Daniella David, M.D.
Jonathan R.T. Davidson, M.D.
Over the past two decades, there has been substantial progress in the treatment of anxiety and related disorders. In this chapter, we review the main findings from double-blind and some open-label trials in each disorder.
Treatment outcome in panic disorder can be measured with the Panic Disorder Severity Scale (PDSS), which can be administered both as a clinician-rated and as a self-rated scale (Shear et al. 1997). Other widely used measures include the Sheehan Panic and Anticipatory Anxiety Scale (PAAS; Sheehan 1986) and the self-rated Marks-Mathews Fear Questionnaire (FQ; Marks and Mathews 1979). Although not always attainable, the desired endpoint is full remission. Effective treatment results in reduced emergency department and laboratory resource utilization (Roy-Byrne et al. 2001).
In 1995, Boyer reported that selective serotonin reuptake inhibitor (SSRI) drugs were more effective than imipramine and alprazolam in treating panic disorder, although a meta-analysis by Otto et al. (2001) failed to confirm these findings. Evidence is now available in support of citalopram (Wade et al. 1997), escitalopram (Stahl et al. 2003), fluoxetine (Michelson et al. 1998, 2001), fluvoxamine (Asnis et al. 2001; Black et al. 1993), paroxetine (Ballenger et al. 1998; Oehrberg et al. 1995; Sheehan et al. 2005), and sertraline (Londborg et al. 1998), and also the nonselective serotonin reuptake inhibitor clomipramine (Lecrubier and Judge 1997). Fluoxetine, paroxetine, and sertraline have been approved by the U.S. Food and Drug Administration (FDA) for treatment of panic disorder.
Patients with panic disorder are often extremely sensitive to activating effects of antidepressants; have poor tolerance of symptoms such as palpitations, sweating, and tremor; and frequently discontinue treatment or drop out. This problem can almost always be prevented by coprescribing a benzodiazepine (Goddard et al. 2001; Pollack et al. 2003) or by starting with low dosages of an SSRI and increasing them gradually as tolerated. Physician availability and thorough preparation and education of patients are crucial. Other common side effects of SSRIs include weight gain, sexual dysfunction, impairment of sleep, and potential drug–drug interactions.
Discontinuation of treatment can lead to relapse, which mimics panic symptoms and is quite distressing. Gradual dosage reduction is recommended, as are patient education, physician availability, and coping strategies, including behavior therapy (Otto et al. 1993). Switching to a long-acting SSRI such as fluoxetine may be considered. Serotonin 2 (5-HT2) or serotonin 3 (5-HT3) receptor antagonists, such as mirtazapine, nefazodone, and ondansetron, may be used to limit some of the symptoms that are mediated through these pathways (e.g., insomnia, agitation, gastrointestinal distress).
The Cross-National Collaborative Panic Study (1992) showed that alprazolam, along with imipramine, was more effective than placebo in panic disorder; Lydiard et al. (1992) showed that alprazolam 2 mg/day was more effective than placebo. Efficacy for clonazepam was also demonstrated in panic disorder (Davidson and Moroz 1998; Rosenbaum et al. 1997; Tesar et al. 1991), and its use for this indication is now FDA approved.
Alprazolam is now regarded as a second-line treatment. Problems include sedation at higher dosages, abuse liability, and discontinuation-related distress. Comparable efficacy and tolerability have been demonstrated for the sustained-release formulation of alprazolam (Pecknold et al. 1994; Schweizer et al. 1993), with decreased likelihood of adverse discontinuation effects.
Clonazepam has an advantage over alprazolam due to its longer half-life; however, it can also produce sedation, depression, and discontinuation symptoms. Bandelow et al. (1995) showed that reduction of panic attacks is an unsatisfactory marker of treatment benefits and therefore should not be relied on as the principal outcome measure. Substantial improvement of quality of life and work productivity were demonstrated in the clonazepam trials compared to placebo (Jacobs et al. 1997). A recent review supports a role for clonazepam alone or in combination with SSRIs and/or cognitive-behavioral therapy (CBT) in the management of panic disorder (Nardi et al. 2013).
A particular concern with benzodiazepines is their use in the elderly, who are more prone to sedation and falls that can result in fractures and potential head injury, and who are also more likely to experience discontinuation problems.
Although tricyclic antidepressants (TCAs) are effective (Andersch et al. 1991; Cross-National Collaborative Panic Study 1992; Fahy et al. 1992; Lecrubier et al. 1997; Lydiard et al. 1993; Mavissakalian and Perel 1989; Modigh et al. 1992), they are considered second-line treatments for panic disorder because of their side effects. Mavissakalian and Perel (1995) found that phobic symptoms responded best if the plasma level of imipramine and desmethylimipramine was in the range of 110–140 ng/mL, whereas control of panic attacks tended to occur at lower plasma levels. As with SSRIs, low starting dosages in the range of 10–25 mg/day are in order, with gradual titration thereafter as per patient tolerance.
Sheehan et al. (1980) found that phenelzine, along with imipramine, was more effective than placebo in the treatment of panic disorder with agoraphobia, and Lydiard and Ballenger (1987) noted that monoamine oxidase inhibitors (MAOIs) may be superior to TCAs. Although MAOIs may still be the best treatment for some patients, the overall role of MAOIs in managing anxiety disorders is now fairly small because of their potential side effects and drug–drug interactions. The role of the safer reversible inhibitors of monoamine oxidase A (RIMAs) in panic disorder is unclear.
The extended-release (XR) formulation of venlafaxine, a serotonin–norepinephrine reuptake inhibitor (SNRI), demonstrated greater efficacy than placebo in patients with panic disorder in a 10-week trial (Bradwejn et al. 2005), was as effective as paroxetine in a 12-week placebo-controlled trial (Pollack et al. 2007), and has received FDA approval for the treatment of panic disorder. The drug is well tolerated, with an adverse-effect profile comparable to that of the drug in depression and other anxiety disorders.
Mirtazapine, a noradrenergic and specific serotonergic antidepressant, demonstrated possible benefit in panic disorder in open trials (Boshuisen et al. 2001; Sarchiapone et al. 2003) and in a double-blind comparison with fluoxetine (Ribeiro et al. 2001); however, double-blind, placebo-controlled trials have yet to be conducted. It is noteworthy that mirtazapine has been associated with the induction of panic attacks in depressed patients undergoing dosage escalation and discontinuation (Berigan 2003; Klesmer et al. 2000).
Reboxetine, a selective noradrenergic reuptake inhibitor, has been found to produce greater improvement than placebo in patients with panic disorder (Versiani et al. 2002), and in general to be well tolerated. In a more recent randomized, single-blind study comparing reboxetine with paroxetine, paroxetine was more effective for panic attacks, but no differences between the treatments were noted for anticipatory anxiety and avoidance (Bertani et al. 2004). These findings suggest perhaps different roles of norepinephrine and serotonin in the treatment of panic disorder. However, the selective noradrenergic reuptake inhibitor maprotiline appears to be ineffective in panic disorder (Den Boer and Westenberg 1988), whereas the data for bupropion are inconclusive (Sheehan et al. 1983; Simon et al. 2003).
Trazodone was less effective than imipramine and alprazolam in the treatment of panic disorder (Charney et al. 1986). The 5-HT1A partial agonist buspirone and the anticonvulsant gabapentin were generally ineffective in panic disorder (Pande et al. 2000; Sheehan et al. 1990). Possible benefit has been reported in open-label trials for other anticonvulsant drugs, including levetiracetam, tiagabine, and valproic acid (Keck et al. 1993; Papp 2006; Zwanzger et al. 2001). A small double-blind, placebo-controlled trial with tiagabine did not show clinical benefits, although cholecystokinin-tetrapeptide (CCK-4)–induced sensitivity to panic attacks decreased (Zwanzger et al. 2009).
Preliminary data suggest improvement in refractory panic disorder when atypical antipsychotics are used as augmentation of SSRI treatment (olanzapine: Sepede et al. 2006; risperidone: Simon et al. 2006) or in higher dosages as monotherapy (olanzapine: Hollifield et al. 2005). A single-blind comparison trial comparing paroxetine and low-dose risperidone found the low-dose risperidone to be as effective as paroxetine in the treatment of panic attacks (Prosser et al. 2009); however, double-blind, placebo-controlled trials are needed. In a recent randomized, placebo-controlled monotherapy trial of quetiapine XR versus divalproex extended release in bipolar patients with comorbid panic disorder or generalized anxiety disorder, quetiapine XR at a dosage range of 50–300 mg/day showed rapid and sustained effects in reducing anxiety symptoms (Sheehan et al. 2013).
Metabotropic glutamate type 2 receptor agonists have shown promise in preclinical models of anxiety but have yet to demonstrate clinical efficacy in panic disorder (Bergink and Westenberg 2005). Similarly, the effect of a cholecystokinin-B receptor antagonist was no different from placebo in patients with panic disorder (Pande et al. 1999a).
Maintenance treatment is recommended for at least 12–24 months, if not longer. In a controlled trial of paroxetine, clomipramine, and placebo, 84% of the paroxetine-treated patients eventually became panic free over the 9-month period (Lecrubier and Judge 1997). In a 4-year naturalistic follow-up study of 367 patients with panic disorder, greater improvements in panic attacks, phobic avoidance, and daily functioning were observed in those who received continuation treatment for 4 years, compared with 1 year (Katschnig et al. 1995), suggesting that recovery continues over several years.
