Safety behaviors are coping tactics by persons with anxiety disorders, especially panic disorder, agoraphobia, and social anxiety disorder, to temporarily diminish feelings of threat and reduce one's anxiety level. Safety behaviors can emerge in response to an external (e.g., situations, persons, activities) or internal (e.g., thoughts, emotions, memories) focus of perceived threat and are anticipatory (avoidant) or consequential (escape) [1].

Safety signals are the people or objects used by patients with anxiety disorders to diminish distress in situations that elicit anxiety. Safety signals maintain anxiety over time by preventing direct confrontation of feared stimuli in the absence of "safe" objects/people and by maintaining perceptions of risk/harm and coping inability. Patient use of safety signals can interfere with therapy progress, especially exposure therapy, and are considered anti-therapeutic. However, safety behaviors may be helpful early in treatment by making exposure therapy more tolerable and less threatening [1].

Safety signals are the people or objects used by patients with anxiety disorders to diminish distress in situations that elicit anxiety. Safety signals maintain anxiety over time by preventing direct confrontation of feared stimuli in the absence of "safe" objects/people and by maintaining perceptions of risk/harm and coping inability. Patient use of safety signals can interfere with therapy progress, especially exposure therapy, and are considered anti-therapeutic. However, safety behaviors may be helpful early in treatment by making exposure therapy more tolerable and less threatening [1].

The distinguishing features of specific anxiety disorders are summarized in the following section. Related conditions of post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) are included because, although no longer classed as anxiety disorders by the 2013 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), they are often included in research that pre-dates 2013 and can co-occur with anxiety disorders [2]. Situations or objects that evoke intense anxiety in patients with agoraphobia, social anxiety disorder, or specific phobia are either avoided or endured with significant personal distress.

Each year in the United States, anxiety disorders (DSM-5 plus PTSD and OCD) impact approximately 42 million adults, or 19% of the population [4,5]. The pattern of sex distribution is consistent among anxiety disorders, and the overall female-to-male ratio is approximately 2:1 across all age ranges [6].

Anxiety disorders with earlier median age of onset are phobias and separation anxiety disorder (15 to 17 years of age), and those with latest age of onset are panic disorder and generalized anxiety disorder (23 to 30 years of age). Lifetime morbid risk is considerably higher than lifetime prevalence for most anxiety disorders, with magnitude of difference much higher for disorders with later than earlier age of onset. Also, the ratio of 12-month to lifetime prevalence roughly reflects persistence, but varies meaningfully in ways consistent with differential persistence of these disorders [7].

The odds for a lifetime diagnosis of any anxiety disorder were calculated, and the same pattern was found for past 12 month diagnosis [8]. These odds are organized according to sex, socioeconomic status, education level, and age. Overall, the risk of developing an anxiety disorder is greater for women/girls than men/boys.

Anxiety symptoms often co-occur with other psychologic symptoms. Depressive symptoms are highly prevalent with more severe anxiety symptoms, with anxiety and depressive symptom severity strongly correlated. Patients with anxiety disorder have high comorbidity rates of major depressive disorder (almost 50%), schizophrenia, substance use disorders, and physical illness [3,11]. Overlapping symptoms of anxiety and depression, such as sleep disturbance, fatigue, and difficulty concentrating, make differentiation challenging. Depressive disorders are sometimes termed "anxious-misery" when high levels of sadness and anhedonia are present [2].

In the United States, 4% to 28% of the population experience panic attacks at some time during their life. The 2.4% annual incidence of panic disorder in the United States is one of the highest prevalence rates worldwide [7,18].

Childhood presence of fearfulness and behavioral inhibition can lead to chronic, disabling SAD. Early recognition of childhood impairments and evidence-based treatment intervention may offset the SAD trajectory of persisting into and through adulthood. Educational-behavioral interventions involving older children/adolescents, parents, school staff, and healthcare providers have been found to reduce the development of social anxiety [51,52,53].

In one study, children with SEPAD were 3.5 times more likely to later develop panic disorder and more than twice as likely to develop any anxiety disorder but did not significantly differ in later development of depression or substance use disorder. These findings were considered supportive of a developmental psychopathology model of anxiety disorders [65].

Altered limbic and prefrontal cortex functioning characterize anxiety disorders, with amygdala hyper-responsivity to threatening stimuli and impaired ventromedial prefrontal contex inhibitory control over limbic-generated, anxiety-inducing signals, associated with aberrant communication and functional connectivity between the amygdala and the prefrontal cortex [67].

