European Neuropsychopharmacology (2006) 16, S109–S118 w w w. e l s e v i e r. c o m / l o c a t e / e u r o n e u r o Generalized anxiety disorder: A comorbid disease David Nutt *, Spilos Argyropoulos, Sean Hood, John Potokar Psychopharmacology Unit, University of Bristol, Bristol, United Kingdom KEYWORDS: Generalized anxiety disorder; Comorbidity; Prevalence; Burden; Diagnosis; Neurobiologic mechanisms Abstract Generalized anxiety disorder (GAD) frequently occurs comorbidly with other conditions, including depression and somatic complaints. Comorbid GAD sufferers have increased psychologic and social impairment, request additional treatment, and have an extended course and poorer outcome than those with GAD alone; therapy should alleviate both the psychic and somatic symptoms of GAD without negatively affecting the comorbid condition. The ideal treatment would provide relief from both GAD and the comorbid condition, reducing the need for polypharmacy. Physicians need suitable tools to assist them in the detection and monitoring of GAD patients—the GADI, a new, self-rating scale, may meet this requirement. Clinical data have shown that various neurobiologic irregularities (e.g., in the GABA and serotonin systems) are associated with the development of anxiety. Prescribing physicians must take into account these abnormalities when choosing a drug. Effective diagnosis and treatment should improve patients' quality of life and their prognosis for recovery. © 2006 Elsevier B.V. and ECNP. All rights reserved. 1. Introduction Generalized anxiety disorder (GAD) is one of the most common conditions that occurs comorbidly with other disorders, particularly other anxiety and depressive disorders. Indeed, comorbidity of mood and anxiety disorders is a hallmark feature of GAD (Judd et al., 1998; Ninan, 2001). Research into GAD is far behind that of many other psychiatric disorders, the main reason being that until fairly recently many eminent physicians still believed that GAD was not a separate disorder, but rather a variant of depression. This misapprehension arose because GAD often occurs comorbidly with depression, which can mask the symptoms of GAD. Consequently it has taken some time to establish that GAD does occur as a discreet condition, and that it definitely is not a form of depression. This was, and still can be, a big * Corresponding author. Psychopharmacology Unit, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, United Kingdom. Tel./ fax: +44 117 331 3143. E-mail address: david.j.nutt@bristol.ac.uk (D. Nutt). hindrance to the progression of research into this important, although somewhat neglected, psychiatric condition. GAD is frequently comorbid with major depressive disorder (MDD), panic disorder (PD), social anxiety disorder (SAD), specific phobia (SP), and post-traumatic stress disorder (PTSD), and is additionally associated with chronic pain conditions, medically unexplained somatic symptoms, and sleep disorders—in fact many physicians believe that much of the insomnia reported by their patients is actually a variant of GAD. These patterns of comorbidity increase the individual and economic burden of GAD and add to the challenge of treatment. Indeed, comorbidity should be thought of as a challenge rather than a nuisance—it is very important clinically, both when considering neurobiologic disorders and the individual comorbidities. This article will discuss the issues surrounding GAD and its various comorbidities. In addition, we will also address the need for appropriate tools to aid the diagnosis of this condition, and appraise the potential role of various neurobiologic mechanisms in the development and treatment of GAD. 0924-977X/$ - see front matter © 2006 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2006.04.003 S110 D. Nutt et al. 2. Prevalence of psychiatric comorbidity Many studies have reported a high prevalence of comorbidity with psychiatric disorders as well as with general medical conditions, both of which lead to a complex clinical presentation. Data from a large general population survey in the USA (the National Comorbidity Survey, NCS) suggest the vast majority (90%) of people with lifetime GAD have a lifetime history of at least one other psychiatric diagnosis (Table 1) (Wittchen et al., 1994). Among individuals with current GAD (defined as the most recent 6-month period of anxiety still ongoing in the 30 days prior to interview), 66% had at least one other concurrent psychiatric disorder: 39% had MDD, 27% agoraphobia, 25% simple phobia, 23% SAD, and 23% PD (Table 1) (Wittchen et al., 1994). Of those diagnosed as having met criteria for GAD within the preceding 12 months, 58% had also experienced an episode of MDD in the previous 12 months; in another US survey (the Midlife Development in the United States Survey, MDUSS), this figure was 70% (Kessler et al., 1999). A representative sample of adults