Several epidemiological studies confirmed that Anxiety Disorders as a group are the most prevalent psychiatric conditions in the United States. The importance of these conditions is underlined by the fact that they cause significant disability, poor quality of life, alcohol and drug abuse. Anxiety disorders are treatable conditions and respond to the front-line interventions such as serotonin reuptake inhibitors and cognitive behavioral therapy. However, only about 60% of patients respond to those treatments to any significant degree. Many still have residual symptoms or stay treatment refractory. The group of anxiety patients that is resistant to the treatment has been shown to have very poor quality of life and have highest rate of suicidal attempts than any other disorders. Many biological, treatment specific and social factors are affecting treatment resistance. In this paper, we are attempting to review reasons for the treatment resistance. In addition, we would like to review current strategies that could be helpful in reducing treatment resistance and aiding people chronically suffering from these severe and disabling conditions.
Anxiety disorders, which include Obsessive Compulsive Disorder, Panic Disorder, Social Phobia, and Generalized Anxiety Disorder, are the largest and the most prevalent group of psychiatric disorders.1, 2, 3 They are also least recognized compared with other major psychiatric syndromes such as mood or psychotic disorders. In fact, although the Epidemiological Catchments Area study first revealed the prevalence of this group of disorders over 20 years ago, they remain poorly understood, understudied, and inadequately treated. Nevertheless, this group is responsible for decreasing productivity, and increasing morbidity, mortality, and alcohol and drug abuse in a large segment of the population.4, 5, 6
A listing of each anxiety disorder and the prevalence rate over 12 months is listed in Table 1.7 The lifetime prevalence estimated without an adjustment for clinical significance is twice the annual prevalence rate indicating that 28.8% or roughly one out of three people has a risk of meeting criteria for an anxiety disorder sometime at some point in their life. In addition, there is a large co-morbidity and overlap with other disorders, specifically with major depression. Furthermore, more mild forms of anxiety disorders can result in permanent disability and even death.8, 9
Anxiety disorders have a serious impact on the health care. That impact is explained not by the cost of treatments of the disorder but by the high cost of frequent medical evaluations and treatment of physical manifestations of the disorder (i.e., muscle pains, aches). Unlike other serious mental conditions where cost is measured by complete disability and inpatient care, in anxiety disorders patients have decrease of productivity and quality of life that are more difficult to measure. However, some studies report that the decrease in productivity and quality of life of severely ill and/or treatment-resistant anxiety patients was comparable to those of schizophrenics.10, 11 Anxiety Disorders Association of America estimates the costs to be over 42 billion dollars per year comparable to those of stroke and cardiovascular disorders.12
Standard treatment of anxiety disorders
Over the last two decades, significant progress has been made in the area of treatment for anxiety disorders. Evidence-based treatments are available for each anxiety disorder with the efficacy of psychological and biological treatment between 60 and 85%.13, 14, 15, 16, 17 Table 2 details the first line pharmacological treatments that are available and FDA approved for the treatment of the anxiety disorder. The selective serotonin reuptake inhibitors (SSRIs) are prescribed as first-line treatments according to most commonly used algorithms and physician guidelines.18 Patients who show immediate intolerance to SSRIs are tried on serotonin norepinephrine reuptake inhibitors (SNRIs) or tricyclic antidepressants and MAOIs that used to be used in practice and research prior to introduction of SSRIs with approximately the same success but with less favorable tolerance (Table 3). The second large group of medications includes benzodiazepines such as alprazolam (Xanax), clonazepam (Klonopin) and lorazepam (Ativan). Benzodiazepines have proven efficacy (over 80% response) and FDA approval for use on generalized anxiety and panic disorder.19 These agents, however, have potential to cause tolerance and dependence, which currently limits their use.20
Cognitive-behavioral treatment of anxiety disorders has also been accepted as a first-line treatment showing response rates in the range of 60–90%.21 However, 10–40% of patients do not respond to psychological treatments and many more have residual symptoms.22 This situation is rather unacceptable taking into account the high prevalence of the disorder, which means that many millions of people continue suffering from anxiety even if they received the best possible treatment. There is a great need to study treatment resistance in anxiety patients. In this article, we will review factors that appear to contribute to treatment resistance in anxiety and review the ways clinicians and researchers address this problem.
