeated sessions of NIR t-PBM may be associated with therapeutic effects on sexual dysfunction. The latter appeared unrelated to the antidepressant effect of t-PBM in our cohort. Lasers Surg. Med. 51:127-135, 2019. © 2018 Wiley Periodicals, Inc.

Transcranial Photobiomodulation for the Treatment of Major Depressive Disorder. The ELATED-2 Pilot Trial.

Objective: Our objective was to test the antidepressant effect of transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light in subjects suffering from major depressive disorder (MDD). Background: t-PBM with NIR light is a new treatment for MDD. NIR light is absorbed by mitochondria; it boosts cerebral metabolism, promotes neuroplasticity, and modulates endogenous opioids, while decreasing inflammation and oxidative stress. Materials and methods: We conducted a double-blind, sham-controlled study on the safety and efficacy [change in Hamilton Depression Rating Scale (HAM-D17) total score at end-point] of adjunct t-PBM NIR [823 nm; continuous wave (CW); 28.7 × 2 cm2; 36.2 mW/cm2; up to 65.2 J/cm2; 20-30 min/session], delivered to dorsolateral prefrontal cortex, bilaterally and simultaneously, twice a week, for 8 weeks, in subjects with MDD. Baseline observation carried forward (BOCF), last observation carried forward (LOCF), and completers analyses were performed. Results: The effect size for the antidepressant effect of t-PBM, based on change in HAM-D17 total score at end-point, was 0.90, 0.75, and 1.5 (Cohen's d), respectively for BOCF (n = 21), LOCF (n = 19), and completers (n = 13). Further, t-PBM was fairly well tolerated, with no serious adverse events. Conclusions: t-PBM with NIR light demonstrated antidepressant properties with a medium to large effect size in patients with MDD. Replication is warranted, especially in consideration of the small sample size.

Double-blind, proof-of-concept (POC) trial of Low-Field Magnetic Stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD).

BACKGROUND: Low-Field Magnetic Stimulation (LFMS) is a novel, non-invasive, sub-threshold neuromodulation technique, shown in preliminary studies to have immediate mood elevating effects in both unipolar and bipolar depressed patients. OBJECTIVE: We aimed to assess the antidepressant augmentation effects at 48 h of LFMS administered on two consecutive days compared to sham treatment in treatment resistant depression (TRD) subjects, using the Sequential Parallel Comparison Design (SPCD). METHODS: Eighty-four eligible subjects with TRD were randomly assigned to double-blind treatment with LFMS 20 min/day for four days, sham treatment 20 min/day for four days, or sham treatment 20 min/day for 2 days followed by LFMS treatment 20 min/day for two days, using the pre-randomization version of the SPCD (randomization 1:1:1). The SPCD analyses used a repeated measures linear modeling approach with maximum likelihood estimation to use all available data, and using a 60-40 weighting of Stage 1 vs. 2 responses, with the primary outcome being measured after 2 and 4 days. RESULTS: Both primary and secondary outcome measures consistently showed no differences between LFMS-treated patients and those treated with sham, with the exception of a slight, non-significantly greater improvement than sham in the visual analogue scale (VAS) sad mood on LFMS-treated patients. LFMS treatment was relatively well tolerated. CONCLUSIONS: We did not observe a significantly greater, rapid efficacy of LFMS compared to sham therapy. Future studies need to examine the possible therapeutic effects of more intensive forms of LFMS, as other forms of neurostimulation typically require longer duration of exposure.

Tissue Type-Specific Bioenergetic Abnormalities in Adults with Major Depression.