in Germany (the German National Health Interview and Examination Survey-Mental Health Supplement, GHS) showed similar patterns of comorbidity; this survey focused on the 12month prevalence rates with a requirement that all diagnostic criteria were fully present in the 12 months prior to interview (Wittchen et al., 2000; Carter et al., 2001). In the GHS, 40% of all 12-month GAD cases had current (within the preceding 30 days) depression, 59% had experienced an episode of MDD within the preceding 12 months, and 56% met criteria for any other anxiety disorder within the preceding 12 months (Carter et al., 2001). These incidence rates reinforce how prevalent comorbid GAD is within the population as a whole. Comparable rates of comorbidity with those observed in general population surveys have been reported in clinical samples, overall rates of comorbidity are high with 45–98% of patients with GAD having lifetime comorbid anxiety, depres- Table 1 Lifetime prevalence of disorders comorbid with GAD in the National Comorbidity Survey (NCS) Comorbid disorder Current GAD a (%) Lifetime GAD b (%) Any of the following Major depression Agoraphobia Simple phobia Social anxiety disorder Panic disorder Dysthymia Mania Alcohol abuse Drug abuse 66.3 38.6 26.7 24.5 23.2 22.6 22.1 12.1 11.2 5.1 90.4 62.4 25.7 35.1 34.4 23.5 39.5 10.5 37.6 27.6 Adapted from Wittchen et al. (1994), with the kind permission of JAMA. a 30-day prevalence of other disorders among respondents with 30-day GAD, defined as the most recent 6-month period of anxiety still ongoing in the 30 days prior to interview. b Lifetime prevalence of other disorders among respondents with lifetime GAD. Figure 1 Increase in comorbidity of GAD and MDD over time in a prospective study (Bruce et al., 2001). sive, or substance use disorders (Noyes, 2001). As in the general population, MDD is the most common disorder occurring comorbidly with GAD in these samples (Noyes, 2001). One study of patients with GAD, which excluded those with concurrent MDD, found that 42% had experienced at least one major depressive episode during their lifetime (Brawman-Mintzer et al., 1993). A prospective study indicated that 39% of patients with GAD had a comorbid diagnosis of MDD at intake, with the rate increasing as the study progressed (Fig. 1) (Bruce et al., 2001). Comorbid anxiety disorders occur with GAD in a substantial proportion of patients with up to 59% of GAD patients having a lifetime history of SAD, and up to 56% a history of SP (Noyes, 2001). PD is also a prevalent comorbidity with GAD. However, many studies of patients with GAD specifically exclude those with PD, so rates of lifetime comorbidity found in such studies are likely to underestimate the true prevalence of comorbid PD (Noyes, 2001). In a study of patients with current GAD, 48% of those also had current PD with or without agoraphobia (Massion et al., 1993); in another study of patients with PD, 63% had GAD (Cassano et al., 1990). In the Harvard/Brown Anxiety Disorders Research Program (HARP), a longitudinal study of over 700 treatment-seeking patients, 62% of those with a diagnosis of lifetime GAD had lifetime PD (14% without and 48% with agoraphobia) (Goisman et al., 1995). Prevalence of comorbidity with PTSD is less well established than other conditions; 39% of a sample of patients with PTSD in primary care had comorbid GAD (Stein et al., 2000). Although in general the prevalence of GAD in children and adolescents is relatively low in relation to other anxiety disorders, when GAD is present in these groups, high rates of comorbidity similar to those seen in adults, are observed (Masi et al., 2001; Wagner, 2001; Masi et al., 2004). A recent study of 157 children and adolescents (7–18 years, mean age 13.4 years) with GAD, who attended an outpatient clinic between 1997 and 2002, found comorbid anxiety disorders in 75% and depressive disorder in 56% (Masi et al., 2004). Although the prevalence of other anxiety disorders appears to diminish with age that of GAD is maintained or even increased in elderly populations (Krasucki et al., 1998). Again, there is considerable comorbidity, with depression in particular, but GAD may be more likely to be secondary to depression in elderly patients (Flint, 1994; Noyes, 2001). A community-based sample of over 4000 elderly patients found Generalized anxiety disorder: A comorbid disease prevalence rates of 12% for depression, 3% for GAD, and 2% for mixed depression-anxiety; comorbidity of GAD and depression was twice as frequent in elderly women as in men (Schoevers et al., 2003). The high rates of psychiatric comorbidity in individuals with GAD had led some to suggest that GAD should not be regarded as a distinct disorder but rather a prodromal stage of depression, but there are several lines of evidence against this proposition (Kessler et al., 2001; Wittchen et al., 2002). For example, the exceedingly high