Long-term randomized controlled trials have reported efficacy for citalopram (Lepola et al. 1998), clomipramine (Fahy et al. 1992), fluoxetine (Michelson et al. 1999), paroxetine (Lecrubier and Judge 1997; Lydiard et al. 1998), and sertraline (Rapaport et al. 2001). In a relapse prevention trial following 3 months of successful open-label treatment, Ferguson et al. (2007) showed that over the course of 7 months, relapse on venlafaxine XR was 22%, compared with 50% on placebo.
Even though there is some similarity between symptoms of relapse and symptoms of drug withdrawal, the existence of discontinuation symptoms is unarguable. A slow taper is recommended (for some benzodiazepines, it may be necessary to taper the drug over weeks or months). Timing of the taper may be important—it is best done when other variables in a patient’s life are as stable as possible. Switching to a longer-acting benzodiazepine such as clonazepam, adding an anticonvulsant such as carbamazepine or valproate (Pages and Ries 1998), and utilizing behavior therapy (Otto et al. 1993) have all been used to ameliorate discontinuation symptoms.
Various elaborations of CBT have demonstrated consistent efficacy for panic disorder, with the common elements being education, cognitive strategies, and exposure to feared sensations and situations (Clum et al. 1993; Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Panic Disorder and Agoraphobia 2003). CBT is a first-line choice, and even when pharmacotherapy is given as the main treatment, principles of CBT should be incorporated into the management plan. It can be of benefit during the process of drug discontinuation, and perhaps in lessening the chance of relapse afterwards.
Social anxiety disorder (SAD) has a lifetime prevalence of 12% (Kessler et al. 2005b). It can be grouped into generalized and nongeneralized types. Generalized SAD is more common in clinical settings, is usually more disabling, and is associated with greater levels of comorbidity and genetic loading. Most of our knowledge about pharmacotherapy for SAD derives from the generalized type, and the literature suggests that different medication approaches may be called for in treating the two subtypes.
Comprehensive treatment of SAD requires that the symptoms of fear, avoidance, and physiological distress are brought under control; comorbidity is treated; disability and impairment are improved; and quality of life is enhanced. Furthermore, evidence from maintenance and relapse prevention studies has confirmed the value of long-term therapy in treatment responders.
Instruments commonly used to measure treatment change in SAD include the clinician- and self-rated Liebowitz Social Anxiety Scale (LSAS; Liebowitz 1987), which assesses 24 performance or interpersonal situations for fear and avoidance. A score of 30 or less is considered to equate with remission. The Social Phobia Inventory (SPIN) is a 17-item self-rating instrument that assesses fear, avoidance, and physiological distress (Connor et al. 2000) and, like the LSAS, is able to detect treatment differences.
Most clinicians consider SSRIs as the first choice for generalized SAD and β-blockers or benzodiazepines as the first choice for nongeneralized SAD. Second-line drugs for generalized SAD comprise the benzodiazepines, venlafaxine (an SNRI), and perhaps other antidepressants, including nefazodone, mirtazapine, and MAOIs. Bupropion and TCAs have been generally disappointing.
Van Vliet et al. (1994) showed fluvoxamine’s superiority over placebo, with response rates of 46% and 7%, respectively. Stein et al. (1999) confirmed the efficacy of fluvoxamine relative to placebo on all symptom domains (i.e., fear, avoidance, and physiological arousal). Controlled-released (CR) fluvoxamine was likewise found to be superior to placebo (Davidson et al. 2004c; Westenberg et al. 2004), and a study in Japan also found fluvoxamine to be effective versus placebo in reducing SAD symptoms and psychosocial disability (Asakura et al. 2007).
Sertraline also has been studied (Blomhoff et al. 2001; Katzelnick et al. 1995; Liebowitz et al. 2003; Van Ameringen et al. 2001; Walker et al. 2000). In the study by Van Ameringen et al. (2001), 53% of patients responded to sertraline as compared with 29% to placebo, and sertraline-treated patients showed improvement on all three symptom domains of the Brief Social Phobia Scale. In a primary care setting, Haug et al. (2000) showed that cognitive therapy and sertraline could be effectively delivered, although the combination did not show any superiority over treatment with drug alone.
Paroxetine’s superiority relative to placebo in SAD has been shown in both short-term efficacy and relapse prevention studies. In the short-term studies by Stein et al. (1998), Allgulander (1999), and Baldwin et al. (1999), rates of response to paroxetine were 55%, 70%, and 66%, respectively, as compared with placebo response rates of 24%, 8%, and 32%. All subjects in the paroxetine trials fulfilled criteria for generalized SAD and showed benefit on the LSAS within 2–4 weeks. Paroxetine CR was also shown to be effective (using LSAS as the primary outcome measure) and well tolerated in a 12-week double-blind, placebo-controlled trial (Lepola et al. 2004).
Fluoxetine, while superior to placebo on primary outcomes in one study (Davidson et al. 2004c), failed to separate from placebo in another study (Kobak et al. 2002), showing a relatively high placebo response rate (30%). Another study found cognitive therapy to be superior to both fluoxetine plus exposure exercises and placebo plus exposure exercises on SAD measures, with no difference between the latter two groups (Clark et al. 2003). Another serotonergic agent, nefazodone, also failed to separate from placebo on most outcome measures (Van Ameringen et al. 2007).
Trials with escitalopram have shown it to be superior to placebo in short-term, long-term, and relapse prevention studies of generalized SAD (Kasper et al. 2005; Lader et al. 2004; Montgomery et al. 2005). Venlafaxine XR has also shown superiority over placebo in two double-blind trials of generalized SAD (Allgulander et al. 2004; Liebowitz et al. 2005).
A double-blind, placebo-controlled trial of mirtazapine in women showed statistically significant superiority for drug over placebo (Muehlbacher et al. 2005). However, a more recent double-blind, placebo-controlled trial in 60 outpatients with generalized SAD who received mirtazapine at dosages of 30–45 mg/day failed to find evidence of efficacy (Schutters et al. 2010).
Paroxetine, paroxetine CR, sertraline, fluvoxamine CR, and venlafaxine XR are currently FDA approved for SAD treatment.
Three major placebo-controlled trials have shown efficacy for benzodiazepines in SAD. Gelernter et al. (1991) showed a modest effect for alprazolam over placebo (38% vs. 20% response rate) at a mean daily dosage of 4.2 mg, although it was generally inferior to phenelzine. Davidson et al. (1993) found a substantial 70% clonazepam response rate compared with a 20% placebo response rate in 75 subjects. Bromazepam was also found to be more effective than placebo (Versiani et al. 1997). A recent double-blind, placebo-controlled trial of augmentation and switch strategies for refractory SAD found that clonazepam augmentation of sertraline treatment (up to 3 mg/day) was superior to placebo augmentation and also to a switch to venlafaxine, with a higher percentage of patients achieving remission (Pollack et al. 2014).
Benzodiazepines provide significant benefits yet are not considered first-line drugs because of their more limited spectrum of action and potential withdrawal difficulties. However, they work rapidly, are well tolerated, and may be particularly useful for individuals with periodic performance-related social anxiety or treatment-resistant SAD.
Gabapentin and pregabalin produce significant effects in SAD. Pande et al. (1999b) found a superior effect for gabapentin over placebo in a trial using flexible dosing (ranging from 900 mg/day to 3,600 mg/day, with 2,100 mg/day being the most common final gabapentin dosage), with response rates of 39% and 17%, respectively. Baseline symptom scores were comparatively high and overall response rates relatively low, suggesting a degree of treatment-resistant illness in the study population. Pregabalin also has shown benefit in generalized SAD (Feltner et al. 2003; Pande et al. 2003). Although pregabalin at a dosage of 150 mg/day was no different from placebo, 600 mg/day produced greater effects than placebo, with response rates of 43% and 22%, respectively. A 26-week double-blind, placebo-controlled maintenance trial of pregabalin at a fixed dosage of 450 mg/day showed that pregabalin not only was superior to placebo in maintaining symptomatic improvement but also was relatively well tolerated (Greist et al. 2011). Levetiracetam failed to differentiate from placebo (Stein et al. 2010). Further work with anticonvulsants is needed, given that these agents are generally well tolerated, safe, and less likely to produce discontinuation symptoms compared with many SSRIs and benzodiazepines.
Moclobemide is safer than older MAOIs and was shown to be almost as effective as phenelzine and significantly better than placebo (Versiani et al. 1992). However, subsequent studies did not support these findings (Noyes et al. 1997; Schneier et al. 1998). The International Multicenter Clinical Trial Group on Moclobemide in Social Phobia (1997) found a modestly greater response rate (47%) for moclobemide at 600 mg/day than for placebo (34%). Moclobemide is approved in some countries but is not available in the United States. Another RIMA, brofaromine, has shown promise in three trials, with response rates of 78%, 50%, and 73%, respectively, compared with placebo response rates of 23%, 19%, and 0% (Fahlén et al. 1995; Lott et al. 1997; van Vliet et al. 1992), but it also is not marketed in the United States.