Definition of the treatment resistance
First of all we need to define the treatment resistance. The definition of treatment resistance is reversely related to the definition of remission and recovery that has been explored and debated in the field of depression.23, 24 In the field of anxiety, this issue is more complicated.25 The absence of anxiety does not always mean recovery. It frequently does not even mean improvement since a phobic patient can have no anxiety when they can successfully avoid a phobic situation. On the other hand, the presence of anxiety does not always indicate pathology and could be a normal response to an ongoing stress. The assessment of remission and recovery in anxiety patients should be multidimensional and should always include functional parameters. If we apply this criterion, the recovery from anxiety states becomes a relatively rare event due to chronic and waxing and waning course.26, 27 We need to probably apply a different and more lax criterion, which is restoration or near restoration of functional status in the presence (absence) of tolerable treatment. With this lax criterion, one can assume that approximately 30% of patients would be considered recovered from the standard treatments and 30–40% of patients would be considered improved. Still 30% of the patients would be barely touched by the contemporary treatments.28
Mechanisms of resistance
Diagnostic factors participating in treatment resistance
Many studies have attempted to analyze predictors of response or conversely nonresponse in anxiety disorders. The factors participating in treatment resistance can be roughly classified as pathology related, environment related, patient related and clinician related (see Table 4). Several factors may be participating in the confusion within this area of research. The diagnostic criteria of anxiety disorder have been changed several times over the last 20 years.29 Current diagnostic categories are essentially statistically validated lists of symptoms characteristic for a given condition. This categorization leads to several problems. For example, the disorders as described in the DSM-IV rarely exist in their pure form, at least in clinically significant cases. There is large overlapping among anxiety disorders themselves and with other disorders that interfere with specificity of clinical management and research.30 Attempts to resolve this issue lead to dimensional or symptomatic or to spectrum approach that leads to other set of problems such as overgeneralization. For example, a widely accepted obsessive-compulsive disorder (OCD) spectrum includes a very diverse group of disorders ranging from autism to kleptomania.31 One of the issues is that symptoms elicited on a cross-sectional interview do not provide us with the full presentation of the disorder. It has been noted that symptoms such as obsessions and compulsions are functionally related to each other but this notion is rarely used in other disorders. Thus, current cross-sectional diagnosis may be one of the factors complicating our ability to effectively treat the anxiety disorders since most of the biological treatments are developed as diagnosis specific (which they are not.)
Additional diagnostic factors of treatment resistance include the presence of personality disorders. This could include the personality disorders that could be confused with anxiety disorders. The examples are OCD personality disorder that could be confused with OCD and borderline personality that is frequently present with panic attacks. Those disorders need to be recognized early in the treatment so that appropriate psychotherapeutic treatments could be administered.
Biopsychosocial models of anxiety and treatment resistance
The exact biological mechanisms of anxiety disorders are unknown.32 Multiple theories exist on different levels of science ranging from molecular all the way to the psychosocial. None of the theories can fully explain the complexity of the anxiety disorders. Biological theories attempt to postulate anxiety as an alarm reaction mediated by specific brain circuits.33 These circuits include amygdale and other limbic structures.34 Activation of these circuits are most often found in animal models and human neuroimaging studies of Panic Disorder and Generalized Anxiety.35 Some other anxiety disorders, such as OCD, have a disturbance of circuits responsible for emotional information processing and integration. These circuits include striatum, cingulum and prefrontal and orbito-frontal connection.36 These circuits are responsible for gating, ordering and integration information about the threat.
Cognitive scientists base their theories of anxiety on a specific way of thinking that is excessive, dichotomized (i.e. back or white) and anxiety provoking.37 Behaviorists explain anxiety disorders as a set of maladaptive coping safety strategies that lead to not testing the validity of the threat and as a result increase anxiety and apprehension. While the theories do not contradict each other, we are yet to see the integration of biological and psychological mechanisms within the framework of united theory of anxiety disorders.
One of the ways to look at the interaction between the psychological and biological is to understand anxiety disorders as three interrelated processes. The first process involves the neuronal circuits responsible for the initial detection and reaction to the threat (i.e. alarm). These circuits well described by several scientists play an important role in all anxiety disorders and specifically in Panic. The amygdale and adjunct limbic system play the central role. The second process involves more extensive threat information analysis. This process is most characteristic of Obsessive Compulsive Disorder. The cortico-striatum-cortical circuit is involved in multiple functions including gating, stop-and-go, and coordination between emotional and thought processing. The disturbance of these processes leads to excessively detailed view of threat information leading in turn to the excessive perception of threat. Patient frequently focuses on a particular aspect of threat rather than all the evidence. This may lead to cognitive distortions typically described in the literature (i.e. overestimation of probability, overgeneralization and all or nothing thinking). The third process is coping with the threat. Normally everyone reacts to a threat with series of safety behaviors such as exploration of the threat, safety behaviors directed to elimination of the threat and avoidance of the threat.
