Novel Treatment Approaches for Refractory Anxiety Disorders

INTRODUCTION

Remarkable progress has been made in the development of medication and psychosocial treatment strategies for anxiety disorders (Ballenger, 2001). However, many patients remain symptomatic despite improvements in therapy. Randomized, controlled trials (RCTs) of pharmacotherapy for anxiety disorders report response rates of 40–70% and remission rates of 20–47% (Ballenger, 1999). In addition, these reported improvement rates may be overestimates because of selection bias, failure to publish negative trials, and exclusion from RCTs of clinically relevant patients with comorbid psychiatric or medical disorders (Roy-Byrne and Cowley, 1998). Anxiety disorders are considered treatment resistant when there are residual symptoms or when symptoms do not improve at all after some form of therapeutic intervention. However, research on treatment-resistant anxiety disorders has lagged behind similar studies of schizophrenia and major depressive disorder (Roy-Byrne and Cowley, 1998). Clearly, much work is needed to advance therapeutic strategies and improve rates of clinically meaningful benefit for patients with treatment-resistant anxiety disorders.

The Anxiety Disorders Association of America convened a 2-day conference in Chantilly, Virginia on June 16–17, 2003 to address the issue of treatment-resistant anxiety disorders and review promising, novel therapeutic approaches. The conference consisted of presentations, open discussions, and workgroup sessions by clinicians and researchers in the fields of psychosocial therapies, psychopharmacology, and neurobiology (Appendix). The panel did not consider obsessive-compulsive disorder (OCD) because some believe that it may be better conceptualized as part of the obsessive-compulsive spectrum disorders and may be moved to a separate diagnostic category in the fifth edition of the diagnostic and statistical manual of mental disorders (DSM-V) (Hollander and Zohar, 2004). In this article, we consider issues associated with treatment resistance, cognitive behavioral therapy (CBT), pharmacologic approaches, and new drug discovery. The review of CBT approaches discusses factors associated with poor response to psychotherapy and focuses on extinction-based learning, which is a concept that can be applied to all anxiety disorders. The pharmacotherapy sections review reported novel pharmacological strategies for refractory anxiety and potential new targets for drug development. Finally, we outline research priorities for studies of treatment-resistant anxiety disorders.

THERAPEUTIC GOALS AND TREATMENT RESISTANCE

Many factors contribute to poor therapeutic response, including treatment-related factors (e.g., incorrect or incomplete diagnosis, inappropriate intervention, inadequate dosing, insufficient treatment duration), patient-related factors (e.g., comorbidity, poor adherence), and logistical factors (e.g., scarcity of trained treatment providers, inadequate insurance coverage). The dissemination of strategies to enhance appropriate diagnosis of anxiety disorders and relevant comorbidities, as well as the optimal use of pharmacologic and psychosocial strategies for their treatment is critical to improve therapeutic outcomes for affected individuals. Patient engagement, influenced by patients' beliefs about anxiety, treatment preferences, experience of stigma, and readiness to change, is also critical. Systematic efforts at optimizing treatment engagement must be addressed before patients truly can be considered to be treatment refractory. Such efforts include patient education about the natural course of the illness, the benefits of effective treatment, and expected time frame for symptom resolution. Guidance about the importance of exposure to feared situations and the use of effective coping strategies and skills development is needed to achieve maximum clinical gains. Finally, the contribution of life stressors, comorbidity, and other factors should be assessed and addressed with appropriate targeted interventions (e.g., individual, couples, or family psychotherapy for intrapsychic or interpersonal difficulties) in a patient with a suboptimal clinical outcome (Roy-Byrne and Cowley, 1998).

There is neither a universally accepted definition of treatment resistance nor consensus on the definitive number and characteristics of interventions needed to constitute an adequate treatment trial for persistently symptomatic anxiety disorders. Nonetheless, it appears intuitive that treatment goals should be to achieve well-defined therapeutic endpoints with sustained resolution of core anxiety symptoms, functional disability, and psychiatric comorbidities. Each anxiety disorder is unique in its natural course, presentation, and associated morbidity, and the metrics of response and remission must consider all affected domains, including vocational and social dysfunction and overall quality of life.