Phenelzine showed positive benefit in four studies (Gelernter et al. 1991; Heimberg et al. 1998; Liebowitz et al. 1992; Versiani et al. 1992). Rates of response to phenelzine were 69%, 85%, 64%, and 65%, respectively, as compared with response rates of 20%, 15%, 23%, and 33% to placebo, and phenelzine overall has been shown to have a strong effect size (Davis et al. 2014). Even though phenelzine is consistently effective, its poor tolerability and risks make it unsuitable except for patients who have been nonresponsive to other treatments and who can adhere to the necessary dietary and medication restrictions.
Olanzapine yielded greater improvement than placebo in a small (n=12) double-blind, placebo-controlled monotherapy trial (Barnett et al. 2002), suggesting that atypical antipsychotics may deserve further investigation in SAD, although their benefits will need to be weighed against their potential metabolic effects. Ondansetron, while producing a statistically significant effect relative to placebo, seems to be of limited clinical benefit (Bell and DeVeaugh-Geiss 1994; Davidson et al. 1997b), although it may be used adjunctively in some cases. Buspirone was ineffective in a double-blind trial, with a 7% response rate (van Vliet et al. 1997).
Despite their intuitive appeal, β-blockers have shown poor effect in treating generalized SAD. For example, atenolol failed to separate from placebo in two trials (Liebowitz et al. 1992; Turner et al. 1994). β-Blockers do show some value in performance-related social anxiety, perhaps by virtue of their ability to reduce peripheral autonomic arousal and block negative feedback. A double-blind trial of mirtazapine failed to show benefit (Schutters et al. 2010). Nefazodone, bupropion, and selegiline have not shown impressive results in open-label reports (Emmanuel et al. 1991; Simpson et al. 1998; Van Ameringen et al. 1999).
A novel therapeutic approach is suggested by the findings of Hofmann et al. (2006), who administered a single dose of D-cycloserine or placebo to patients with social anxiety disorder treated with CBT. The drug was given prior to each CBT session and enhanced the benefit of CBT to a greater extent than did placebo. The postulated mechanism of action relates to drug-facilitated extinction of learned fear via glutamatergic pathways. However, a recent placebo-controlled multisite trial of CBT augmentation with D-cycloserine in generalized SAD by the same authors found that although D-cycloserine augmentation was associated with approximately a 30% faster rate of improvement, there was no difference in response or remission rate compared with placebo (Hofmann et al. 2013).
A study comparing the neurokinin-1 antagonist GR205171 against citalopram and placebo in 36 social phobia patients found response rates of 41.7%, 50%, and 8.3%, respectively, as well as a significant reduction in regional cerebral blood flow (rCBF) in the rhinal cortex, amygdala, and parahippocampal–hippocampal regions during a stressful public speaking task with the active agents (Furmark et al. 2005).
Connor et al. (2006) reported benefit for one-time intradermal bilateral axillary injections of 50 units of botulinum toxin type A for subjects with SAD and troublesome axillary hyperhidrosis. Effects persisted over 8 weeks and were superior to those of placebo for sweating, daily function, and activities. All subjects received concomitant paroxetine for other aspects of SAD.
One placebo-controlled trial of fluvoxamine in children ages 6–17 years showed that it was superior to placebo in SAD, generalized anxiety disorder (GAD), and the combination: 76% of the fluvoxamine group responded, as compared with 19% of the placebo group (Research Unit on Pediatric Psychopharmacology Anxiety Study Group 2001). Double-blind trials of immediate-release (IR) paroxetine (Wagner et al. 2004) and venlafaxine XR (March et al. 2007) have produced positive results in children and adolescents with generalized SAD.
A multisite trial in 488 children (ages 7–17 years) with a primary diagnosis of separation anxiety disorder, GAD, or SAD compared CBT alone, sertraline alone, combination CBT and sertraline, and placebo. CBT monotherapy and sertraline monotherapy were each superior to placebo in reducing anxiety symptoms in children (59.7% and 54.9% response rate, respectively); however, the combination treatment had the best response rate (80.7%) (Walkup et al. 2008). At follow-ups at 24 and 36 weeks, the majority of acute responders maintained their response, and the combination treatment maintained its advantage over the CBT and sertraline monotherapies (Piacentini et al. 2014).
SAD is a chronic illness, and treatment is generally recommended for years. Sutherland et al. (1996) reported that at 2-year follow-up, subjects who had received an active drug rather than placebo were doing better. Relatively few relapse prevention studies have been done. In a 12-month trial with clonazepam, Connor et al. (1998) showed a 20% relapse rate in those switched to placebo, compared with 0% in those who continued taking clonazepam. Stein et al. (1996) reported that 62% of the subjects relapsed when switched double-blind from paroxetine to placebo after 12 weeks, compared with only 12% who relapsed during maintenance treatment with paroxetine.
CBT is efficacious in SAD, being comparable to pharmacotherapy (Davidson et al. 2004b; Fedoroff and Taylor 2001), but little is known as to whether adding CBT to medication lowers the relapse rate, and so far the limited evidence does not suggest any potentiating effects when the treatments are combined (Davidson et al. 2004b), except in children (Walkup et al. 2008). In a comparative study of drug and psychotherapy, Heimberg et al. (1998) showed that phenelzine and CBT were approximately similar, although phenelzine had an edge in more severely symptomatic patients. On the other hand, when subjects who had discontinued treatment were followed up, rates of relapse tended to be lower in those who had received CBT than in those who had taken phenelzine. A later study by the same group (Blanco et al. 2010) showed superior outcomes for combined phenelzine and CBT over each treatment given alone.
Specific phobia is among the most common psychiatric disorders, with a lifetime prevalence of 8%–12.5% (Alonso et al. 2004; Kessler et al. 2005b) and 12-month prevalence of 3.5%–9% (Alonso et al. 2004; Kessler et al. 2005a). Although the disorder is characterized by an early onset (median age at onset is 7 years) (Kessler et al. 2005b), most individuals are unimpaired by their symptoms and rarely seek treatment (Magee et al. 1996; Stinson et al. 2007; Zimmerman and Mattia 2000). However, for a minority of individuals, specific phobia causes significant disability and requires treatment. The generally accepted treatment of choice is exposure therapy, which is uniformly and rapidly effective, with techniques including virtual reality as well as in vivo exposure and muscle tension exercises (for blood–injury phobia) (Swinson et al. 2006). Few studies have evaluated the efficacy of pharmacological approaches, and no drug has yet been approved by the FDA for treating specific phobia. No standard ratings exist for this disorder, although the Marks-Mathews FQ is quite suitable for blood–injury phobia and some other fears. A modification of this scale, the Marks-Sheehan Main Phobia Severity Scale (MSMPSS; Sheehan 1986), can be recommended.
Serotonergic drugs have shown efficacy in treating symptoms of fear and avoidance in a variety of anxiety disorders and thus would seem logical choices in specific phobias. In a small (n=11) 4-week double-blind controlled trial, subjects receiving paroxetine (up to 20 mg/day) showed a 60% response rate, compared with 17% for subjects receiving placebo (Benjamin et al. 2000). A more recent randomized double-blind pilot trial compared escitalopram versus placebo over 12 weeks in 12 adults with specific phobia (Alamy et al. 2008). No difference was observed on the primary outcome; however, 60% of escitalopram-treated subjects showed response (based on a Clinical Global Impression Scale [CGI] Improvement score of 1 or 2), compared with 29% of subjects receiving placebo (effect size=1.13). The findings from these two small trials require validation in larger controlled trials. In contrast, in a controlled trial of the serotonergic and noradrenergic TCA imipramine in 218 phobic subjects (agoraphobic, mixed phobic, or simple phobic) receiving 26 weeks of behavior therapy, no difference was observed between imipramine and placebo (Zitrin et al. 1983).
In a long-term controlled study of clonazepam in social phobia, Davidson et al. (1994) observed that clonazepam was superior in reducing symptoms of anxiety related to blood–injury phobia as measured by changes in the blood–injury phobia subscale of the Marks-Mathews FQ. Intermittent use of benzodiazepines also may be helpful in the acute treatment of the somatic anxiety that accompanies specific phobia, although this usage has not been an area of active investigation.
Using a novel approach, Ressler et al. (2004) investigated the effect of a cognitive enhancer, D-cycloserine, as an adjunct to psychotherapy. D-Cycloserine is an N-methyl-D-aspartate (NMDA) receptor partial agonist that has demonstrated improvement in extinction in rodents. Subjects with acrophobia (n=28) were randomly assigned to receive a single dose of D-cycloserine or placebo prior to each of two virtual reality exposure therapy sessions. The combination of D-cycloserine and exposure therapy was associated with greater improvement in the virtual reality setting, as well as on a variety of anxiety domains. These changes were noted early in treatment and were maintained at 3-month follow-up. A recent small (n=35) double-blind, placebo-controlled randomized trial of D-cycloserine enhancement of prolonged exposure therapy in dog- or spider-phobic children showed that D-cycloserine helped children to better retain their fear extinction learning (Byrne et al. 2015).
Specific phobia tends to be a chronic condition. Although psychotherapeutic approaches can be beneficial in the short term, evidence suggests that the initial gains noted with treatment may not be sustained over the long term (Lipsitz et al. 1999). Pharmacological augmentation may help to extend the benefits of exposure therapy over time.