The anxiety patients engage in the same behaviors but due to heightened alarm and faulty information processing their behaviors become excessive and interfere with their function instead of helping it. Excessive security behaviors (i.e. washing in OCD patients) could lead to resetting the alarm to even higher level because those behaviors invariably fail to protect 100% while taking a long time. Avoidance of threat, which is another coping strategy frequently, prevents patients from assessing the threat and as such increases the informational distortions.
Psychosocial models of anxiety underscore interplay between biological and environmental factors. Even catastrophic stressors are not always recognized by patients and their physicians. Severe persistent stressors for most part go undetected and impact the treatment response. The patient who is in the midst of a severe stress would less likely respond to the treatment.38 Unfortunately, research in assessment of environmental factors is lagging despite their importance. Especially it is true about the research directed to measure the degree of severe persistent stress.
Another major factor of treatment resistance is alcohol and drug abuse. Frequently, co-morbid in anxiety patients it is also frequently unnoticed. It can effect resistance through non-compliance and through interaction between medications and alcohol or drugs. In addition, use of alcohol to reduce anxiety could interfere with the behavioral strategies.
Predictors of nonresponse in clinical literature
The best information about patient-related factors is usually derived from analysis of predictors of response/nonresponse. Usually the factors identified by these methods related to severity of illness, co-morbidity and presence of personality disorders and noncompliance with the treatment.39, 40
Studies analyzing usual care delivery in primary care produced some insight on treatment resistance in ‘care as usual’.41 The studies indicated that inadequate recognition, inadequate training, incorrect use of antidepressants and lack of understanding and the use of CBT are among the main reasons for patient's non-response. For example, Katon determined that many patients in primary care administered medications for very short period of time.42 This is particularly important for OCD where higher than usual doses of SSRIs usually require (i.e. more than 100 mg of fluoxetine per day) usually for at least 10 weeks before one sees an adequate response. The titration could be too rapid or the doses are inadequate. Frequently, Panic patients who usually require smaller than usual doses and slower titration (i.e. 5 mg of fluoxetine initially with increases every 2 weeks) are started on 20 mg of fluoxetine causing excessive anxiety and treatment discontinuation. Patients in primary care as well in general psychiatry clinics most often do not receive correct psychological treatments.43 Patients are frequently not educated about medication response and have incorrect expectations. The literature also notes the inadequacy in training of many psychologists in contemporary methods of the treatment of anxiety.44
Strategies for improvement of treatment resistance
One of the strategies in improving outcomes and diminishing treatment resistance is reevaluation and optimization of the treatment. Patient who failed or insufficiently responded to at least two SSRI and one SNRI and a behavior therapy should be reevaluated by a psychiatrist who is familiar with the treatment of anxiety for identification of the reasons for the treatment failure. Multiple factors mentioned above should be explored. The presence of co-morbidity, personality disorder and environmental factors should be assessed. Motivation for treatment and treatment compliance needs to be explored. Adequacy of medication treatment needs to be assessed. Once the assessment is performed, the clinician may try a previously attempted treatment but in adequate dose and for an adequate duration of time. If noncompliance is an issue then better patient education and motivational techniques could be employed.45
Augmentation strategies have been tried for the treatment-resistant cases. These include adding buspirone, or lithium, combining two SSRI or SSRI with SNRI. Using tricyclic antidepressants with SSRI could be very helpful especially in case of clomipramine–SSRI combination for OCD. However, this combination needs to be well monitored with blood levels of a tricyclic to avoid complications that may include seizures.
The use of long-term benzodiazepines for the long-term treatment of resistant anxiety is controversial due to large comorbidity of anxiety disorders with addictions. However, some long-term studies indicated that these medications could be used in chronic anxiety patients with a great degree of success and that those who do not have comorbid addictive disorders actually decrease their medications over time. These are powerful medications and their cognitive side effects should be taken into consideration especially in elderly populations.