Consensus standards have been proposed for response and remission based on improvement in multiple dimensions of individual anxiety disorders (Ballenger, 2001), though there is little empiric validation for these criteria and a lack of universal adoption by leading professional societies. Nonetheless, it is encouraging that these guidelines focus on the resolution or significant improvement in core anxiety symptoms, functional impairment, and comorbid depression. Proposed general endpoints for remission across anxiety disorders include reduction in Hamilton Rating Scale for Anxiety scores to ≤7, Sheehan Disability Scale scores to ≤1 (i.e., mildly disabled), and Hamilton Rating Scale for Depression scores to ≤7. In addition, disorder-specific remission criteria include reduction in the Panic Disorder Severity Scale to <7 for panic disorder, Liebowitz Social Anxiety Scale score to ≤30 for social anxiety disorder, and the Treatment Outcome for Posttraumatic Stress Disorder (PTSD) Scale score to ≤5 or 6 for PTSD (Ballenger, 2001).

COGNITIVE-BEHAVIORAL APPROACHES

It is difficult to identify a standard trial of CBT because of the remarkable heterogeneity of interventions for anxiety disorders. For example, exposure interventions may include imaginal, in vivo or interoceptive exposure, or the use of virtual reality technology for hard-to-arrange exposures.

Attempts at defining treatment resistance in this context are fraught with difficulty given the wide range of CBT and the diversity of anxiety disorders. Nonetheless, certain key items should be addressed. An adequate course of CBT should include a full protocol of treatment, ideally defined by interventions found to be effective in at least two controlled trials. Treatment protocols often include 12–16 sessions of a combination of information, cognitive restructuring, and exposure interventions, with skill rehearsal and exposure in home-practice assignments (Barlow, 2001). The use of protocol-driven CBT for anxiety disorders is well tolerated, cost-effective, and efficacious acutely and in the long term (Foa et al., 2002; McHugh et al., in press; Otto et al., 2004), with evidence for further gains following acute CBT as patients consolidate and extend learning-based approaches (Liebowitz et al., 1999).

Supportive interventions, such as brief relaxation treatment or breathing retraining do not constitute an adequate CBT trial as these symptom management procedures alone do not, for example, add to the efficacy of CBT protocols for panic disorder (Schmidt et al., 2002). Failure to respond to an initial CBT protocol suggests the need for alternative interventions (e.g., greater attention to changing cognitions, refinement of the target or intensity of exposure interventions), other empirically supported treatments, or combined treatment modalities. Relevant recent findings on extinction learning and context that can be applied across the anxiety disorders are reviewed, and next-step strategies for non-response are considered.

EXTINCTION LEARNING AND LIMITING FACTORS

Anxiety disorders are characterized by exaggerated distress and disability in response to phobic cues. As long as an individual can learn and integrate new experiences with phobic stimuli, exaggerated responses to phobic cues should respond to extinction learning, and anxiety, thus diminish. However, this assumes that the correct fears are being targeted and appropriate learning conditions are identified and established by the therapist.

Informational and cognitive interventions often are used to facilitate and enhance initial exposure to fears, which are designed to become increasingly relevant to core fears as therapy progresses. Balance must be maintained between conditions that facilitate exposure to avoided phobic cues and conditions where exposure provides useful learning. Strategies that avert or attenuate anxiety in phobic situations (i.e., “safety behaviors”) may temporarily alleviate anxiety, but reduce long-term efficacy (Powers et al., 2004; Salkovskis et al., 1999).

What is learned during extinction in one context (e.g., when safety behaviors or medications are available) may not generalize to a different context (e.g., when no safety behavior or medications are available) (Bouton, 2002). Stronger findings have been reported for shifts in internal context, such as medication effects (Mystkowski et al., 2003). Therapeutic approaches for treatment-resistant anxiety disorders should include strategies that maximize fear extinction during exposure and generalize this learning across contexts, seeking to reverse the effects of distraction, safety cues, and context shifts on the longer-term acquisition of a sense of safety when confronted by phobic cues (Powers et al., 2006).