rates of GAD and MDD comorbidity are confined to certain clinical studies with potential for self-selection bias, while the rates of comorbidity in the general population are not higher than for most other mood or anxiety disorders. Furthermore, symptom profiles of GAD and MDD are different (Kessler et al., 2001). Although frequently comorbid, GAD occurs sufficiently often independently of MDD for it to be regarded as a separate diagnostic entity (Brawman-Mintzer et al., 1993; Kessler et al., 1999). In general, GAD is temporally the primary disorder in cases of comorbidity with MDD (Kessler, 2000); in a study of depressed patients with comorbid GAD (11% of the total depressed sample), GAD preceded the first episode of MDD in 63% of cases (Fava et al., 2000). Primary GAD is a significant predictor of subsequent depression (Kessler, 2000; Bruce et al., 2001). In addition to comorbidity with mood and anxiety disorders, personality disorders are common in patients with GAD, with up to 50% of patients with GAD having been reported to meet criteria for a personality disorder (Sanderson et al., 1994; Garyfallos et al., 1999), a rate comparable with that associated with other anxiety disorders (Sanderson et al., 1994; Noyes, 2001). Cluster C personality disorders are the most frequently occurring type in patients with GAD, as they are in other anxiety disorders such as PD and obsessive-compulsive disorder (OCD), but avoidant personality and interpersonal sensitivity may be particular features of, or associations with, GAD (Garyfallos et al., 1999; Noyes, 2001). 3. Prevalence of non-psychiatric medical comorbidity Patients suffering from chronic conditions such as arthritis, headache, or chronic obstructive pulmonary disease frequently have mood or anxiety disorders. Similarly GAD, in common with depression and other anxiety disorders, is often accompanied by chronic pain symptoms such as backache, headache, gastrointestinal pain, joint pain, or migraine (Puca et al., 1999; Juang et al., 2000; Sheftell and Atlas, 2002; Brenes, 2003; Bensenor et al., 2003; McWilliams et al., 2003; Zwart et al., 2003; Grothe et al., 2004). Some studies have found that GAD is the most frequently diagnosed anxiety disorder among patients presenting with both headache and an anxiety disorder, occurring in 14% of patients with episodic cluster headache (60% of all those with a concomitant anxiety disorder) (Jorge et al., 1999) and in 45% of patients with tension-type headache (84% of those with a concomitant anxiety disorder) (Puca et al., 1999). A significant proportion of patients with GAD also manifest concurrent irritable bowel syndrome (IBS) (Tollefson et al., 1991). S111 Sleep complaints are also frequent among patients with GAD (Belanger et al., 2004), and GAD is the most prevalent diagnosis in patients suffering from insomnia with an associated mood or anxiety disorder (Monti and Monti, 2000). Some 60–70% of patients with GAD have an insomnia complaint, the severity of which parallels that of the anxiety disorder (Monti and Monti, 2000). Sleep disturbance in GAD seems to be more a problem of sleep maintenance than onset (Monti and Monti, 2000). A sample of patients with GAD reported difficulties in initiating sleep (48%), maintaining sleep (64%), and early waking (57%); the vast majority (87%) reported never having experienced insomnia without having excessive worries, although insomnia severity and GAD severity were not correlated (Belanger et al., 2004). Depending on the type and severity of a sleep complaint, physicians may consider certain aspects to be symptomatic of the GAD, but true insomnia should be considered a comorbidity. 4. Burden of comorbidity In general, comorbidity in GAD patients is associated with greater severity, more impairment, increased help-seeking, and worse outcome of the primary disorder, than in the patients without comorbidity (Bakish, 1999; Wittchen et al., 2000; Noyes, 2001). Undeniably these patients are more of a burden, or challenge, for their physician. As a consequence the economics surrounding comorbidity are all negativeincluding increased healthcare and hospitalization rates, and a greater number of sick days. In fact comorbid GAD, especially with depression, leads to a considerable increase in loss of productivity through days off work. Data from the NCS and the MDUSS surveys show that while individuals with (12-month) GAD or MDD showed more impairment than individuals with neither disorder, and similar levels of impairment to each other, those with GAD and comorbid MDD showed more impairment than those with only one of the two disorders (Fig. 2) (Kessler et al., 1999). For example, according to the MDUSS over 50% of patients with comorbid GAD and MDD considered their mental health to be poor/fair, compared with 25% and 29% of those with either respective condition in isolation (Kessler et al., 1999). In the GHS survey, measures