In case of co-morbidity, one may target the co-morbid conditions such as bipolar disorder or psychosis first and then attempt to treat anxiety disorder. This could lead to the use of multiple pharmacological treatments at the same time. However, polypharmacy is considered to be a rule rather than exception in complicated co-morbid cases. Recent surge of co-administration of mood stabilizers (lithium, gabaergic antiepileptics and atypical antipsychotics) may be explained by very high prevalence of bipolar disorders and psychoses in anxiety patients (Table 5).
Combining CBT and medications for patients resistant to either treatment alone deserves further scientific exploration. Several studies conducted in anxiety patients including panic disorders OCD and Social Phobias did not reveal clear superiority of combination treatment over either treatment strategy administered alone.46, 47, 48, 49 However, combined algorithms administered in primary care are clearly more effective than treatment as usual.
One has to explore the targets of these treatments to understand the nature of the treatment failure. Medication such as an SSRI is likely to suppress the increased alarm reactivity by suppression of the alarm system (i.e. amygdale and related areas). In larger doses, they may improve information processing by slowing transmission in the cortico-striato-cortical circuits. However, it is unlikely that medications can affect complex behavioral coping strategies such as safety behaviors and avoidance directly. Improvement in those behaviors occurs, most likely, secondary to reduction in fears and takes several weeks. Patients with OCD frequently perceive their medications nonworking even though they felt calmer on the medication. They were, however, still continuing to perform their rituals because they were not instructed otherwise. Severity of rituals and avoidance was one of the most reliable predictors of nonresponse in a meta-analysis of a large sample of OCD patients treated with SSRIs.50 Convergent, behavioral interventions most likely do not affect alarm reactivity and information processing directly. Cognitive therapy may improve thinking by making the patients test alternative hypotheses related to fear response, but it is not clear that cognitive strategies are effective alone in majority of anxiety patients. Choosing alternative coping behaviors most likely secondary ‘resets’ the alarm and improves their processing of the threat information. Using excessive medication could be counterproductive because it could fully suppress anxiety, affect information processing and slow down the extinction processes. Keeping this theory in mind one may combine both treatment strategies rationally to achieve a greater success. However, that strategy is more difficult to implement in a controlled studies because it requires flexibility in medication administration. Most of the controlled trials, however, used a set dose schedule for the medication treatments.
Experimental treatment strategies
Non-response to single treatments and their combinations calls for the development of new treatments of anxiety disorders. A few of the have been recently tested.
Herbal preparations are extensively used by anxiety disorders patients.51 They frequently take the herbals surreptitiously, that is, without knowledge of the physician administering pharmacological treatment. One has to remember that despite the general belief that herbals are safer that may not be so. Some of the most potent poisons and mind altering drugs could be herbals. The surreptitious use for the herbals needs to be further explored in anxiety patients since it may contribute to the treatment resistance. There are also possible interactions between the herbal preparations and SSRIs, which clinicians need to pay attention to.
One of the most fruitful areas of research was recently the use of combined SSRI–antipsychotic treatments for non-psychotic anxiety disorders including OCD, agoraphobia and Social Anxiety disorders. Nonpsychotic OCD patients seem to show moderate response to atypical antipsychotics that has been documented in multiple reports, case studies and some of the controlled studies, although the information is still scarce (Table 5). The use of antipsychotic is complicated by wide range of side effects they bring into the clinical picture. Their usefulness long term reminds to be documented in anxiety patients.52
The use of Gaba-ergic antiepileptics seems to be growing. This is prompted by multiple reports involving gabapentin, pregabalin and tiagabin among others.53, 54 While these medications are less dependency forming than benzodiazepines they are also less effective. Some newer agents such as pregabaline seem to have more antianxiety properties, but this remains to be documented in large controlled clinical trials.
Multiple pharmacological medications with novel mechanisms of action have been recently tested. Those include medication with peptide mechanisms of action, that is, substance P, NK, CRF antagonists.55, 56 None of these novel medications are yet approved on the US market and most of the recent experiments failed to prove their efficacy. It seems that while acting on more specific systems the medications losing their efficacy.