Attention to shifts in context, specifically internal context provided by pharmacotherapy, is relevant to combining medications with CBT. Context effects may explain the loss of efficacy seen in combination treatment trials when medications are later discontinued (e.g., Barlow et al., 2000). However, maintenance and extension of treatment gains are common when CBT is provided during and after medication taper (Otto et al., 2002).

Context effects introduce additional complexity into the selection of the next-step strategy following partial response to CBT. Should patients be switched to pharmacotherapy, risking the introduction of context effects that may require additional CBT to prevent relapse in the future? If there was no response to CBT, then there is little reason to be concerned about context effects introduced by medications. However, if patients achieved a partial response to CBT, further honing of the targets of CBT interventions and identification of context effects that may be preventing generalization of exposure-based learning should be considered before addition of pharmacologic alternatives.

There is a dearth of evidence addressing whether troubleshooting and persisting with CBT is better than switching treatment modalities (Kampman et al., 2002). In one small randomized trial, continuation of exposure-based treatment alone was at least as effective as its combination with imipramine or cognitive therapy (Fava et al., 1997). Further, dropout data from controlled trials of CBT and pharmacotherapy indicate that CBT tends to be more tolerable and acceptable than medication alternatives (Otto et al., 2005). Nonetheless, non-response to initial CBT does provide a call to therapists to re-evaluate whether core fears are being adequately targeted by cognitive and exposure interventions, with consideration of altering the timing, modality, and context (including the presence of safety cues that may undermine the efficacy of exposure treatments), to try to enhance response to additional CBT (e.g., Powers et al., 2004, 2006; Smits et al., 2006).

In addition, recent research has introduced a new approach to combined treatment, in which pharmacotherapy is used to enhance therapeutic learning rather than attenuate symptoms (Ressler et al., 2004). The N-methyl-D-aspartate (NMDA) agonist, D-cycloserine (DCS) augments extinction learning in animal models after a single dose administered immediately before extinction trials (Walker et al., 2002). In a proof of concept translational RCT, 28 patients with acrophobia were randomized to virtual-reality exposure (VRE) therapy plus one of two doses of DCS or placebo, administered before each of 2 weekly VRE sessions (Ressler et al., 2004). DCS resulted in significantly less fear of heights compared with placebo during the trial as well as following treatment. In an independent replication of the DCS enhancement effect, Hofmann et al. (2006) demonstrated better outcome in a sample of 27 outpatients with primarily generalized social anxiety disorder when treated with DCS versus placebo in the context of a five-session CBT protocol combining study pills with the latter four sessions of increasingly challenging public speech exposures. Furthermore, recent evidence also supports the efficacy of combined treatment with DCS for OCD, although there are indications that with ongoing exposure therapy CBT alone can catch up to the boost in efficacy provided by DCS (Kushner et al., in press). If these promising findings are further replicated, this strategy for combined treatment suggests a potentially expeditious way to improve the speed of onset and, perhaps, overall efficacy of CBT for anxiety.

CBT FOR PHARMACOTHERAPY NON-RESPONDERS

CBT has been successfully used to facilitate discontinuation of benzodiazepines and antidepressants (Otto et al., 2002; Schmidt et al., 2002) as well as to boost response in patients who have failed previous medication trials for panic disorder and PTSD (Otto et al., 2003, 1999; Heldt et al., 2006). Accordingly, CBT remains a central strategy for patients who do not respond fully to pharmacotherapy.

PHARMACOLOGIC APPROACHES

Though not intended as a study of treatment resistance, the results of a study in PTSD have relevance for the management of treatment-resistant anxiety disorders in general. Of 128 patients with PTSD who did not respond to an acute 12-week trial of sertraline, 54% converted to responders during a subsequent 24-week continuation phase (Londborg et al., 2001), suggesting that treatment may need to be continued for months beyond the typical acute 6–12-week course to consider a patient truly treatment refractory. However, as it is frequently difficult for patients to adhere to treatment for months with an inadequate response, initiation of alternative or additional treatment strategies is often necessary to maintain a sense of therapeutic optimism.