of impairment taken as a whole suggested that respondents with (12-month) comorbid GAD and MDD suffered highest impairment as measured either by a reduction of at least 50% in overall activity, or by the number of days of impairment, within the preceding month (Wittchen et al., 2000). In the NCS, more respondents with lifetime GAD and any other comorbid disorder reported interference of their symptoms with their life and activities than those with pure GAD (Table 2) (Wittchen et al., 1994; Judd et al., 1998). Individuals with 12-month GAD and MDD have lower quality of life, as assessed by general health, mental health, social functioning, and vitality scales, than those with pure MDD (Wittchen et al., 2000). Similar indications of a greater burden of comorbid GAD include functional impairment and duration of illness. Comorbidity of GAD and depression is associated with a lower chance of remission from depression (Sherbourne and Wells, 1997), and an episode of MDD or PD comorbid with GAD decreases the probability of a patient achieving remission S112 D. Nutt et al. Figure 2 Effect of comorbidity on measures of impairment in the NCS and MDUSS surveys among patients with or without 12-month GAD and/or MDD (Kessler et al., 1999). (A) Perceived mental health, NCS (B) Perceived mental health, MDUSS (C) Days of work impairment in past month, NCS (D) Days of work impairment in past month, MDUSS. from GAD (Bruce et al., 2001). Yonkers et al. found that the likelihood of a patient achieving remission from both GAD and a comorbid condition after 1 year was half that of a patient with pure GAD achieving remission from the disorder (Yonkers et al., 1996). Comorbidity with GAD in patients with SAD increases severity of social anxiety and avoidance, general anxiety, depressed mood, functional impairment, and overall psychopathology in comparison with those without comorbid GAD (Mennin et al., 2000). In another study, full or partial remissions were less likely to occur in patients with personality disorders and poor relationships (Yonkers et al., 2000). The World Health Organization study on psychologic problems in primary care, a cross-cultural study covering 14 countries, also found that marked social disability was more frequent among patients with GAD with a comorbid psychiatric disorder (46%) than those with pure GAD (25%) (Maier et al., 2000), and that patients with comorbid GAD suffered more days of disability than those Table 2 Effect of comorbidity with any other disorder on interference with daily activities, help seeking, and medication use in lifetime GAD in the NCS Interference Pure GAD Comorbid GAD Total for combined pure and comorbid GAD populations Help seeking Medication Any of these % SE % SE % SE % SE 28.1 51.2 49.0 0.08 0.04 0.04 48.2 67.9 66.0 0.10 0.04 0.03 24.1 46.2 44.0 0.08 0.04 0.04 59.2 84.4 82.0 0.10 0.03 0.02 Reproduced from Wittchen et al. (1994), with the kind permission of JAMA. Generalized anxiety disorder: A comorbid disease with pure GAD (Ormel et al., 1994). Comorbidity of GAD and other anxiety or depressive disorders also increases risk of suicide (Rudd et al., 1993; Allgulander and Lavori, 1993; Masi et al., 2001; Wittchen et al., 2002). In patients with chronic medical conditions, comorbid anxiety reduces levels of functioning and well-being (Sherbourne et al., 1996). Comorbidity has a significant impact on medical utilization (Wittchen et al., 2002). GAD is the most prevalent anxiety disorder in primary care (Maier et al., 2000) as well as in patients with chronic medical conditions (Sherbourne et al., 1996), and is one of the most common diagnoses in patients presenting with medically unexplained somatic symptoms (Roy-Byrne, 1996). Individuals with comorbid GAD are more likely to seek professional help, seek psychiatric outpatient treatment, and take medications for GAD symptoms than those with pure GAD (Table 2) (Wittchen et al., 1994; Bland et al., 1997; Judd et al., 1998). A study of over 1000 patients with GAD found that comorbidity resulted in increased costs for hospitalization, laboratory tests, medications, and absenteeism from work (Souetre et al., 1994). 5. The therapeutic challenge of comorbidity Comorbidity adds to the therapeutic challenge of GAD and has several implications for its management (Noyes, 2001). Comorbidity, with depression in particular, significantly lowers the probability of GAD being successfully diagnosed and treated (Wittchen et al., 2002). Commonly, patients may present with multiple unexplained physical rather than psychiatric symptoms, the cause of which the primary care physician (PCP) is unable to determine using the standard laboratory tests such as blood tests, or an electrocardiogram. Patients become dissatisfied and frequently become labeled as “difficult patients”, further hampering recognition and diagnosis. Moreover, because a diagnosis is not forthcoming these