GAD is a common disorder, with a lifetime prevalence of 5%–6% (Wittchen and Hoyer 2001), and is the most prevalent anxiety disorder in primary care, with rates that exceed 8% (Goldberg and Lecrubier 1995). GAD tends to be a chronic and disabling condition with lifetime rates of comorbidity as high as 90% (Blanco et al. 2014), particularly depression (prevalence rate greater than 60%), which can increase the severity and burden of the disorder. Unlike prevalences of other anxiety disorders, GAD prevalence tends to increase with age, with a lifetime prevalence of 11% in individuals older than 65 years and late-life onset occurring in at least 25% of cases (Zhang et al. 2014).
Assessment of response in almost all GAD pharmacotherapy trials has been with the clinician-administered Hamilton Anxiety Scale (Ham-A; Hamilton 1959), which measures psychic and somatic symptoms of anxiety; remission is usually defined as a Ham-A score of 7 or less. The self-rated Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith 1983) is also widely used and is capable of detecting differences in treatment efficacy.
Benzodiazepines have been widely used to treat acute and chronic anxiety since their introduction in the 1960s. Their activity is mediated through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor. The efficacy and relative safety of benzodiazepines in short-term use (i.e., several weeks or months) are well established (Rickels et al. 1983; Shader and Greenblatt 1993). However, the longer-term use of these drugs is more controversial and can be associated with the development of tolerance, physiological dependence, and withdrawal (if abruptly discontinued), as well as troublesome side effects, including ataxia, sedation, motor dysfunction, and cognitive impairment. Furthermore, these drugs should be avoided in patients with a history of substance use disorders, and long-term use may infrequently lead to the development of major depression (Lydiard et al. 1987).
Benzodiazepines have been shown to be effective in GAD, as reported by Rickels et al. (1993). The appeal of these drugs lies in their rapid onset of action, ease of use, tolerability, and relative safety. Findings from several 6- to 8-month trials of maintenance treatment for chronic anxiety have indicated continued efficacy of benzodiazepines over time (Rickels et al. 1983, 1988a, 1988b; Schweizer et al. 1993). Because GAD tends to be a chronic disorder, many patients may need to continue pharmacotherapy with benzodiazepines (or other drugs) for many years, and long-term use of benzodiazepines may lead to the complications listed above.
Approximately 70% of patients with GAD will respond to an adequate trial of a benzodiazepine (Greenblatt et al. 1983), which corresponds to the equivalent of a 3- to 4-week treatment course of up to 40 mg/day of diazepam or 4 mg/day of alprazolam (Schweizer and Rickels 1996). Discontinuation should be managed by slow taper to minimize withdrawal symptoms, rebound anxiety, and relapse potential. Some evidence suggests that benzodiazepines may be more effective in treating the autonomic arousal and somatic symptoms of GAD but less effective for the psychic symptoms of worry and irritability (Rickels et al. 1982; Rosenbaum et al. 1984).
As our understanding of the phenomenology of GAD has grown, there has been a greater emphasis on the psychic component of the disorder (DSM-5; American Psychiatric Association 2013). Given these changes, along with the high rates of comorbid depression in GAD and the anxiolytic activity of many of the newer classes of antidepressants, the use of benzodiazepines as a primary treatment for GAD is less recommended.
The azapirones are believed to exert their anxiolytic effect through partial agonism of 5-HT1A receptors. Several trials have indicated that buspirone is superior to placebo and comparable to benzodiazepines in treating GAD, with fewer side effects and without concerns for abuse, dependence, and withdrawal (Cohn et al. 1986; Enkelmann 1991; Petracca et al. 1990; Rickels et al. 1988b; Strand et al. 1990), although other studies have reported conflicting results (Fontaine et al. 1987; Olajide and Lader 1987; Ross and Matas 1987). Buspirone appears to be more effective in treating the psychic component of anxiety (Rickels et al. 1982), and possibly anxiety with mixed depressive symptoms (Rickels et al. 1991), than in treating the somatic and autonomic symptoms of anxiety (Schweizer and Rickels 1988; Sheehan et al. 1990). An adequate trial of buspirone in GAD would be 3–4 weeks of treatment at a dosage of up to 60 mg/day, in divided doses. Treatment-limiting effects of the drug include greater potential for side effects at higher dosages, slower onset of action, more variable antidepressant effects, and possibly reduced effectiveness in patients with a prior favorable response to benzodiazepines (Schweizer et al. 1986).
In a 6-week trial comparing imipramine and alprazolam, similar improvement was observed with both treatments by week 2; however, imipramine appeared to be more effective in treating the psychic anxiety component, whereas alprazolam was more effective in attenuating somatic symptoms (Hoehn-Saric et al. 1988). In an 8-week double-blind, placebo-controlled trial of imipramine, trazodone, and diazepam (Rickels et al. 1993), diazepam showed an early-onset effect by week 2, primarily on somatic symptoms. Over the next 6 weeks, however, psychic anxiety symptoms were more responsive to the antidepressants. Overall, imipramine was more efficacious than diazepam, trazodone was comparable to diazepam, and all treatments were superior to placebo. In a controlled trial comparing imipramine, paroxetine, and 2′-chlordesmethyldiazepam, early onset of action was again noted with the benzodiazepine by week 2, but overall greater improvement was noted with the antidepressants by week 4, especially in psychic symptoms (Rocca et al. 1997).
A number of SSRIs are effective in GAD. Paroxetine IR at 20–50 mg/day has been shown to be as effective as imipramine and more effective than 2′-chlordesmethyldiazepam (Rocca et al. 1997). Compared with placebo, a similar dosage range of paroxetine IR was associated with significant reduction in anxiety after 8 weeks of treatment (Bellew et al. 2000; Pollack et al. 2001; Rickels et al. 2003), with an improvement in Ham-A-rated psychic anxiety observed as early as 1 week after initiating treatment (Pollack et al. 2001). Paroxetine IR also improves social functioning in patients with GAD (Bellew et al. 2000).
Escitalopram was found to be superior to placebo in improving anxiety symptoms, disability, or quality of life in three 8-week trials at a dosage range of 10–20 mg/day dose range (Davidson et al. 2004a; Goodman et al. 2005), and it was found to be equivalent to paroxetine IR in a 6-month trial (Bielski et al. 2005). In a larger placebo-controlled trial, escitalopram 10 mg/day was superior to paroxetine 20 mg/day, and escitalopram dosages of both 10 mg/day and 20 mg/day were superior to placebo (Baldwin et al. 2006). A relapse prevention study found that sustained treatment with escitalopram 20 mg/day up to 74 weeks reduced the relapse rate (19%) relative to placebo substitution (56%) (Allgulander et al. 2006).
Sertraline was demonstrated to be superior to placebo in GAD in a 12-week (Allgulander et al. 2004) and a 10-week (Brawman-Mintzer et al. 2006) double-blind, placebo-controlled trial; sertraline was well tolerated and showed beneficial effects on Ham-A-rated psychic and somatic anxiety symptoms compared with placebo (Dahl et al. 2005).
Several placebo-controlled trials have confirmed the short-term efficacy of venlafaxine XR in GAD over 8 weeks on both psychic and somatic symptoms. In a trial of 365 adult outpatients treated with venlafaxine XR (75 mg/day or 150 mg/day), buspirone (30 mg/day), or placebo, the Ham-A-adjusted mean scores of the anxiety and tension items were significantly improved at both active drug dosages compared with placebo; venlafaxine XR was superior to buspirone on the HADS anxiety subscale (Davidson et al. 1999). In a second trial of 541 outpatients on either venlafaxine XR (37.5 mg/day, 75 mg/day, or 150 mg/day) or placebo (Allgulander et al. 2001), the venlafaxine 75 mg/day and 150 mg/day dosages showed superior efficacy compared with placebo on all primary outcome measures (with improvement in psychic anxiety noted earlier than somatic symptoms), whereas the 37.5 mg/day dosage was superior to placebo on only one measure (the Anxiety subscale of the HADS). In a third trial of fixed dosages (75 mg/day, 150 mg/day, and 225 mg/day) of venlafaxine XR (Rickels et al. 2000), venlafaxine XR was superior to placebo on all outcome measures, with the most robust effects observed at 225 mg/day. Venlafaxine XR significantly reduced psychic anxiety but not somatic symptoms.
Venlafaxine XR also has shown long-term efficacy in GAD. In two 6-month controlled trials of fixed (37.5 mg, 75 mg, or 150 mg/day) (Allgulander et al. 2001) and flexible (75–225 mg/day) (Gelenberg et al. 2000) dosages of venlafaxine XR, significant improvement in anxiety was observed as early as 1 week, and efficacy was sustained over the 28-week treatment period. In the fixed-dosage study, the greatest effect was observed with the 150-mg/day dosage. Significant improvement in social functioning was noted at the two higher dosages by week 8 and was sustained over the 6 months of the trial.
Venlafaxine XR is also effective in treating GAD with comorbid depression (Silverstone and Salinas 2001). After 12 weeks of treatment with venlafaxine XR (75–225 mg/day), fluoxetine, or placebo, significant reduction was observed in both Ham-A-rated anxiety and Hamilton Rating Scale for Depression (Ham-D; Hamilton 1960)–rated depression only in subjects receiving venlafaxine XR. The response was delayed somewhat in subjects with comorbid GAD and depression as compared with those with depression alone, suggesting that individuals with comorbidity may benefit from a longer course of treatment.