Neurotransmitters allow communication between brain regions. Alterations in neurotransmitter systems implicated in anxiety disorder pathogenesis include the monoamines serotonin (5-hydroxytryptamine or 5-HT), norepinephrine, and dopamine. Aberrant limbic signaling is associated with decreased inhibitory signaling by gamma-amino-butyric acid (GABA) or increased excitatory neurotransmission by glutamate. Many other neurotransmitter systems participate in the modulation of fear and anxiety, including the neuropeptide substances P, N, and Y; corticotropin-releasing factor (CRF); and endocannabinoids. Abnormalities in these systems are associated with structural and functional alterations in specific brain areas, such as the amygdala, prefrontal cortex, locus coeruleus, and hippocampus, and represent the therapeutic targets of drug therapy [70].

Patients with panic disorder/agoraphobia have shown subclinical abnormalities in balance system function that seemed to influence agoraphobia severity and contribute to dizziness and disorientation symptoms in complex sensory environments (e.g., shopping malls, traffic, crowds). These patients also display greater balance control reliance on non-vestibular, proprioceptive, visually dependent cues and greater balance system reactivity to peripheral visual stimulation. These possibly link to a more active visual alarm system involving visual, vestibular, and limbic areas. Patients with panic disorder/agoraphobia also show high sensitivity to light or brightness stimuli with photophobic behavior and abnormal retinal and pupillary reflex responses possibly linked to serotonergic and/or dopaminergic dysfunction. This overall amplified sensitivity to environmental stimuli suggests that agoraphobia involves activation of complex systems beyond panic attack fear and behavioral avoidance, including emotional responses to destabilizing/distressing environmental stimuli and operant-learning avoidance of experiences that provoke this distress [86].

Amygdala, anterior cingulate cortex, and insula hyperactivity is believed to be the underlying pathophysiology of specific phobia. Neuroimaging studies have shown increased amygdala activation with exposure to phobic-relevant cues, and heightened activity in thalamic, insula, and dorsal anterior cingulate cortex regions [93,94,95]. Meta-analyses suggest the left amygdala/globus pallidus, left insula, right thalamus, and cerebellum regions are all more active among patients with a phobia compared with controls when exposed to phobic-relevant stimuli. Acute, exaggerated parasympathetic nervous system activity with exposure to stimuli is thought to underlie the vasovagal syncope experienced by up to 80% of people with blood-injection-injury phobia [96]. Exposure-based therapy leads to deactivation in the right frontal cortex, limbic cortex, basal ganglia, and cerebellum, and increased activity in the thalamus [97].

With agoraphobia, specific phobia, and SAD, the requirement that patients recognize their anxiety as excessive or unreasonable has been eliminated. This change was based on evidence that individuals with such disorders often overestimated the danger in "phobic" situations and that older individuals often misattributed "phobic" fears to aging. Instead, the anxiety must be out of proportion to the actual situational danger or threat, with consideration of cultural contextual factors [102].

The DSM-5 (and previous DSM editions) has been criticized for emphasis on reliability at the expense of diagnostic validity and for use of symptom-based diagnosis when symptoms alone may not best inform treatment selection. In response, the National Institute of Mental Health is developing the Research Domain Criteria, a new taxonomy for mental disorders that draws from genetics, neuroscience, and behavioral science [103]. Additionally, the DSM-5-TR, which was released in March 2022, includes the addition of prolonged grief disorder; the inclusion of symptom codes for suicidal behavior and nonsuicidal self-injury; refinement of criteria; and comprehensive literature-based updates to the text [104].

GAD is characterized by excessive and inappropriate worrying that is persistent and not restricted to particular circumstances. Patients have physical anxiety symptoms and key psychologic symptoms. GAD is often comorbid with major depressive disorder, panic disorder, phobia, health anxiety, and OCD [3]. The DSM-5 diagnostic criteria for GAD remain unchanged from previous editions [2,102]:

Agoraphobia is defined as the fear of panic attacks occurring in places or situations from which escape might be difficult or embarrassing or where help may not be available. These situations can include crowds, going outside the home, or using public transportation and are either avoided or endured with significant personal distress [3]. Agoraphobia can become severely disabling, and more than 33% of patients diagnosed with agoraphobia cannot endure leaving their home environment. Roughly 66% of patients with panic disorder develop agoraphobia [2].