patients will often continue to complain about their symptoms, generating irritability in the treating physician, which in turn results in the patient becoming more stressed. The prevalence of comorbidity associated with GAD makes it imperative that patients fulfilling diagnostic criteria for GAD are carefully evaluated for depressive and other anxiety symptomatology (Kaufman and Charney, 2000). Depressed patients with GAD in whom the comorbidity has not been recognized, would commonly be treated with a selective serotonin reuptake inhibitor (SSRI), with variable success from patient to patient; they also need to be assessed and monitored for suicidal ideation. It is possible that effective, early treatment of GAD might prevent comorbid conditions that tend to develop later (Noyes, 2001). This is an important consideration not least because, as discussed earlier, primary GAD is a significant predictor of subsequent depression (Kessler, 2000; Bruce et al., 2001). Any treatment must relieve the patient's anxiety without aggravating their comorbid condition; ideally, the anxiolytic treatment would additionally have efficacy against the comorbid condition, reducing the need for polypharmacy. Unfortunately, as patients with comorbidity are often specifically excluded from clinical trials of antidepressant and anxiolytic agents, there is an insufficient evidence base on treatment responses in patients with GAD S113 and comorbidities, and treatment decisions have to be made largely on the basis of related clinical trials and personal experience. The benefits of psychologic therapy for GAD may extend to comorbid conditions, perhaps as a result of overlapping symptoms or of generalization of therapeutic skills. Psychotherapy for GAD in a sample of patients with comorbid disorders such as social and simple phobia (but not MDD) was found to be associated with a reduction in the number of additional diagnoses and coexisting conditions, with the reduction being significantly greater among patients for whom therapy for GAD was successful than among those for whom psychotherapy for GAD was not successful (Borkovec et al., 1995). Cognitive-behavioral therapy for PD was found to be effective in reducing the frequency and severity of comorbid conditions, which included GAD, though comorbidity tended to reduce the likelihood of marked improvement of PD (Tsao et al., 1998). 6. Clinical data for GAD drug treatments There are several classes of pharmacologic agent with proven efficacy in the treatment of anxiety disorders (Ballenger, 1999). However few studies have looked at treatment response in patients with comorbid GAD and depression—physicians need a drug that effectively treats both conditions without the need for polypharmacy and which does not aggravate the comorbidity. Currently there is no single therapeutic agent that can combine the speed of onset of a benzodiazepine (BZD) with the efficacy of an SSRI. There is substantial evidence that SSRIs and serotonin and norepinephrine reuptake inhibitor (SNRIs) can be effective against depression with associated anxiety. There are, however, disadvantages to SSRI/SNRI use including a relatively slow onset of action, which often necessitates their combination with a short course of BZDs to achieve initial symptom control. There can also be unpleasant side effects of SSRIs/SNRIs, such as nausea and sexual dysfunction, in addition to the recent concerns regarding suicide risk. There have been few studies of SSRIs/SNRIs specifically in patients with a diagnosis of GAD and comorbid depression. Those that have been completed have involved fairly small numbers of patients or have been open label. Subanalysis of a subgroup of 92 patients with comorbid MDD and GAD from a doubleblind, placebo-controlled trial found that after 12 weeks of treatment, venlafaxine, but not fluoxetine, had effected a reduction in both HAM-D (Hamilton Rating Scale for Depression) and HAM-A (Hamilton Rating Scale for Anxiety) scores that was significantly greater than placebo (Silverstone and Salinas, 2001). Comparison with 276 non-comorbid patients from the trial suggested meaningful symptom relief took more time in the patients with comorbidity, and that these patients may require a longer period of treatment (Silverstone and Salinas, 2001). In a small study of 32 outpatients with GAD and either MDD (n = 21) or dysthymia (n = 11), although venlafaxine reduced depressive symptoms in patients with comorbid MDD after 8 weeks, significant reduction of anxiety scores required more time and did not occur in some patients (Perugi et al., 2002). Open-label trials have reported that non-SSRI/SNRI antidepressants mirtazapine and moclobemide may also be of some value in treating S114 patients with comorbid GAD and MDD (Goodnick et al., 1999; Pini et al., 2003). Pharmacotherapeutic trials of GAD with comorbid conditions other than depression are even