There is agreement that the goal of treatment is to achieve remission, (e.g., a final Ham-A score ≤7). Pooled analysis of data from the two long-term studies noted earlier (Allgulander et al. 2001; Gelenberg et al. 2000) has determined that remission is attainable in GAD (Meoni and Hackett 2000). By 2 months, approximately 40% of those receiving venlafaxine responded to treatment, and 42% attained remission. By 6 months, the proportion of those in remission increased to almost 60%, whereas responders declined to 20%, in contrast to a remission rate of less than 40% with placebo.
Venlafaxine XR has some advantages over the benzodiazepines—notably, antidepressant activity, lack of potential for abuse and dependence, and efficacy in treating symptoms of psychic anxiety. Nonetheless, venlafaxine can be associated with some adverse effects in the long term, including sexual dysfunction and blood pressure elevation in some patients. Abrupt discontinuation of treatment can be associated with unpleasant side effects, most commonly dizziness, light-headedness, tinnitus, nausea, vomiting, and loss of appetite, and the discontinuation syndrome is worse if one abruptly stops at higher dosage levels (Allgulander et al. 2001).
Duloxetine, another SNRI antidepressant, has shown efficacy superior to placebo in GAD (Allgulander et al. 2007; Rynn et al. 2008) in the range of 60–120 mg/day and also appears to lessen the chance of relapse during maintenance therapy. A recent randomized, placebo-controlled, flexible-dose study demonstrated that duloxetine was effective and well tolerated in the treatment of GAD in children and adolescents ages 7–17 years (Strawn et al. 2015).
One interesting application of SSRIs in GAD is in combination with nonbenzodiazepine hypnotics such as eszopiclone (Pollack et al. 2008a) and zolpidem (Fava et al. 2009), which may be particularly suited where insomnia is a major problem.
The antidepressant mirtazapine also has demonstrated anxiolytic properties (Ribeiro et al. 2001). However, published reports of its effect in GAD are limited to a small open-label study in major depression and comorbid GAD (Goodnick et al. 1999) and a small open-label GAD trial in 44 outpatients (Gambi et al. 2005). Although the results were encouraging, data from controlled trials are needed to adequately assess a possible role for mirtazapine in GAD.
A 12-week double-blind active comparison trial of bupropion extended-release at 150–300 mg/day versus escitalopram at 10–20 mg/day in 24 subjects found similar Ham-A-rated anxiolytic efficacy of bupropion extended-release and escitalopram (Bystritsky et al. 2008). Notwithstanding these intriguing findings, the current body of clinical evidence supports the use of SSRIs or SNRIs before agents that are primarily noradrenergic in action.
Hydroxyzine blocks histamine1 (H1) and muscarinic receptors. In three controlled trials, hydroxyzine was superior to placebo (Ferreri and Hantouche 1998; Lader and Scotto 1998; Llorca et al. 2002). Recent reports of hydroxyzine-related ventricular arrhythmias have led to cautionary labeling in Europe in the use of this drug and restriction of the maximum dosage to 100 mg/day (European Medicines Agency 2015).
The α2δ calcium channel antagonist pregabalin was superior to placebo in four studies of GAD (Feltner et al. 2003; Pande et al. 2003; Pohl et al. 2005; Rickels et al. 2005). Efficacy was noted early in treatment, but the ability of this drug to successfully treat some of the comorbid disorders associated with GAD is unknown. A recent review of six short-term double-blind, placebo-controlled pregabalin trials in GAD showed that pregabalin treatment significantly improved both psychic and somatic Ham-A-rated GAD symptoms, with a dose–response effect that plateaued at 300 mg/day (Lydiard et al. 2010). Pregabalin has shown efficacy and reasonably good tolerability in elderly patients with GAD (Montgomery 2006). In a long-term trial in 624 GAD patients, responders to 8 weeks of open-label pregabalin at 450 mg/day were randomly assigned to receive pregabalin or placebo for 24 weeks (Feltner et al. 2008). Relapse rates were significantly lower for pregabalin (42%) than for placebo (65%), although attrition rates for pregabalin were higher (21.4% vs. 15.3%).
The GABA reuptake inhibitor tiagabine failed to separate from placebo on key measures in three placebo-controlled multicenter trials (Pollack et al. 2008b).
Evidence for antipsychotic monotherapy in GAD is limited for some agents and more robust for others. An open-label trial suggested benefit for ziprasidone (Snyderman et al. 2005). Flupenthixol is approved for the treatment of depression in some countries and was shown in one controlled study to be superior to amitriptyline, clotiazepam, and placebo in subjects with refractory GAD (Wurthmann et al. 1995). Sulpiride is also used in similar situations (Bruscky et al. 1974; Chen et al. 1994).
The strongest evidence supporting atypical antipsychotic use in GAD at present is for quetiapine XR, which was shown to be effective and superior to placebo in a multicenter trial, and at 150 mg/day was effective for both psychic and somatic anxiety symptoms, with improvement being noted as early as 4 days (Bandelow et al. 2010). The active comparator in this trial, paroxetine 20 mg/day, showed a lesser effect on somatic anxiety and a higher prevalence of sexual side effects. Remission rates were 42.6%, 38.8%, and 27.2% for quetiapine XR, paroxetine, and placebo, respectively. A longer-term double-blind, placebo-controlled multicenter maintenance trial with quetiapine XR at 50–300 mg/day in 432 patients found it to be effective in preventing recurrence of anxiety symptoms (Katzman et al. 2011).
Long-term use of atypical antipsychotics carries some concerns about tolerability and safety, especially in regard to weight gain and metabolic adverse effects, and these concerns need to be balanced against the long-term benefits in GAD in terms of reduction of disability and improved functionality.
Riluzole, a presynaptic glutamate release inhibitor, showed promise in a small open-label study at a daily dosage of 100 mg (Mathew et al. 2005).
Agomelatine, a serotonin 5-HT2C antagonist and melatonin1/2 receptor agonist, is efficacious in GAD (Stein et al. 2008).
Complementary treatments have had mixed results in GAD. Homeopathy was found to be ineffective in one trial (Bonne et al. 2003). The herbal remedy kava did not separate from placebo in one trial (Connor and Davidson 2002), although Sarris et al. (2009) showed some evidence supporting the benefit of a water-soluble formulation of kava in subjects with short-term GAD-like symptoms. Liver damage remains a potentially devastating concern, however, and even the preferred aqueous extract cannot be regarded as entirely safe, particularly at kava dosages above 250 mg/day (Teschke and Schulze 2010). Two small placebo-controlled trials suggested that chamomile and Ginkgo biloba may have modest anxiolytic effects in patients with mild to moderate GAD (Amsterdam et al. 2009; Woelk et al. 2007). Kasper et al. (2014) demonstrated that lavender oil extract at dosages of 80 mg/day and 160 mg/day was superior to placebo and was better tolerated than paroxetine in a four-arm trial of subjects with DSM-5 GAD. Later studies by these researchers showed that the compound reduced 5-HT1A receptor binding in the hippocampus, anterior cingulate cortex, and fusiform and temporal gyri.
A meta-analysis of GAD studies by Hidalgo et al. (2007) showed that the effect sizes (in diminishing order from strongest to weakest) for each drug or drug group versus placebo were as follows: pregabalin, 0.50; hydroxyzine, 0.45; venlafaxine XR, 0.42; benzodiazepines, 0.38; SSRIs, 0.36; buspirone, 0.17; and homeopathy and herbal treatment, −0.31.
Drugs that have been approved in the United States for treating GAD or historical forerunners of the disorder include a large number of benzodiazepines, buspirone, paroxetine IR, escitalopram, venlafaxine XR, and duloxetine. Pregabalin is not approved in the United States but is approved for GAD in Europe.
There is also convincing evidence in favor of efficacy for CBT in GAD, with sustained benefit over 2 years of follow-up. These findings have been well reviewed by Swinson et al. (2006). There are no clinically informative studies to compare, or combine, CBT and pharmacotherapy in GAD, but on pragmatic grounds, one may consider their combination in patients who have shown only a partial response to a thorough course of either CBT or medication alone.
Although obsessive-compulsive disorder (OCD) has moved to a new disorder category—Obsessive-Compulsive and Related Disorders—in DSM-5, we have retained it in this chapter because of its similarities to anxiety disorders in presentation and treatment approaches.
According to the National Comorbidity Survey Replication (NCS-R), the lifetime and 12-month prevalence rates for OCD are 1.6% and 1.0%, respectively (Kessler et al. 2005a, 2005b). OCD has been recognized as the tenth leading cause of disability worldwide (Murray and Lopez 1996). Treatment can be grouped broadly into psychosocial and psychopharmacological approaches, the latter being our focus here. The chief rating scale for treatment studies of OCD remains the Yale-Brown Obsessive Compulsive Scale (Y-BOCS; Goodman et al. 1989), a 10-item observer-rated measure.
A series of placebo-controlled studies completed in the late 1980s and the early 1990s led to the first approved treatment of OCD in the United States and other countries (Clomipramine Collaborative Study Group 1991). Clomipramine is a potent serotonin reuptake inhibitor (SRI) but is not selective for serotonin, because its demethylated metabolite is a norepinephrine reuptake inhibitor (NRI). The anti-OCD effect of clomipramine correlates with the plasma level of the SRI parent drug, suggesting that reuptake inhibition of serotonin is the critical factor underlying the drug’s benefit. Moreover, selective noradrenergic reuptake inhibitors such as nortriptyline and desipramine have been shown to lack efficacy in OCD (Leonard et al. 1988; Thorén et al. 1980).