Patients with SAD highly inflate perceived social costs from committing hypothetical blunders. Accounting for much of this social cost inflation are concerns about revealing self-flaws and, in particular, concerns over appearing socially incompetent [117].

SEPAD is characterized by fear or anxiety concerning separation from those to whom an individual is attached. Common features include excessive distress when experiencing or anticipating separation from home, and persistent and excessive worries about potential harms to attachment figures or untoward events that might result in separation [3].

In primary care settings, panic disorder prevalence is around 10%, with GAD co-occurring in 68% of patients with panic disorder and in 38.6% of those with major depression [34,122]. The American Academy of Family Physicians states that rates of missed diagnoses and misdiagnosis of GAD and panic disorder are high in primary care, with symptoms often ascribed to physical causes [121]. One study of older patients with GAD found low rates of anxiety symptom recording (34%) and anxiety disorder diagnosis (9%) despite high levels of healthcare utilization [123]. In the current managed care environment, anxiety is usually treated in the primary care setting, and given the increasing time constraints imposed on primary care providers, it is not surprising that anxiety disorders are under-recognized and undertreated [70].

Many patients with anxiety and depressive symptoms do not seek help, and in those who do, anxiety symptoms are often not the presenting complaint. Patients and providers often have difficulty initiating discussion of emotional problems and distress. Primary care providers with greater sensitivity to nonverbal communications have been found more likely to detect and diagnose anxiety, while those tending to "blame" patients make fewer psychologic inquiries and are less accurate in detecting distress [3,124].

A diagnosis of SAD should rule out avoidant personality disorder. Some symptoms of avoidant personality disorder resemble SAD, such as a pervasive pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation. However, avoidant personality disorder is distinguished by non-social avoidance that extends to novel situations and positive affect. Roughly 36% of patients with SAD are comorbid for avoidant personality disorder, and some believe avoidant personality disorder is a more severe variant of SAD [130,131].

It is important to rule out medication side effects as the underlying cause of anxiety by obtaining a complete list of currently used prescribed, over-the-counter, and herbal medications. Examples of common medications with anxiety side effects are asthma medications (e.g., albuterol, theophylline), herbal medicines (St. John's wort, ginseng, ma huang), corticosteroids, and antidepressants [2].

Advances in anxiety disorder neuroscience have increasingly pointed to the necessary role of fear extinction learning (through exposure therapy) in addressing underlying pathophysiology. While efficacy is shown with CBT and exposure, patients can have difficulty with the demanding and exhausting therapy process, and many who do manage to complete therapy respond partially and relapse with time. Efforts to improve CBT/exposure outcomes have led to the investigation of augmenting agents. In contrast to standard anti-anxiety drugs, these agents are not anxiolytic but are used to promote and accelerate long-term adaptive changes in brain function initiated by successful exposures [137].

Pathologic SEPAD is associated with a pervasive negative influence on treatment response. Comorbid SEPAD is highly correlated with poor treatment response and patient outcomes across a range of anxiety and mood disorders. SEPAD negatively impacts response to major depression treatment and is linked to worse symptom chronicity and quality of life. SEPAD decreases CBT response and predicts worse outcomes in patients treated for panic disorder, GAD, or SAD. SEPAD also predicts nonresponse to selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) in patients with panic disorder with agoraphobia [98,140].

Psychotherapy and drug therapy show similar efficacy in most anxiety disorders. Psychotherapy plus drug (combination) therapy outcomes vary and are conflicting, and current evidence does not support routine combination therapy as initial treatment. However, patients lacking response to CBT or drug therapy may benefit from adding the other modality [120].

Antidepressants are generally recommended as first-line therapy for panic disorder because, unlike benzodiazepines, antidepressants treat comorbid depression and lack abuse risk and potential side effects of excessive sedation, cognitive impairment, and ataxia. All major antidepressant classes are comparably effective, but SSRIs and, increasingly, serotonin-norepinephrine reuptake inhibitors (SNRIs) are recommended over TCAs and MAOIs due to better safety and tolerability [172].

It is now recognized that SSRIs differ in pharmacologic effect, including activity beyond SERT inhibition [179,180]:

Meta-analyses suggest alprazolam, lorazepam, and diazepam are effective but comparable in GAD efficacy, while clonazepam shows much greater efficacy in the treatment of panic disorder than alprazolam, lorazepam, and diazepam, which all have modest efficacy [224].