As is true for CBT, there is a relative dearth of data about pharmacotherapy for treatment-resistant anxiety disorders. Most available information comes from small, open-label, or retrospective reports. Nonetheless, the need for more effective and better-tolerated treatments has prompted exploration of pharmacological augmentation, novel uses of non-traditional anxiolytic drugs, and new drug development. No drug has yet received FDA approval for refractory anxiety so, as is typical in the management of refractory states, use of pharmacologic strategies in this context is off-label. In this section, we note evidence from randomized controlled trials (and in their absence, case series or reports) on pharmacotherapy for refractory anxiety disorders and novel uses of non-traditional antianxiety agents.

ATYPICAL ANTIPSYCHOTICS

Augmentation of existing antianxiety treatments with atypical antipsychotics having mixed effects at dopaminergic and serotonin receptors appears to be an effective strategy for refractory anxiety disorders as evidenced by double-blind randomized controlled trials with risperidone and olanzapine for generalized anxiety disorder (GAD) (Brawman-Mintzer et al., 2005; Pollack et al., 2006) and PTSD (Bartzokis et al., 2005; Hamner et al., 2003; Monnelly et al., 2003; Stein et al., 2002). Further there are case studies reporting the efficacy of olanzapine for refractory panic disorder (Etxebeste et al., 2000; Khaldi et al., 2003) and one small randomized controlled trial with olanzapine monotherapy suggesting its efficacy in social anxiety disorder (though not specifically refractory patients) (Barnett et al., 2002).

ANTICONVULSANTS

Open-label case reports and case series suggest the adjunctive efficacy of anticonvulsants for refractory GAD, including gabapentin, which acts as an α₂ delta voltage-gated, calcium ion channel antagonist and may enhance γ-aminobutyric acid (GABA) synthesis (Pollack et al., 1998), the voltage-gated calcium channel modulator levetiracetam (Pollack, 2002) and the selective GABA reuptake inhibitor tiagabine (Crane, 2003). In addition, reports suggest efficacy for gabapentin (Pollack et al., 1998), tiagabine (Zwanzger et al., 2001), and valproic acid (Ontiveros and Fontaine, 1992) for refractory panic. Further, case and chart reviews describe the potential efficacy of the addition of gabapentin (Brannon et al., 2000), topiramate (Berlant and van Kammen, 2002), tiagabine (Berigan, 2002), phenytoin (Bremner et al., 2004), valproate (Szymanski and Olympia, 1991), and levetiracetam (Kinrys et al., 2006), in individuals with civilian or combat-related PTSD, providing signals for efficacy in the domains of sleep duration, nightmare frequency and severity, and intrusive recollections. Likewise, efficacy was suggested for topiramate, an anticonvulsant that blocks sodium channels, increases GABA levels, and potentiates GABA activity at non-benzodiazepine receptors (Shaywitz and Liebowitz, 2003; Van Ameringen et al., 2004), valproic acid (Kinrys et al., 2003), and levetiracetam (Simon et al., 2004) in open-label trials in social anxiety disorder.

Though not specifically tested in refractory patients, pregabalin, an α₂ delta voltage-gated, calcium ion channel antagonist that has anticonvulsant and analgesic effects has been demonstrated to be effective for GAD and social anxiety disorder in controlled trials (Feltner et al., 2000; Rickels et al., 2005), with suggestions of an onset of anxiolytic response similar to the benzodiazepine comparator. Similarly, lamotrigine, an antagonist at sodium and calcium channels as well as a modulator of GABA and glutamatergic activity, was demonstrated effective in a small, randomized placebo-controlled study of individuals with PTSD (Hertzberg et al., 1999), as was gabapentin in an RCT for social anxiety disorder (Pande et al., 1999a).