more limited. BZDs may have efficacy in patients with GAD and comorbid IBS. In an open-label trial of alprazolam a significant anxiolytic response was seen in 94% of the 32 patients treated within 6 weeks, and a concomitant reduction in IBS severity in 89% and a small post-treatment rebound effect was observed (Tollefson et al., 1991). Merging of data from 3 double-blind, placebo-controlled studies of comorbid GAD and post-stroke depression (combined total of 27 patients) suggested that nortriptyline (a tricyclic antidepressant) was more effective than placebo in relieving anxiety and depressive symptoms, although the anxiety symptoms improved more rapidly than the depressive symptoms (Kimura et al., 2003). Insomnia associated with mild-to-moderate GAD can be treated with anxiolytic BZDs, which shorten latency to sleep, prolong sleep, reduce the number of night-time awakenings, and improve sleep quality; patients with more severe GAD may require higher doses of BZDs for weeks or months (Monti and Monti, 2000). As a result of the potential for dependence and withdrawal symptoms observed with BZDs (Lader, 1999), SSRIs may be a preferable pharmacotherapy, though onset of efficacy is slower; trials of such agents in patients with GAD and sleep problems are needed. Also, sedative properties can result in daytime sedation, which is undesirable, and can lead to decreased performance and accidental injury. 7. The Generalized Anxiety Disorder-Inventory (GADI) Recently our research has focused on trying to understand how GAD can be rated and diagnosed appropriately in relation to other psychiatric disorders. This has been carried out through the development of a new scale that assists in rating GAD severity. The GADI was modeled on the types of scales that have previously been designed for patient-rated assessment of anxiety disorders, such as the Social Phobia Inventory (SPIN), developed by Jonathan Davidson (Connor et al., 2000). The symptoms of GAD, as published in the Diagnostic and Statistical Manual of Mental Disorders, third edition-revised (DSM-IIIR), the DSM-IV, and the World Health Organization's (WHO's) Tenth International Classification of Diseases (ICD10), were used to develop a 19-item self-rating scale (GADI) that fulfilled the required criteria: easy to administer and score. Patient's self-assessment of the severity of each of the 19 items is rated on a scale from 0 to 4 (not at all, a little bit, somewhat, very much, and extremely). The full-scale score, therefore, gives a maximum score of 76, with higher scores corresponding to a greater level of anxiety. The patient is asked to rate how they have felt over the previous 2 weeks in relation to each of the questions posed. Data were collected for GAD patients, patients with another anxiety disorder or depression, and a control population (university students). A factor analysis was then carried out on the initial data, which showed that 3 factors explained 60% of the patient variance. These factors were a cognitive factor (8 items relate to this factor), such D. Nutt et al. as worry or apprehension, and 2 somatic factors; the first of these comprising symptoms such as trembling, dizziness, or paresthesias (9 items relate to this factor), and the second, which was quite independent, comprising sleep problems (2 items relate to this factor) (Argyropoulos et al., 2001). These 3 independent factors comprise the full spectrum of GAD. The data showed significant differences between the GAD patients versus students (control population), and the other anxiety and depression patient cohort (Fig. 3). It should, however, be noted that this scale is intended for use in monitoring the status of patients, not as a diagnostic tool. In addition, its psychometric properties are still under evaluation. 8. Neurobiologic mechanisms in GAD The scientific basis for the pharmacologic treatment of anxiety disorders, including GAD, is mainly derived from empirical data supporting the efficacy of drug therapies. Furthermore, clinical data suggest that there are neurobiologic anomalies associated with these anxiety conditions, which may be reversed or corrected through pharmacologic intervention. Such abnormalities have been recognized for several neurotransmitter-receptor systems, including dopamine, norepinephrine, the gamma-amino butyric acid (GABA)-BZD receptor complex, and serotonin (5-HT) (Johnson and Lydiard, 1995). 