In the Clomipramine Collaborative Study Group (1991) trial, the Y-BOCS score was reduced by about 40% in the active-drug group compared with a reduction of about 5% in the placebo group, consistent with findings by Huppert et al. (2004) that OCD has a remarkably low placebo response rate. Clomipramine and SSRIs are equivalent in the treatment of OCD (Koran et al. 1996); however, because of its side effects, clomipramine is considered a second-line treatment.
Today, SSRIs are considered the first-line treatment for OCD, and fluvoxamine, fluoxetine, sertraline, and paroxetine have been approved by the FDA for that indication (Greist et al. 1995a, 1995b; Tollefson et al. 1994). Clomipramine, fluvoxamine, fluoxetine, and sertraline are also effective and indicated for treating OCD in children (Flament et al. 1985; Liebowitz et al. 2002; March et al. 1998; Riddle et al. 2001), although CBT and the combination of CBT with an SSRI may be more effective (Ivarsson et al. 2015). When an SSRI drug is to be used in the treatment of OCD, it may need to be given at higher dosages, and it may take a longer time to work effectively (Ninan et al. 2006; Stein et al. 2007). Most clinicians believe that treatment should be long-term to reduce the chance of relapse (Pato et al. 1990), although the dosage might be lowered without loss of benefit (Ravizza et al. 1996).
Long-term pharmacological treatments of OCD have suggested sustained response beyond the acute treatment phase. In addition, clomipramine, paroxetine, sertraline, and escitalopram all have been shown to be more effective than placebo in prevention of OCD relapse (Fineberg et al. 2005, 2007). SSRIs appear to be well tolerated in these studies.
Up to 60% of OCD patients show at least a partial response to SSRIs, although full remission is rare. Relapse can occur even during SSRI treatment, and comorbidity is common. The following augmentation, combination, and other novel strategies have been reported as offering benefit:
The addition of fluvoxamine to clomipramine (Szegedi et al. 1996) may be helpful for partial responders, as fluvoxamine inhibits clomipramine’s demethylation, thus increasing the amount of available clomipramine and producing a potentiating effect. Monitoring of plasma levels and electrocardiograms is important with this combination to avoid toxicity and seizures.
The use of intravenous clomipramine (Fallon et al. 1992) prevents first-pass metabolism, and side effects may be less severe. A double-blind trial of intravenous clomipramine suggested greater benefit with intravenous loading than with oral loading (Koran et al. 1997).
In treatment-naive (i.e., without refractory OCD) patients, the addition of quetiapine (moderate dosage) to high-dosage citalopram treatment was more effective than placebo augmentation (Vulink et al. 2009).
The benzodiazepine clonazepam has been added to clomipramine treatment with mixed benefit (Pigott et al. 1992) and to sertraline treatment with no added benefit (Crockett et al. 1999).
Patients with SRI-refractory OCD may benefit from antipsychotic augmentation. A meta-analysis demonstrated significant benefits for haloperidol and risperidone over placebo augmentation in OCD patients who failed to respond to an adequate SRI trial, whereas evidence for olanzapine and quetiapine was less robust (Bloch et al. 2006). However, quetiapine was superior to aripiprazole as an augmentation strategy in patients with OCD that was resistant to SRI treatment (Shoja Shafti and Kaviani 2015).
The addition of lithium, buspirone, desipramine, gabapentin, or ondansetron to SRIs has produced very limited benefits in studies to date, although there may be occasional patients for whom such combinations are helpful.
Topiramate augmentation of maximum-dosage SSRI treatment in patients with treatment-refractory OCD had a beneficial effect on compulsions, but not obsessions, and was poorly tolerated (Berlin et al. 2011).
One report suggested that St. John’s wort (Hypericum perforatum) produced some improvement after 12 weeks of treatment in 12 patients with OCD (Taylor and Kobak 2000). However, a subsequent and adequately powered placebo-controlled study was negative (Kobak et al. 2005).
Inositol, a naturally occurring second-messenger precursor, led to greater OCD symptom improvement than placebo at a dosage of 18 g/day for 6 weeks (Fux et al. 1996).
Neurosurgical approaches (cingulotomy or anterior capsulotomy) can be helpful for refractory OCD. Between 25% and 50% of subjects show marked improvement, and the side-effect burden of this procedure is small (Baer et al. 1995; Jenike et al. 1991; Pepper et al. 2015).
Small but promising studies also suggest benefits from deep brain stimulation for patients with treatment-refractory OCD (Denys et al. 2010; Greenberg et al. 2006; Pepper et al. 2015).
rTMS studies have been limited in number of subjects and methodology and have yielded mixed results in patients with treatment-refractory OCD (Mantovani et al. 2010; Ruffini et al. 2009; Sachdev et al. 2007; Sarkhel et al. 2010). A recent meta-analysis of rTMS augmentation of SSRI treatment in medication-resistant OCD showed positive results (Ma and Shi 2014).
CBT is well established in the treatment of OCD, and evidence for its efficacy is strong, including as maintenance therapy (Eddy et al. 2004; Foa et al. 2005; Peselow et al. 2015). CBT employing exposure with response prevention is a first-choice option for OCD. One landmark study demonstrated that exposure with response prevention was superior to stress management training as an augmentation strategy in clomipramine partial responders (Simpson et al. 2008).
Although both posttraumatic stress disorder (PTSD) and acute stress disorder (ASD) were moved to a new disorder category—Trauma- and Stressor-Related Disorders—in DSM-5, we continue to include them in this review of anxiety-related conditions because of the similarities between their presentations, treatment interventions, and comorbid conditions and those of the anxiety disorders.
Posttraumatic stress disorder is a chronic and disabling disorder with a lifetime prevalence of about 7% (Kessler et al. 2005a). It can lead to significant functional impairment and inflict an enormous burden on society.
Treatment of PTSD must target the core symptoms of the disorder, focusing on improving resilience and quality of life and reducing comorbidity and disability. Widely used instruments (most of which are linked to DSM-IV [American Psychiatric Association 1994] criteria) include the Clinician-Administered PTSD Scale (CAPS; Weathers et al. 2001) and the more globally oriented Short PTSD Rating Instrument (SPRINT; Connor and Davidson 2001). Self-rating scales include the Davidson Trauma Scale (DTS; Davidson et al. 1997a), the PTSD Checklist (PCL; Weathers et al. 1991), and the SPRINT, which also has been validated as a self-rating. DSM-5 (American Psychiatric Association 2013)-based instruments (e.g., CAPS, PCL) have been developed and are in the process of being validated.
The TCAs and MAOIs were among the first pharmacological agents studied in controlled trials of PTSD. More recently, several controlled multicenter trials have shown efficacy for the SSRIs and SNRIs. With the documented antidepressant and anxiolytic effects of these agents and the high rates of comorbid depression in PTSD (Kessler et al. 1995), antidepressants would seem a logical choice for PTSD treatment.
Tricyclic antidepressants. Two controlled trials of TCAs in male combat veterans with DSM-III-defined (American Psychiatric Association 1980) PTSD showed benefit for amitriptyline and imipramine (Davidson et al. 1990; Kosten et al. 1991). A recent report suggests that the now-ignored TCAs deserve reappraisal, given their efficacy in populations with traditionally SSRI-resistant PTSD (Davidson 2015) and the superiority of desipramine over paroxetine in improving drinking-related measures in male veterans with comorbid alcohol-related disorders (Petrakis et al. 2012).
Monoamine oxidase inhibitors. In a study of male combat veterans, Kosten et al. (1991) compared phenelzine (15–75 mg/day) with placebo and found a 45% decrease in Impact of Event Scale (IES) scores from baseline for phenelzine, compared with a 5% decrease for placebo, but no improvement was noted in depressive symptoms with either treatment. The RIMA brofaromine has been assessed in two controlled trials of PTSD: a U.S. sample composed predominantly of combat veterans (n=114) (Baker et al. 1995) and a civilian European sample with few veterans (n=68) (Katz et al. 1994–1995). The U.S. study failed to show a difference between the treatments, and findings from the European study were mixed. Finally, the RIMA moclobemide was assessed in 20 subjects with PTSD meeting DSM-III-R (American Psychiatric Association 1987) criteria (Neal et al. 1997). Following 12 weeks of treatment, 11 subjects no longer met the full PTSD criteria, providing a signal that the drug might be effective in PTSD.
Selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors. Three controlled trials support the efficacy of fluoxetine in PTSD. In these studies, fluoxetine was administered at dosages of 20–80 mg/day for 5–12 weeks in samples including both civilians and combat veterans with PTSD meeting DSM-III-R (Connor et al. 1999; van der Kolk et al. 1994) or DSM-IV (Martenyi et al. 2002a) criteria. Significant improvements in clinician-rated structured interviews from baseline to end of treatment were noted, as were significant improvements in resilience and reduction in disability (Connor et al. 1999). Symptomatic improvement was noted as early as week 6 (Martenyi et al. 2002a).
Two studies of maintenance therapy with fluoxetine over a period of 1 year have shown reductions in the rate of relapse, as compared with placebo substitution (Davidson et al. 2005; Martenyi et al. 2002b).