Benzodiazepine treatment of anxiety disorders is controversial. While effective in rapid anxiety reduction, the potential drawbacks with long-term use are substantial. These agents are indicated when potent, short-term anxiolytic effects are necessary to permit infrequent exposure to feared stimuli and potentially severe anxiety, such as airplane travel [121,129,136]. Clonazepam, lorazepam, and alprazolam are effective for short-term use in panic disorder, GAD, and SAD, but ineffective for, and potentially worsening, comorbid depression [28]. The rapid anxiolytic effects make benzodiazepines highly appealing to patients with anxiety, but aside from this specific context, benzodiazepine prescribing for as-needed use is discouraged [136,225,226]. Benzodiazepines can reinforce pill taking, serve as a safety signal that undermines self-efficacy, and become incorporated into conditioned fear responses; these concerns are heightened with as-needed use. On-demand dosing links pill taking to rapid anxiety reduction, powerfully reinforcing avoidance in anxiety-provoking situations and encouraging longer-term reliance on the drug. This iatrogenic effect also contributes to poor CBT response.

The current recommended prescribing is for time-dependent use, instead of panic response-dependent use, to minimize the risks [121]. This would also seem to maximize risk of withdrawal syndrome from uninterrupted versus intermittent drug exposure.

Benzodiazepines are also useful in the initial weeks of SSRI/SNRI initiation, to rapidly reduce anxiety and possible early anxiogenic medication side effects before the onset of SSRI/SNRI anxiolytic effects [121,129,136]. However, patients may discontinue the antidepressant when co-prescribed a rapidly effective benzodiazepine, believing the benzodiazepine's symptom relief makes the SSRI/SNRI unneeded. Supportive therapy with regular visits or phone contacts may also help patients remain adherent until the delayed onset of antidepressant benefits appears or early antidepressant side effects lessen [227].

Another indication for benzodiazepine use is for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress. Perhaps the greatest prescribing challenge with benzodiazepines is preventing short-term use from insidiously developing into long-term use. Patients with the most severe anxiety may obtain the greatest relief and become most hesitant to discontinue use [228]. In many cases, clinicians ignore the recommended two- to four-week prescribing limit, mainly because alternative options with superior anxiolytic effects are not available [229]. Clinicians intending to prescribe alprazolam should carefully consider the likelihood that its use will remain restricted to the very short term—a few days to a couple weeks—to see the patient through a crisis [228].

A 2015 meta-analysis found SSRI withdrawal symptoms can occur with any SSRI but are exceedingly more frequent with paroxetine [248]. Common symptoms include dizziness, nausea, headache, confusion, low energy, weakness, sleep disturbance, flu-like symptoms, restlessness, agitation, anxiety, panic, anger, and irritability. Less common and more severe symptoms include electric-shock sensations, vertigo, paresthesias, intensified suicidal ideation, aggression, derealization, depersonalization, and visual/auditory hallucinations. Symptoms do not greatly differ between patients with anxiety versus mood disorders. The authors concluded that the typical SSRI withdrawal syndrome begins within a few days of cessation and lasts two to three weeks [248]. Variations include late onset and protracted duration up to one-year follow-up. Several cases of persistent postwithdrawal disorders induced by paroxetine have been described.

Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [248]. Patient characteristics that predict increased vulnerability are not known. Recognition of withdrawal symptoms requires careful exploration, as they can be misidentified as signs of impending relapse. Even when withdrawal symptoms are recognized, clinical management is hindered by the lack of research.

SSRI cessation may trigger complex phenomena related or unrelated to the onset of withdrawal, such as hypomania, mania, and persistent postwithdrawal disorders. Iatrogenic comorbidity describes the lasting effects from treatment well beyond their time of administration, such as mood instability and high reactivity to environmental stimuli in persistent postwithdrawal disorders [248].

Among 20 patients with remitted panic disorder with agoraphobia followed over one year after SSRI cessation, nine experienced SSRI withdrawal syndrome that subsided within one month [249]. Exceptions were three patients taking paroxetine, who experienced worsened mood, fatigue, and emotional lability with trouble sleeping, irritability, and hyperactivity. One patient prescribed clonazepam after three months of symptom persistence improved considerably but was later unable to discontinue clonazepam. A second patient did not improve with clonazepam or fluvoxamine, and symptoms subsided only with paroxetine reinstatement. In a third patient, clonazepam had little benefit, paroxetine reinstatement was refused, and symptoms persisted unchanged over one year [249].