Conversely, medications with multiple mechanisms of action or ‘poly-pharmacy cocktails’ seem to be most effective in the treatment-resistant population.57 The scientific literature does not contain any good efficacy data for polypharmacy. However, it is apparent that the use of multiple medications with different indications is a rule rather exception in the treatment-resistant anxiety patients. Some of the best teachers of contemporary psychopharmacology are actively teaching a rational polypharmacy.58 In practice, experienced psychopharmacologists arrive to those complex regimens by trial and error in the attempt to decrease the suffering of this population which is often immense. The logic behind the polypharmacy is understandable. Treatment-resistant patients usually suffer from several syndromes that may include, for example, OCD, Panic, Bipolar Disorder and some form of psychosis. If one attempt to use a single agent in this kind of a patient they usually get worse. For example, high doses of an SSRI required to treat the OCD may trigger mania or psychotic reaction in bipolar or psychotic patient with OCD as primary presentation. The ultimate cocktail found in some patients could include: an SSRI, sometimes in a mixture with an SNRI, a GABA-ergic mood stabilizer, an atypical antipsychotic and a benzodiazepine.
For same of the patients, this regimen could be appropriate and even life saving. For some of them it could mask an underlying problem by numbing the feeling and not addressing abnormal coping of these patients. The examples of this could be an oversedated OCD patient, who continues his compulsive behaviors or a PTSD patient where the core traumatic even has never been addressed in psychotherapy. In my opinion, the extensive polypharmacy in patients should be periodically reevaluated and a second opinion should be obtained. It is especially important when the patient is treated with a complicated regimen for more than 2 years without clear improvement. Sometimes a ‘subtraction’ of medications from a polypharmacy regimen could lead to an improvement.
Some of the prospective treatments, even experienced psychopharmacologists may be reluctant to administer. A once a week opioid receptor agonist trial in OCD patients has shown some success and is under investigation.59 Since potential adversities of these treatments are high they should probably still be conducted only in specialized centers under scrutiny of researchers and with explicit informed consents until more evidence is gathered.
There is some evidence for the efficacy and safety of intravenous clomipramine, which may become the optimal strategy in treatment-resistant cases. Researchers have suggested that the ratio of clomipramine to its metabolite desmethylclomipramine (which also inhibits noradrenaline reuptake) is increased with parenteral treatment through reduction of first-pass hepatic metabolism, and that this explains the greater tolerability and efficacy of the intravenous form of the drug.60 In a double-blind, randomized, controlled trial in patients with treatment-refractory OCD, Fallon and Mathew61 found that nine of 21 patients treated with 14 days of clomipramine infusions and 7 days of oral treatment were responders, compared with none of 18 in the placebo group. Improvement was maintained to the end of blind ratings at 3 weeks, and the regimen was well tolerated.
Behavioral and other psychotherapies
Anxiety disorder patients who do not respond to ordinary behavioral strategies could utilize more extensive CBT treatment. This treatment is usually provided as an intensive outpatient, partial hospitalization or residential treatment.62, 63 Many of these programs specifically targeting OCD are currently available around the country. The programs generally offered different length of treatment ranging from several weeks to several months and different degree of intensity.
Many authors recognized limitations of narrow behavioral approach in the treatment-resistant population. Other psychotherapeutic modalities including focused cognitive, mindfulness, meditation, interpersonal and psychodynamic have recently been tried in anxiety populations with various degree of successes.64, 65, 66 It is clear that a complex patient may require a long-term complex psychotherapeutic approach rather than a brief behavioral strategy.
Electroconvulsive therapy has a role in cases of treatment-refractory anxiety complicated by severe comorbid depression, but it is not believed to be consistently effective for primary treatment-refractory OCD or Panic Disorder.67, 68 In one uncontrolled case series, the majority of patients with treatment-refractory OCD improved considerably for a year following such therapy.69 Although the response was associated with improved depression ratings, the authors suggested an independent effect on obsessional symptoms. Use of ECT in treatment-resistant PD is also controversial since some clinicians suggest that panic attacks worsen in this population and only depression improves.
Several nonpharmacological experimental treatment strategies are under development and testing. This includes Deep Brain Stimulation (DBS), Vagus Nerve Stimulation (VNS), and Repetitive Transcranial Magnetic Stimulation (rTMS).
Deep brain stimulation
Bilateral DBS has been used successfully for essential tremor and Parkinson's disease since about 1995.70 Significant adverse events from the DBS procedure have included equipment failure or lead wire breakage, intracranial hemorrhage, infection, seizures, and paresis.71 Since 1999 when Netherlands's neurosurgeon discovered OCD response to DBS, there have been multiple publications on the use of DBS in treatment refractory OCD.72, 73 Initial results seem to be promising but need to be confirmed in larger trials using sham surgeries and treatments.