NOVEL USES OF NON-TRADITIONAL ANXIOLYTICS AND OTHER PHARMACOLOGIC STRATEGIES

Pindolol, a β-blocker with antagonist effects on the 5HT_1A autoreceptor (thus potentially facilitating serotonergic activity) was demonstrated effective in a double-blind randomized, placebo-controlled trial of selective serotonin reuptake inhibitor (SSRI)-resistant panic disorder (Hirschmann et al., 2000), though not social anxiety disorder (Stein et al., 2001), with significant improvement observed at 2 weeks. Prazosin, a centrally active α₁-adrenergic antagonist, showed evidence of efficacy for the treatment of nightmares, sleep disturbance, and overall PTSD symptoms in a 20 week, double-blind, placebo-controlled crossover study of 10 combat veterans with chronic PTSD (Raskind et al., 2003). Similarly small case series suggest the potential efficacy of combined treatment with a tricyclic antidepressant and SSRI for panic disorder refractory to antidepressant monotherapy (Tiffon et al., 1994), buspirone augmentation of SSRI non-responders with social anxiety disorder (Van Ameringen et al., 1996) and the addition of triiodothyronine for PTSD (Agid et al., 2001).

NEW TARGETS FOR DRUG DEVELOPMENT

A tremendous research effort is underway to discover drugs that target specific neuronal systems involved in mediating the stress response. By focusing on discrete neurobiological pathways, it is hoped that anxiolytic drugs will be discovered that normalize pathological activity in brain circuits and produce fewer adverse effects, including tolerance, dependence, and withdrawal effects (Nemeroff, 2003). Identification of multiple serotonin receptors has allowed investigation of compounds that act selectively at individual receptors and may be better tolerated than currently available SSRIs. Drugs with GABA-potentiating properties that are distinct from those of the benzodiazepines also are being studied as anxiolytics, as in the studies of the anticonvulsants described earlier. The GABA-A α₂ subtype has been identified as a potential target for anxiolytic effects without sedation or dependence (Mohler et al., 2001).

Some of the most promising avenues of new drug development involve non-monoamine, non-GABA neurotransmitters. For example, substance P (tachykinin NK1), corticotropin-releasing factor (CRF), L-glutamate, and other neurotransmitters that are pivotal to the regulation of anxiety and stress responses may be ideal targets for new drug development. Reports from preclinical studies have shown that manipulation of these neuronal systems produces evidence of anxiolytic and antidepressant effects.

NEXT-GENERATION SSRIS

The SSRIs increase available serotonin in the synapse and lead to indiscriminate activity at multiple different serotonin receptors, some of which are believed to be associated with SSRI-related side effects. The observations that mice lacking 5-HT_1A receptors exhibit pronounced anxious and fearful behaviors and do not respond to SSRIs (Gross et al., 2002) has led to studies of specific postsynaptic 5-HT_1A receptor agonists as possible treatments for anxiety disorders (Gorman, 2003). A recent neurobiological substrate has been identified for treatment resistance in anxiety disorders to SSRIs. Subjects with generalized social anxiety disorder possessing the “short” arm of the serotonin transporter gene were significantly less likely to respond (40% non-responder rate) to maximally titrated SSRIs in comparison to subjects with the “long” arm of the serotonin transporter gene (Stein et al., 2006). Similar results for SSRI treatment resistance have been noted in panic disorder (Perna et al., 2005). It is not clear what the functional consequences of possession of the short versus long arm of the serotonin transporter imply, but these important observations may provide clues to the pharmacogenomic underpinnings of SSRI treatment resistance.

NEUROPEPTIDES

Neuropeptides are short-chain amino acids that act as neurotransmitters in regions of the brain involved with regulation of mood and stress responses. Recognition of a large number of neuropeptide targets for anxiety disorders has provided the rationale for studies of small-molecule neuropeptide receptor ligands. Some of the most promising neuropeptide targets for anxiolytic drug discovery are substance P, CRF-1, CRF-2, neuropeptide Y, CCK-2, and galanin (Herranz, 2003; Holmes et al., 2003). A cholecystokinin (CCK) antagonist has been studied in patients with panic disorder (Pande et al., 1999b) and GAD (Adams et al., 1995), but was not more effective than a placebo. A possible explanation for the failure of the CCK antagonist to demonstrate its efficacy may be related to its relatively poor penetration.