8.1. Benzodiazepine receptor binding The recognized effectiveness of BZDs in reducing anxiety has meant that GAD research has focused on the GABA-BZD system. Indeed, the theory that patients with GAD may have a deficiency in the GABA-BZD system, in the form of either reduced receptor sensitivity or a deficit of endogenous inhibitory transmitters, has been postulated. Data obtained from human brain imaging studies indicate that the frontal cortex and medial temporal lobe are involved in experiencing and controlling fear and anxiety (Nordahl et al., 1990; Wu et al., 1991; De Cristofaro et al., 1993; Rauch et al., 1996). Tiihonen et al. tested the hypothesis that BZD receptor binding is decreased in the Figure 3 Preliminary self-rater data from the Generalized Anxiety Disorder-Inventory (GADI). Generalized anxiety disorder: A comorbid disease S115 left temporal pole and increased in the right prefrontal area among patients with GAD. The cerebral BZD receptor binding and distribution were investigated using single photon emission computed tomography (SPECT) analysis with a new 123I-labeled specific BZD receptor radioligand, NNC 138241. The findings showed that binding of the radioligand was significantly decreased in the left temporal pole in patients with GAD compared with controls, but no significant difference was seen in the right prefrontal cortex (Tiihonen et al., 1997). These results are not unlike those observed in the positron emission tomography (PET) binding study of 11Cflumazenil in PD patients for whom a universal reduction in BZD binding has been reported versus healthy controls (Malizia et al., 1998). Together these data confirm that in both GAD and in PD, patients have reduced central BZD receptor function. 8.2. Tryptophan depletion 5-HT is known to play an important role in a wide variety of functions including anxiety, appetite, and sleep, although the precise details of these processes have yet to be clearly defined. Further illumination of this scenario has been hindered by the fact that until quite recently it has not been possible to directly measure the concentration of 5HT in the brain. In the last decade neurotransmitter depletion protocols have offered another method to study the neurobiologic systems involved in psychiatric conditions, including anxiety and depression disorders, dementia, and bulimia nervosa (Smith et al., 1997; Barr et al., 1997; Kaye et al., 2000; Bell et al., 2002; Porter et al., 2003; Argyropoulos et al., 2004). In particular, tryptophan depletion has emerged as an essential tool in the investigation of 5-HT functionality. The aim of tryptophan depletion is to reduce the concentration of 5-HT in the brain. This is achieved by using up the body's reserves of the 5-HT amino acid precursor tryptophan. The level of tryptophan in the plasma is dependent on the balance between dietary intake of protein and on its removal from the plasma due to protein synthesis. Free tryptophan (~5%), in the plasma, is actively transported across the blood-brain barrier by a protein pump. Five other large neutral amino acids (LNAAs), including valine and isoleucine, also compete for the use of this protein pump. Once transported into the brain, tryptophan can take part in the synthesis of 5-HT. The tryptophan molecule is first converted to 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase; 5-HTP is then decarboxylated by the enzyme aromatic acid decarboxylase to produce 5-hydroxytryptamine (5-HT). The rate-limiting factor in this process is the availability of tryptophan in the plasma. Fig. 4 illustrates the processes involved in the transport of tryptophan into the brain and its synthesis into 5-HT. As previously discussed, free plasma tryptophan levels may vary with the amount of dietary tryptophan and the rate of protein synthesis. Completely removing tryptophan from the diet will only reduce the plasma concentration by 15– 20%. A much greater reduction in plasma tryptophan can be achieved by giving subjects a large bolus of LNAAs via a tryptophan-free drink. This has two effects: the liver is stimulated to synthesize protein, thus removing even more Figure 4 Processes involved in the transport of tryptophan into the brain, and its synthesis into 5-HT (reproduced from Bell et al., 2001, with the kind permission of the Royal College of Psychiatrists). tryptophan from the plasma; the LNAAs compete with what little tryptophan is left in the circulation to cross the blood– brain barrier, thus further restricting the entry of tryptophan into the brain (Reilly et al., 1997). In depression, tryptophan depletion studies have shown a marked, rapid adverse decrease in mood in patients treated with SSRIs (Delgado et al., 1999). Patients previously euthymic on an SSRI will experience a severe reoccurrence of the mood disorder ~5 h after the tryptophan depletion. The mood disorder disappears quite rapidly when the tryptophan is replaced. This study has been used to uncover the fact that SSRIs do not free the patient from their depression, but rather stop them from experiencing it. In effect, if 5-HT is removed, then the patient's depression will return; that is to say tryptophan depletion causes a relapse (Smith et al., 1997; Barr et al., 1997). Our own studies in PD and SAD also show that patients, who have recovered with SSRI treatment will relapse if 5-HT is taken away (Bell et al., 2002; Argyropoulos