In some patients with anxiety disorder, and especially those with depressive comorbidity, consideration of overdose fatality is necessary when deciding on therapy options. Lethality rates from intentional overdose involving single medication ingestions of agents commonly prescribed for depression and anxiety were calculated from data obtained during the period 2000–2014 [252]. TCAs remain the most lethal antidepressants, with fatality rates from 31–142 per 10,000 ingestions. Amitriptyline is associated with the greatest lethality in overdose and alone accounted for 37% of all deaths from antidepressants [252]. Lithium, bupropion, venlafaxine, quetiapine, and valproic acid had rates of 6.9–12.0 per 10,000 ingestions, while citalopram and fluvoxamine had rates of 3.9–4.1 per 10,000. Fluoxetine, sertraline, paroxetine, and escitalopram had the lowest overdose lethality rates at 0.79–1.34 per 10,000 ingestions [252].

Several options as second-line agents have efficacy in GAD comparable to first-line agents but possess potential side effects or other risks that preclude first-line use [120]. Benzodiazepines would be considered first in most cases, except where there is a risk of substance abuse, while bupropion XL would likely be reserved for later. Quetiapine XR remains a good choice in terms of efficacy, but given the metabolic concerns associated with this atypical antipsychotic, it should be reserved for patients who lack response or cannot tolerate antidepressants or benzodiazepines [120]. It is important to note that drugs such as beta-blockers (e.g., propranolol) prescribed to address the physical symptoms of anxiety are ineffective in the treatment of GAD [243].

The first-line drugs recommended for the treatment of panic disorder are SSRIs or venlafaxine XR [120]. Research suggests that the largest effect size is found with clonazepam, followed by venlafaxine and fluoxetine [224]. Despite a sizeable number of pharmacologic options, less than 50% of patients with panic disorder experience full and sustained remission to first-line medication therapy [287].

CBT is the criterion-standard psychologic treatment for SAD. Cognitive techniques that address SAD include restructuring and challenging maladaptive thoughts, and the behavioral component typically involves exposure therapy. The efficacy of CBT is supported by many randomized controlled trials, with outcomes that vary but are typically similar to pharmacotherapy. Some reports suggest that, after treatment discontinuation, gains achieved with CBT may persist longer than those achieved with pharmacotherapy. CBT for SAD can be administered in group or individual formats. Although some studies have reported that individual CBT is superior to group CBT, meta-analyses have failed to find significant differences in efficacy between the two modalities. There is evidence to support the effectiveness of exposure therapy alone, but efficacy compared with CBT is equivocal [120].

Exposure-based therapies are the treatments of choice and show a high degree of successful remission for all phobias. In vivo exposure and virtual reality exposure can be effective, with in vivo exposure superior to imaginal and virtual reality exposure at post-treatment but not at follow-up [307]. The effectiveness of exposure-based therapy is enhanced when exposure sessions are grouped closely together; when exposure is prolonged, real (not imagined), and provided in different settings; and when there is some degree of therapist involvement instead of being entirely self-directed. A greater number of sessions have been shown to predict more favorable outcomes. There is no evidence that flooding is more effective, and patients usually find graded, progressive exposures more tolerable [307].

A variety of psychotherapeutic options have been found effective for the treatment of specific phobias, with some approaches recommended for particular phobias (Table 4) [120]. For blood-injection-injury phobias, an effective approach is combining exposure therapy with muscle tension exercises (applied tension) designed to prevent fainting. Using stress-reducing medical devices, such as decorated butterfly needles and syringes, has significantly reduced needle phobia and stress in pediatric and adult patients. With dental phobias, use of CBT can reduce avoidance of oral injections and decrease patient anxiety [120,307].

Long-term treatment of specific phobia is rare. CBT and exposure therapies show sustained benefits at long-term follow-up assessments following a time-limited course of treatment [120].

Pharmacotherapy has a minimal role in specific phobia treatment, largely from the lack of drug therapy research and the success of exposure therapies. Alprazolam benefit was studied in 28 women with flying phobia during two air travel exposures, one week apart. Compared with subjects given pre-flight placebo for both flights, those receiving alprazolam before the first flight had less anxiety and symptoms but greater heart and respiratory rates. Those given alprazolam had a substantial increase in panic attacks during the second flight compared with the first flight (71% vs. 7%), greater overall anxiety, and further elevation in heart rate. Alprazolam increased physiologic activation under acute stress conditions and hindered the therapeutic effects of exposure therapy for flying phobia [120,308]. These findings require replication to determine clinical utility.