Sertraline has been compared against placebo in 10 trials, and positive results have emerged in 3 of these (Brady et al. 2000; Davidson et al. 2001; Panahi et al. 2011), while 7 were either ambiguous or negative. A pooled analysis of the positive trials showed an early effect on anger at 1 week (Davidson et al. 2002). This finding is of significance, given that angry temperament can be associated with violence and a greater risk for cardiac events (Williams et al. 2001), as well as increased heart rate and blood pressure, in PTSD (Beckham et al. 2002). A recent placebo-controlled trial of sertraline in Iranian veterans of the Iran–Iraq war showed that sertraline was superior to placebo and was well tolerated (Panahi et al. 2011). Other short-term studies of sertraline in PTSD have been negative (Brady et al. 2005; Davidson et al. 2006b; Friedman et al. 2007; Tucker et al. 2003) or inconclusive (Zohar et al. 2002). A trial in children by Robb et al. (2010) failed to show any difference between drug and placebo.
Continued sertraline treatment over 9 months was associated with sustained improvement in more than 90% of subjects, and more than 50% of initial nonresponders responded with continued treatment (Londborg et al. 2001). Improvement was sustained over 15 months, with a relapse rate of 5% for sertraline and 26% for placebo, suggesting that the drug provides prophylactic protection against relapse (Davidson et al. 2001). Sertraline was also effective in improving quality of life and reducing functional impairment, with more than 55% of patients functioning at levels within 10% of the general population. These gains were maintained with long-term treatment, whereas treatment discontinuation was more likely to lead to deteriorating function, although not to levels observed prior to treatment (Rapaport et al. 2002).
The efficacy of paroxetine in PTSD has been shown in two 12-week controlled multicenter trials, including flexible-dose (n=307; paroxetine 20–50 mg/day) (Tucker et al. 2001) and fixed-dose (n=451; paroxetine 20 mg/day or 40 mg/day) (Marshall et al. 2001) regimens. Compared with placebo, paroxetine produced significant improvement in overall PTSD symptomatology, individual symptom clusters, and functional impairment. Response rates ranged from 54% to 62% for paroxetine, compared with 37% to 40% for placebo.
Findings from two open-label studies of fluvoxamine at dosages of 100–250 mg/day—an 8-week study in civilians (n=15; Davidson et al. 1998) and a 10-week study in combat veterans (n=10; Marmar et al. 1996)—showed that the drug was effective in treating PTSD symptoms. Treatment with fluvoxamine (mean=194 mg/day) also was associated with significant improvement in autonomic reactivity, with reductions in heart rate and blood pressure on exposure to trauma cues to levels that are indistinguishable from those of control subjects (Tucker et al. 2000). These findings are encouraging, although larger controlled trials are needed to determine the efficacy of the drug in PTSD.
Two large multicenter studies have established efficacy for venlafaxine XR up to 300 mg per day, in one case for as long as 6 months. Rates of remission exceeded 50% in the longer-term trial, and resilience was significantly improved in one of the two studies (Davidson et al. 2006a, 2006b).
In summary, the SSRIs are efficacious in the treatment of PTSD, and paroxetine IR and sertraline are approved for PTSD treatment. SSRIs and SNRIs show a broad spectrum of activity, with significant reduction in some symptoms as early as 1–2 weeks after treatment initiation, sustained and continued improvement, and in some cases remission, with long-term treatment up to 15 months. These drugs are generally well tolerated, although some adverse effects (e.g., sexual dysfunction, sleep disturbances, and weight gain) may lead to treatment discontinuation.
Other antidepressants. An 8-week controlled trial of mirtazapine in 29 outpatients with PTSD showed a 65% response rate on clinician-rated global assessment with mirtazapine compared with a rate of 20% with placebo, with significant improvement on several measures of PTSD as well as general anxiety (Davidson et al. 2003).
Six open-label studies of nefazodone in civilians and combat veterans with PTSD have been reported (Hidalgo et al. 1999). Treatment with nefazodone (50–600 mg/day) over 6–12 weeks was associated with significant reduction in severity of overall PTSD, as well as in each of the symptom clusters. Of particular note was improvement in sleep, which is often disrupted in PTSD and sometimes worsened by treatment with SSRIs. Davis et al. (2004) have demonstrated superior efficacy for nefazodone relative to placebo in combat veterans. However, concerns about potential liver damage have limited the drug’s use in PTSD.
Benzodiazepines are often prescribed to treat acute anxiety in the aftermath of a trauma; however, findings have been disappointing. An open-label study of alprazolam and clonazepam in 13 outpatients with PTSD found reduced hyperarousal symptoms but no change in intrusion or avoidance/numbing (Gelpin et al. 1996). In a crossover design, subjects received 5 weeks of treatment with either alprazolam or placebo followed by 5 weeks of the alternative therapy (Braun et al. 1990). Minimal improvement was observed in anxiety symptoms overall, with no improvement in core PTSD symptoms. Clonazepam 2 mg was not different from placebo in controlling nightmares in a 2-week single-blind crossover study in which the test drug was added to preexisting treatment (Cates et al. 2004). Thus, the evidence does not support the use of benzodiazepines in the management of core PTSD symptoms, even though they appear to be widely used for that purpose (Mellman et al. 2003). Furthermore, a recent meta-analysis of the efficacy of benzodiazepines in the treatment of PTSD found them to be not only ineffective but also potentially harmful, in terms of increasing the risk of developing PTSD if prescribed after recent trauma as well as worsening aggression, depression, and comorbid substance use (Guina et al. 2015), Benzodiazepines should therefore be considered relatively contraindicated for use in PTSD or after recent trauma exposure.
Lipper et al. (1986) proposed that the pathophysiology of PTSD may involve sensitization and kindling processes and, to this end, that anticonvulsants might be of therapeutic benefit. In testing this hypothesis, Lipper and colleagues found that 7 of 10 Vietnam War veterans who received open-label carbamazepine (600–1,000 mg/day) for 5 weeks reported improvement, particularly in intrusion and hyperarousal symptoms. Three subsequent open-label studies, two with sodium valproate in combat veterans (Clark et al. 1999; Fesler 1991) and one with adjunctive topiramate in a civilian PTSD sample (Berlant and van Kammen 2002), also reported positive effects. However, two more recent double-blind, placebo-controlled trials of divalproex monotherapy in combat veterans with PTSD were negative (Davis et al. 2008a, n=85; Hamner et al. 2009, n=29).
Topiramate has received mixed reports in PTSD. An initial trial was negative (Tucker et al. 2007); however, a more recent double-blind, placebo-controlled trial in 70 civilians (men and women) showed positive effects on re-experiencing and numbing/avoidance symptoms for topiramate at a mean dosage of 102.9 mg/day (Yeh et al. 2011). Topiramate at dosages up to 300 mg/day in a prospective 12-week, randomized, placebo-controlled, flexible-dose trial also decreased alcohol consumption and cravings and improved hyperarousal symptoms in 30 veterans diagnosed with PTSD and alcohol use disorder (Batki et al. 2014).
The largest placebo-controlled trial of an anticonvulsant to date found no difference between tiagabine (at a dosage of up to 16 mg/day) and placebo in a 12-week multicenter trial in 232 patients (Davidson et al. 2007). In a small placebo-controlled trial of lamotrigine (200–500 mg/day) in 15 outpatients (Hertzberg et al. 1999), a response rate of 50% was noted with lamotrigine, compared with a placebo response rate of 25%.
Antipsychotics. In a monotherapy trial of olanzapine (Butterfield et al. 2001), 15 subjects were randomly assigned 2:1 to treatment with olanzapine (up to 20 mg/day) or placebo. No differences were observed between the treatments; however, it is difficult to interpret the findings in this small sample, especially given the high placebo response rate (60%). In a recent small randomized, placebo-controlled trial of flexible-dose olanzapine monotherapy in a population with non-combat-related chronic PTSD, olanzapine was found to be superior to placebo, though approximately half of the patient sample experienced significant weight gain (Carey et al. 2012). Other reports of antipsychotics are based on augmentation therapy in SSRI partial responders. Several placebo-controlled studies, mainly of augmentation therapy, have found superior efficacy for low-dosage risperidone in both civilian and veteran populations (Bartzokis et al. 2005; Hamner et al. 2003; Monnelly et al. 2003; Reich et al. 2004; Rothbaum et al. 2008), as well as for olanzapine (Stein et al. 2002). In the Monnelly et al. (2003) study, particular benefit was noted for irritability, and in the Hamner et al. (2003) study, psychotic symptoms were relieved. However, a recent large double-blind, placebo-controlled trial of adjunctive risperidone treatment in a patient population with military-related PTSD and SSRI-resistant symptoms found no major benefit for risperidone, although statistically significant changes occurred on some measures (Krystal et al. 2011).
In a double-blind, placebo-controlled monotherapy trial of quetiapine in 80 patients with chronic PTSD, a significant improvement in CAPS scores, as well as in reexperiencing and hyperarousal subscores, was seen by the end of the 12-week trial at an average dosage of 258 mg/day (range 50–800 mg/day) (Villarreal et al. 2016).