Brain bioenergetic abnormalities have been observed frequently in adults with major depressive disorder (MDD); however, results have been inconsistent regarding whether decreased or increased metabolism was observed. Phosphorus-31 magnetic resonance spectroscopy (31P MRS) allows for the quantification of bioenergetic molecules, containing high-energy phosphates, over the whole brain as well as measuring the differences between gray matter and white matter. We recruited 50 subjects with a current diagnosis of MDD, not currently treated with psychotropic medication, between ages of 18 and 65 (mean±SD age: 43.4±13.6; 46% female) and 30 healthy volunteers, matched for age and gender (39.0±12.5 years of age; 36.6% female). All subjects received a T1 MP-FLASH scan for tissue segmentation followed by 31P MRS, chemical shift imaging scan with 84 voxels of data collected over the entire brain utilizing a dual-tuned, proton-phosphorus coil to minimize subject movement. Phosphocreatine and inorganic phosphate (Pi) varied in opposite directions across gray matter and white matter when MDD subjects were compared with controls. This finding suggests alterations in high-energy phosphate metabolism and regulation of oxidative phosphorylation in MDD patients. In addition, within the MDD group, gray matter Pi, a regulator of oxidative phosphorylation, correlated positively with severity of depression. These data support a model that includes changes in brain bioenergetic function in subjects with major depression.

Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis.

We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD). While still experimental, preliminary data on the use of PBM for brain disorders are promising. PBM is low-cost with potential for wide dissemination; further research on PBM is sorely needed. We found clinical and preclinical studies via PubMed search (2015), using the following keywords: "near-infrared radiation," "NIR," "low-level light therapy," "low-level laser therapy," or "LLLT" plus "depression." We chose clinically focused studies and excluded studies involving near-infrared spectroscopy. In addition, we used PubMed to find articles that examine the link between PBM and relevant biological processes including metabolism, inflammation, oxidative stress, and neurogenesis. Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating MDD, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury. Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD.

Diagnosis and treatment of major depressive disorder.

Major depressive disorder is a common illness, particularly in patients with medical and neurologic conditions. This article summarizes current data on the epidemiology, diagnosis, and treatment of major depression, with special emphasis on the diagnosis and treatment of depression in medical and neurologic patients. We reviewed the role of pharmacotherapies, psychotherapies, somatic treatments, and alternative remedies and we included practical advice for clinician regarding the timing and sequence of these treatments, the role of standardized depression scales, and the criteria for referrals to specialty consultants.

Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder.

BACKGROUND: Low cerebral bioenergetic metabolism has been reported in subjects with major depressive disorder (MDD). Thyroid hormones have been shown to increase brain bioenergetic metabolism. We assessed whether changes in brain bioenergetics measured with phosphorus magnetic resonance spectroscopy ((31)P MRS) correlate with treatment outcome during augmentation treatment with triiodothyronine (T3) in MDD. METHODS: Nineteen subjects meeting DSM-IV criteria for MDD who had previously failed to respond to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs received open label and prospective augmentation treatment with T3 for 4 weeks. We obtained (31)P MRS spectra before and after treatment from all MDD subjects and baseline (31)P MRS from nine normal control subjects matched for age and gender. RESULTS: At baseline, depressed subjects had lower intracellular Mg(2+) compared with control subjects. Seven MDD subjects (38.9%) were treatment responders (>or= 50% improvement). Total nucleoside triphosphate (NTP), which primarily represents adenosine triphosphate (ATP), increased significantly in MDD subjects responding to T3 augmentation compared with treatment nonresponders. Phosphocreatine, which has a buffer role for ATP, decreased in treatment responders compared with nonresponders. CONCLUSIONS: The antidepressant effect of thyroid hormone (T3) augmentation of SSRIs is correlated with significant changes in the brain bioenergetic metabolism. This seems to be a re-normalization of brain bioenergetics in treatment responders. Further studies will determine whether these findings can be generalized to other antidepressant treatments.

31P-magnetic resonance spectroscopy and thyroid hormones in major depressive disorder: toward a bioenergetic mechanism in depression?

In this paper we review studies of brain cellular high-energy phosphate metabolism, as measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS), in subjects with major depressive disorder (MDD). We also review the literature on the role of thyroid hormones on the cellular high-energy phosphate metabolism in multiple organs. Finally, we review data on the efficacy of thyroid hormones as adjuvant treatment in MDD. The framework established by these findings enables us to hypothesize that dysfunction of brain cellular energy metabolism is a vulnerability factor for MDD, and that correcting cellular energy metabolism (e.g., with thyroid hormones) is a valid therapeutic strategy for improving the symptoms of MDD. We discuss our hypothesis in the context of other current theories on the mechanism of thyroid hormones in MDD.