Vagus nerve stimulation (VNS)
The vagus nerve (10th cranial nerve) is best known for its efferent function with parasympathetic inervation to organs such as the heart and gut. However, approximately 80% of vagal nerve fibers are afferent sensory fibers and relay information from the body to the brain. These afferent fibers project via the nucleus tractus solitarii (NTS) to the locus ceruleus (LC) and parabracial nucleus (PB). The LC and PB project to all levels of the forebrain including the hypothalamus, orbital frontal cortex, amygdala, and bed nucleus of the stria terminalis. In theory, direct stimulation of the vagus afferent fibers could affect sensory input to limbic, brain stem and cortical areas known to be involved in mood and anxiety disorders. VNS has had an excellent safety record in seizure patients.74 It has also been recently approved by FDA as an adjunct treatment for treatment-resistant depression.75 Many of treatment refractory depressed patients in pivotal studies were also suffering from anxiety, which improved simultaneously with depression. However, true efficacy of this treatment in refractory anxiety populations remains to be explored. The most common adverse event related to implantation is mild pain at the incision site that typically resolves over the 2 weeks following surgery. There are currently seven patients with OCD, two patients with PTSD and one panic disorder patient implanted with the device. Acute and long-term data are not available on these patients yet.76
Repetitive transcranial magnetic stimulation
Introduced in mid-1980s, transcranial magnetic stimulation is a noninvasive mean of stimulating the cerebral cortex. It involves placing an electromagnetic coil on the scalp and passing a rapidly alternating high-intensity current through the coil. This sets up a magnetic field, which passes through the cranium and induces local electrical changes on the surface of the cortex. Therapeutically, rTMS has received the most attention with treatment-resistant depression.77 Greenberg et al78 found that rTMS may be helpful in OCD whereas Alonso et al.79 who randomly assigned 18 patients with OCD to real or sham rTMS did not find any difference between the treatment groups. Overall review of the field produced mixed results.80 However, a recent study opens the possibility that a different set of rTMS parameters may need to be used for the treatment of anxiety and OCD and that research needs to be continued.81
OCD was the only anxiety disorder where the neurosurgical approach has been explored. With the failure to find effective therapies for OCD over the past three decades, psychosurgery has become an intervention of last resort.82 It is important to balance the risks of nonintervention (social, physical and psychological complications, including suicide) against those of surgery (frontal lobe dysfunction and psychological complications including personality alteration, substance abuse and suicide), which are not excessive with current techniques. Unfortunately, in the absence of a controlled comparison with ‘sham’ surgery, efficacy remains unproven. Recent retrospective and prospective studies have reported response in 30–60%83. A ‘gamma knife’ using cobalt 60 has been used in some centers to create surgical lesions without opening the skull, making a controlled comparison with sham surgery feasible. The procedures favored across various centers include cingulotomy, subcaudate tractotomy, capsulotomy, and limbic leucotomy (cingulotomy plus subcaudate tractotomy). No conclusive data exist on comparative efficacy or safety. Further research is needed to identify the best target sites. For these procedures, a ‘stereotactic’ frame is used, and target sites are visualized with magnetic resonance imaging. It is hypothesized that such lesions disrupt dysfunctional neural circuits by severing connections between the orbitomedial frontal lobes and limbic or thalamic structures. However, the observation that most patients take weeks or months to improve suggests that secondary effects such as nerve degeneration may be important.
Treatment resistance is a significant problem in anxiety patients affecting approximately one out of three patients with diagnosis of anxiety disorder. Due to high prevalence of AD, this problem translates into significant mortality, morbidity and decrease in quality of life. There also significant cost to society associated with high disability and high health care utilization. The treatment resistance occurs due to multiple factors and clinicians need better ways to study and address them. A careful assessment of treatment-resistant anxiety patients by an experienced clinician who is aware of the current psychobiological treatments of anxiety is very important. Development of the new treatment modalities is the task of future generations of researchers in this important field of science.
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I like to thank Lauren Kerwin and Mary Grace Savella for their help with the preparation of this manuscript. This work was supported in part by Saban Family Foundation.
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Bystritsky, A. Treatment-resistant anxiety disorders. Mol Psychiatry 11, 805–814 (2006) doi:10.1038/sj.mp.4001852
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