The unmet need for SEPAD-specific treatment has led to psychotherapies that focus on relationships and separation anxiety. These approaches use the therapist-patient relationship to recapture and better understand important elements of earlier pathologic parent-child relationships. Panic-focused psychodynamic psychotherapy is an affect-focused therapy that specifically targets separation anxiety as a core component of panic disorder. Preliminary efficacy is shown in patients with prominent separation anxiety symptoms across different anxiety and mood disorders. High separation anxiety levels constitute a central organizing element in patient self-perception as incompetent and unable to manage developmentally normative tasks without the presence of their central attachment figures. Panic-focused psychodynamic psychotherapy emphasizes free association, centrality of transference, unconscious thoughts that underlie physical sensations of panic, and difficulty with separation and autonomy. The therapist focuses on these processes as they relate to panic symptoms. Common themes of difficulty with separations and unconscious rage inform interpretive interventions. The pre-determined 24-session, 12-week time limit enhances the opportunity to work with separation anxiety and permits the re-experiencing and better understanding [98].

Dosing and dose timing of DCS is essential. Most trials reporting positive results used low-dose DCS (50–250 mg) one to two hours before three to five exposure sessions. Studies with negative results often used higher doses (≥250 mg), chronically (before 12 exposures), and more than one to two hours before an exposure. Higher-dose DCS shows weaker NMDA partial agonist or antagonist effects. Key extinction learning processes occur hours following exposure, and DCS blood concentration peaking at four to six hours makes it more effective taken within one to two hours before exposure for peak activity to coincide with key extinction processes. Repeated DCS use can desensitize the NMDA receptor complex, leading DCS to effectively work as an NMDA antagonist. Long-term antidepressants can induce neurochemical changes at the glycine binding site of the NMDA receptor complex, which alters the action of DCS. Therefore, use of DCS should consider the narrow therapeutic window and the need to be administered without concomitant medication, acutely, and at low doses one to two hours pre-exposure [310].

DCS is associated with serious risks. DCS not only enhances cognitive processes during fear extinction learning but also during fear memory reconsolidation, thus improving good exposures and worsening bad exposures. If fear-inducing stimulus re-exposure during fear memory reactivation is too brief relative to the strength of fear conditioning or if fear decrease during exposure is inadequate, little extinction is induced and DCS can augment the process of fear memory reconsolidation to worsen symptoms [310].

Several randomized controlled trials have been conducted using placebo or active controls. In 21 patients with panic disorder with or without agoraphobia given inositol 12 g/day or placebo for four weeks, significant decreases were found in the frequency and severity of panic attacks and agoraphobia severity with inositol relative to placebo [335]. Another randomized controlled trial compared myo-inositol 18 g/day with fluvoxamine 150 mg/day in patients with panic disorder with or without agoraphobia. Both drugs led to significant but comparable improvements in anxiety symptoms/severity, agoraphobia symptoms/severity, and global impression. In the first month, reduction in the number of panic attacks per week was significantly greater with inositol than fluvoxamine (4.0 vs. 2.4). Nausea and fatigue were significantly more common with fluvoxamine [336].

Other randomized controlled trials found that myo-inositol 12 g/day in 28 patients with major depression significantly reduced Hamilton Depression Rating Scale scores (vs. placebo) after four weeks; and 18 g/day given to patients with OCD for six weeks led to significant reductions in OCD symptom scores (vs. placebo) [335]. A review of supplements and herbal therapies with purported anxiolytic efficacy concluded myo-inositol was one of very few with demonstrated effectiveness [337]. The published research needs larger trials but is intriguing in light of a study in which patients with severe depression receiving treatment with rTMS showed significantly elevated prefrontal cortex myo-inositol levels, and this elevation correlated with extent of clinical improvement [338]. A meta-analysis of inositol for depression and anxiety disorders found that the agent may be particularly beneficial for treatment of depression [339].

Yoga is an ancient mind/body practice that involves different techniques in physical postures, controlled breathing, deep relaxation, and meditation that have positive and specific influences. Research on yoga has demonstrated significant improvements in emotional self-regulation with consequent reductions in depression, stress, and anxiety levels and improvements in mood, quality of life, and well-being [346]. Several studies have found significant anxiolytic effects with yoga in patients with GAD or panic disorder, and it is considered the complementary therapy with strongest evidence of safety and efficacy in anxiety disorders.