Prazosin and guanfacine. Raskind et al. (2003) reported encouraging results for intractable PTSD-related nightmares in a placebo-controlled crossover study of prazosin, an α1-adrenergic antagonist, at dosages of up to 10 mg/day. The initial findings were confirmed in a second and larger placebo-controlled, double-blind augmentation trial in combat veterans, using dosages of up to 15 mg daily; benefits were most apparent for nightmares and sleep quality, but the drug also produced greater global improvement (Raskind et al. 2007). In a randomized, placebo-controlled crossover study of prazosin in 13 patients with civilian trauma–related PTSD, Taylor et al. (2008) found that prazosin significantly increased total and rapid eye movement (REM) sleep time, reduced trauma-related nightmares and awakenings, and improved PCL and CGI scores. A study comparing prazosin with quetiapine for nighttime PTSD symptoms found similar short-term effectiveness for the two drugs but a greater likelihood of treatment discontinuation due to adverse effects for quetiapine (Byers et al. 2010). A recent randomized controlled 15-week trial in active-duty soldiers showed prazosin to be effective in decreasing global PTSD symptoms and to be well tolerated at maximum dosages of up to 25 mg/day for men and 12 mg/day for women (Raskind et al. 2013).
In contrast, two placebo-controlled studies of the α2-adrenergic agonist guanfacine in veterans with PTSD found no benefit (Davis et al. 2008b; Neylan et al. 2006).
Additional approaches. Given the prevalence of comorbid depression with PTSD and the effectiveness of triiodothyronine (T3) augmentation in some individuals with treatment-refractory depression, it is possible that T3 augmentation also may be of benefit in PTSD. Five subjects with PTSD taking an SSRI were treated with open-label T3 (25 μg/day) for 8 weeks (Agid et al. 2001). Improvement was noted as early as 2 weeks, and by the end of treatment, four of the five subjects showed at least partial improvement in depressive symptoms and hyperarousal. The mechanism for these effects is unknown, and further controlled studies of this augmentation strategy are needed. Cyproheptadine, an antihistaminic drug, was no more effective than placebo for nightmares over 2 weeks in a series of 69 combat veterans with PTSD (Jacobs-Rebhun et al. 2000). The naturally occurring compound inositol was ineffective in a small placebo-controlled trial (Kaplan et al. 1996). Innovative treatments with some promise include the NMDA agonist D-serine (Heresco-Levy et al. 2009; de Kleine et al. 2012) and the neurokinin-1 receptor antagonist GR205171 (Mathew et al. 2011).
Low-intensity repetitive transcranial magnetic stimulation (rTMS)—in particular, right-sided rTMS applied to the dorsolateral prefrontal cortex (Boggio et al. 2010)—has shown some promise in PTSD, as has acupuncture (Hollifield et al. 2007). An open trial of electroconvulsive therapy (ECT) in 20 patients with chronic, treatment-refractory PTSD showed improvement in CAPS-rated PTSD symptoms, independent of depressive symptoms (Margoob et al. 2010). Larger double-blind studies are needed before these somatic treatments can be recommended for PTSD.
An open trial in 166 active-duty soldiers with multiple combat deployments reported that stellate ganglion block led to improvement in PCL scores that was sustained at 6 months (Mulvaney et al. 2014). However, a recent randomized, placebo-controlled trial of this procedure in 42 military service members with PTSD found no benefit (McLay et al. 2015).
Ketamine infusion was compared with an active placebo control (midazolam) in a randomized, double-blind, crossover trial in 41 subjects with chronic PTSD (Feder et al. 2014). The authors reported rapid and significant reduction in PTSD symptoms 24 hours after the infusion, as well as improvement in comorbid depression. Larger controlled trials are needed to further assess the benefits of this intervention.
CBT has been extensively studied in PTSD and shows overall efficacy (Bisson and Andrew 2005). In one large well-designed multicenter trial (Schnurr et al. 2007), the effect size and number-needed-to-treat results for CBT were of the same order of magnitude as those found in comparable trials of antidepressant drugs for PTSD. However, there are only limited data on the combined use of antidepressants and CBT (Rothbaum et al. 2006; Schneier et al. 2012; Simon et al. 2008), and there have been no head-to-head trials of CBT and medication monotherapies. Exposure is regarded as the key therapeutic principle in the numerous variants of CBT and is recommended as a first-line treatment for PTSD. Modest preservation of gains is found at long-term follow-up (Bradley et al. 2005), but much pathology remains.
There has been recent interest in enhancement of exposure therapy by using nonantidepressant drugs that modulate memory through one of the following mechanisms: 1) strengthening fear extinction learning, 2) disrupting memory consolidation, or 3) enhancing engagement in therapy (Dunlop et al. 2012). Among agents in the first category are D-cycloserine, yohimbine, methylene blue, and hydrocortisone. The second category includes propranolol, mifepristone, and rapamycin. The last category refers specifically to 3,4-methylenedioxymethamphetamine (MDMA), with more than one positive trial of MDMA in facilitation of intensive psychotherapy (White 2014). At present, the evidence for drug-based enhancement of exposure therapy for PTSD is not clear, and the long-term deleterious effects of such interventions need to be studied further, but it may be a promising therapeutic approach.
ASD develops shortly after a traumatic event; it includes symptoms of intrusion, negative mood, dissociation, avoidance, and arousal that persist for at least 3 days and up to 1 month following the trauma and that cause significant distress and/or functional impairment (American Psychiatric Association 2013). ASD was first included in DSM-IV and further modified in DSM-5, and it has been suggested that early intervention may help to alter the course of PTSD, which would imply early identification and treatment of those with or at risk for ASD.
The effects of open-label treatment with risperidone have been reported in four inpatient survivors of physical trauma with ASD; this drug showed possible benefit in flashback symptoms (Eidelman et al. 2000).
A controlled pilot study assessed the effects of low-dosage imipramine compared with chloral hydrate in 25 pediatric burn patients with ASD (Robert et al. 1999a). After 1 week of treatment, 38% of the subjects responded to treatment with placebo, compared with 83% responding to imipramine, and an early report noted reduction in intrusion and hyperarousal symptoms (Robert et al. 1999b). Unfortunately, a subsequent placebo-controlled trial failed to replicate these promising initial findings (Robert et al. 2008).
The effects of β-adrenergic blockade in reducing subsequent PTSD following acute trauma were also evaluated (Pitman et al. 2002). Within 6 hours of the trauma, subjects were treated with either propranolol (n=18; 40 mg four times per day) or placebo (n=23) for 10 days, followed by a 9-day taper period. PTSD was noted in 30% of the placebo group compared with 10% of the propranolol group 1 month after the trauma, and at 3-month follow-up, physiological arousal rate to trauma cues was 43% in the placebo group compared with 0% of the propranolol group. However, a follow-up double-blind, randomized controlled 14-day trial of propranolol and gabapentin versus placebo, administered within 48 hours of admission to a surgical trauma unit, did not demonstrate any benefits of the two active drugs over placebo on depressive or PTSD symptoms (Stein et al. 2007).
A short-term trial with temazepam versus placebo in the acute aftermath of trauma showed no long-term benefits and possibly worse PTSD outcomes at 6-week follow-up (Mellman et al. 2002).
Three promising studies have found greater long-term benefit for short-term hydrocortisone versus placebo in high-risk subjects recovering from septic shock, cardiac surgery, or acute respiratory distress syndrome (Hauer et al. 2009; Schelling et al. 2006). In subpopulations with critical illness–related corticosteroid insufficiency, this might be an attractive treatment approach for preventing PTSD. One limitation of the authors’ work, however, has been the absence of baseline PTSD ratings before administration of hydrocortisone.
SSRI trials in ASD have been negative so far. Shalev et al. (2012) showed that prolonged exposure therapy and cognitive therapy both initially prevented PTSD in recent trauma survivors with ASD at the 1-month and 5-month follow-ups, whereas escitalopram did not. However, at the 36-month follow-up, the study groups (prolonged exposure, cognitive therapy, escitalopram, placebo, and no intervention) had similar PTSD rates, as measured by the CAPS (Shalev et al. 2016). Similarly, a double-blind, placebo-controlled 24-week trial in 31 subjects with full or partial ASD showed no difference between escitalopram and placebo (Suliman et al. 2015).
Treatment with morphine in the immediate aftermath of traumatic injury was associated with lower rates of PTSD in a sample of 696 U.S. military personnel identified through records review (Holbrook et al. 2010). Morphine may act by inhibiting stress-enhanced fear learning; however, further studies are needed to assess the immediate and long-term effects of this intervention. Shortened forms of CBT appear to be effective for acute PTSD-like states, with persistence of gain at 4-year follow-up (Bryant et al. 1998, 2003).
Twenty years ago, few would have thought that one class of drugs, the SSRIs, all of which were initially introduced for depression, would have established primacy in most major anxiety (or anxiety-related) disorders. Their position is based on numerous placebo-controlled trials, and they are considered first-line drugs for treatment of these disorders, followed closely by the SNRIs. There is evidence that these drugs also offer some protection against relapse. However, they are not 100% successful, they carry some limiting side effects, and they may require supplementation with, or substitution by, drugs from other categories. We have reviewed the main clinical trials of these other drugs and expect further progress in the pharmacotherapy of anxiety and related disorders, with both established drugs and novel categories. Among many unexplored areas, we need to know more about the treatment of resistant and comorbid anxiety disorders, combined psychotherapy and pharmacotherapy interventions, the comparative efficacy of pharmacotherapy and psychosocial treatments, and possible early interventions that may help prevent and/or alleviate the severity and chronicity of these conditions.
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