The substance P antagonists are being investigated as treatments for depression and anxiety disorders. In late 2003, further development of MK-869, a substance P (NK1) antagonist that was studied through phase III clinical trials of depression (Kramer et al., 1998), was halted because of a failure to demonstrate efficacy. A second NK1 antagonist, L759274, is being studied in depression (Kramer et al., 2004). Efficacy of the CRF-1 receptor antagonist, R121919, was suggested by the findings of a small, open-label study of patients with major depression (Zobel et al., 2000). However, development of R121919 is no longer being pursued because of concerns about hepatotoxicity. Clinical trials of other CRF-1 receptor antagonists are currently underway (Gorman, 2003).

OTHER MOLECULAR TARGETS

Other molecular targets are being investigated as avenues toward anxiolytic drug development. The excitatory neurotransmitter, L-glutamate, and its NMDA and metabotropic glutamate (mGlu) receptors are potential drug development targets. The non-competitive NMDA receptor antagonists (MK-801) and mGlu receptor agonists (LY354740) possess antidepressant and anxiolytic properties preclinically (Papp and Moryl, 1994; Schoepp et al., 2003), and the NMDA receptor antagonist, riluzole (Mathew et al., 2005) has been observed to exert anxiolytic effects in patients with anxiety disorders. In contrast, the NMDA partial agonist, DCS, failed to show efficacy in a small pilot study in patients with PTSD (Heresco-Levy et al., 2002), although, as noted, appeared to enhance the effect of CBT in the treatment of acrophobia and social anxiety disorder (Hofmann et al., 2006; Ressler et al., 2004). Brain-derived neurotrophic factor (BDNF), which is critical to neuronal plasticity, is inhibited by stress and has therefore been recognized as a potential target for drug development in mood and anxiety disorders (Hall et al., 2003; Rasmusson et al., 2002). Neurosteroid modulators of the GABA system, such as allopregnanolone, are being studied for anxiolytic effects (Lydiard, 2003). Other molecular targets of interest are the opioid receptor partial agonists (Dautzenberg et al., 2001) and cytokine modulators (Koh and Lee, 2004).

FUTURE DIRECTIONS

The most pressing research priorities for advancing the treatment of refractory anxiety disorders were identified. There is a remarkable lack of empirical data in this area. When data are available, it is often obtained from small controlled trials, open-label pilot studies, case reports, or chart reviews. Therefore, the following list of research priorities are evidence-based when possible, but also include suggestions that are based on the opinions and clinical experiences of the experts who participated in this conference.

RESEARCH PRIORITIES FOR PSYCHOTHERAPY AND PHARMACOTHERAPY TRIALS

RESEARCH PRIORITIES FOR NEW DRUG DEVELOPMENT

CONCLUSIONS

Anxiety disorders are common and are associated with significant distress and dysfunction. Currently available interventions have demonstrable efficacy for reducing anxiety-related symptomatology. However, many patients remain symptomatic despite treatment, and a significant proportion remain impaired. Despite this, few controlled studies address inadequate treatment response in anxiety disorders. The need for refined CBT strategies pales in comparison to the importance of disseminating CBT for anxiety disorders more generally, as these interventions are rarely received by patients in clinical practice (Goisman et al., 1999). These data join a larger literature indicating that in clinical care across the United States, few patients receive an adequate “dose” of psychotherapy (Hansen et al., 2002), a finding that is in concordance with the high rates of inadequate pharmacotherapy observed in primary care and specialty care settings (Roy-Byrne et al., 1999; Wang et al., 2000; Weilburg et al., 2003). Optimal use of available medications and the development of novel pharmacological strategies and agents along with the further application of empirically derived psychosocial therapies offer promise in improving this current situation, but a concerted research effort is warranted to systematically evaluate potential areas of importance and prudently use scarce resources. This article summarizes the current state of knowledge and serves as a call to action to mobilize efforts aimed at improving the lives of the many individuals who are adversely impacted by anxiety disorders.