et al., 2004). Interestingly, in OCD, tryptophan depletion studies do not appear to cause a relapse in the patient's condition (Barr et al., 1994). What happens in the case of GAD? The key to the PD and SAD studies has been the use of challenge tests: the patients are tryptophan depleted and then given a provoking agent, which is something similar to a panicogenic challenge. To secure a similar effect in GAD patients we use an inhalation of CO2 at 7.5% for 20 min, which leads to a significant level of anxiety (20–30 on the Visual Analog Scale). In addition, patients suffer many of the symptoms of GAD: heavy headed, headaches, tension, and worry making it a very interesting GAD model. In this model, taking away the 5-HT has very little effect until patients are challenged—that is to say when they put on the mask to breath CO2. Those observing can see an increase in anticipatory anxiety, which is not evident if patients are not tryptophan depleted. The CO2 then subsequently increases the patient's anxiety. We believe that this is evidence that in panic, in SAD, and likewise in GAD, SSRIs are suppressing the anxiety because they are increasing the serotonin—if you take the tryptophan source of 5-HT away, the anxiety condition returns. S116 9. Conclusions Comorbidity in GAD is common, and is associated with reduced probability of successful diagnosis, greater impairment, more severe symptoms, less favorable treatment outcome, and increased utilization of healthcare services. It is now accepted, after much heated debate, that GAD is a specific, distinct disorder in its own right, and not merely a variant of depression. GAD is not always associated with comorbidity, but because of the patterns of comorbidity frequently associated with GAD, it may be helpful, in terms of recognition and diagnosis, to view the disorder as involving a specific set of psychologic dysfunctions that manifest as a complex matrix of anxious-somatic or anxious-somatic-depressive symptoms (Stein, 2001). Thus, physicians should aim to recognize symptom dimensions such as anxiety or panic in their presenting patient. In addition, primary care physicians should also assess for any additional symptoms of anxiety, depression, or somatization in patients presenting with any one of these sets of complaints. It is also important for physicians to be aware that patients who present without psychiatric symptoms, but with multiple unexplained physical problems may well also be suffering from GAD. In both instances an appropriate treatment choice may hasten the relief of symptoms. There is a need for an appropriate tool to assist in the recognition of GAD patients and to monitor their progress. The GADI is a new self-rating scale that is currently in development, which is specifically targeted at GAD. Initial data suggest that the scale is easy to self-administer and that it can differentiate between GAD and other anxiety and depression disorders. It should, however, be noted that the GADI needs further validation in the clinical trial environment, especially versus some of the older, more established, but less sensitive scales, such as the HAM-A. It is anticipated that the GADI will perform well in this setting. The GABA system may be important in the development and treatment of certain anxiety conditions, such as GAD and PD. SPECT and PET data have confirmed that in both these anxiety disorders patients have reduced central BZD receptor number, which should be accounted for in the treatment choices made by the physician. In addition, the symptoms of the various anxiety conditions and depression potentially overlap—at least by the way that SSRIs work in the different disorders. The tryptophan depletion data at least for some of these disorders, including depression, PD, SAD, and GAD, seems to indicate that making more serotonin available at the synapse is important in keeping a person well. In conclusion it is apparent that GAD patients often suffer from comorbid mood and anxiety disorders such as MDD or PD, or from somatic conditions, such as chronic pain or sleep conditions. Regrettably few studies have examined the response to treatment in patients with comorbid GAD and these other conditions—physicians require a drug that will effectively treat both the GAD and the other comorbid conditions, without employing polypharmacy. At present there is no single therapy that can provide the speed of onset of a BZD with the efficacy of an SSRI. Unfortunately comorbidity also increases the individual and economic burden of GAD and adds to the therapeutic challenge of D. Nutt et al. treatment. Regardless of all of these negatives, physicians and researchers must learn to perceive comorbidity as a challenge rather than a problem, to ensure a more stable future for this patient group. References Allgulander, C., Lavori, P.W., 1993. 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