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J Psychopharmacol OnlineFirst, published on October 2, 2008 as doi:10.

1177/0269881108096505

Review

A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD)

Journal of Psychopharmacology 00(00) (2008) 1–24 © 2008 British Association for Psychopharmacology ISSN 0269-8811 SAGE Publications Ltd, Los Angeles, London, New Delhi and Singapore 10.1177/0269881108096505

JR Davidson (Professor Emeritus), Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. W Zhang Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. KM Connor Clinical Neuroscience and Ophthalmology, Merck Research Laboratories, Merck & Co., Inc., North Wales, PA 19454, USA. J Ji Dept. of Mental Health, Shanghai Medical School, Fudan University, Dept. of Psychological Medicine, Zhongshan Hospital, Shanghai 200032, China. K Jobson Department of Psychiatry, University of Tennessee, Knoxville, TN 37996, USA. Y Lecrubier European College of Neuropsychopharmacology, Hôpital La Salpetriere, Paris, France. AC McFarlane The University of Adelaide, Centre for Military and Veterans’ Health, Adelaide, SA 5000, Australia. DJ Newport Women’s Mental Health Program, Emory University School of Medicine, Atlanta, Georgia 30322, USA. DJ Nutt Psychopharmacology Unit, Dept. of Community-based Medicine, University of Bristol, Bristol BS1 3NY, United Kingdom. DN Osser Department of Psychiatry, Harvard Medical School, VA Boston Healthcare System, Brockton Campus, 940 Belmont Street, Brockton, MA 02301, USA. DJ Stein Dept. of Psychiatry and Mental Health, University of Capetown, Cape Town, South Africa. ZN Stowe Women’s Mental Health Program, Emory University School of Medicine, Atlanta, Georgia 30322, USA. O Tajima Dept. of Mental Health, Kyorin University, School of Health Sciences, Tokyo, Japan . M Versiani Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. Abstract
Generalised anxiety disorder (GAD) is defined as excessive and uncontrollable worry and anxiety about everyday life situations. It is a chronic disorder, and is associated with substantial somatisation, high rates of comorbid depression and other anxiety disorders, and significant disability. The evidence base for pharmacotherapy and psychotherapy has continued to grow, and a wide range of drug choices for GAD now exists. Current guidelines for GAD generally restrict themselves to presentation of the evidence for various treatments, which, as a result, generally do not offer detailed discussion or recommendation of strategies beyond the first level of treatment, or take into account the individual circumstances of the patient. Thus, there is a lack of algorithm-based treatment guidelines for GAD. Our aim is, therefore, to present an algorithm for the psychopharmacologic management of GAD, intended for all clinicians who treat patients with GAD, where issues of pharmacotherapy are under consideration. We also hope that these GAD algorithms and other guidelines can help to identify high-priority areas that need further study. In this algorithm, we provide a sequenced approach to the pharmacotherapy of GAD, taking into account salient symptomatology and comorbidity, levels of evidence and extent of response. Special issues, including comorbidity, insomnia, suicidality, substance abuse, treatment adherence, pregnancy and lactation, cross-cultural issues, use of medication in the elderly, psychosocial treatment and dosing issues are also addressed.

Key words
algorithm; generalised anxiety disorder; international psychopharmacology algorithm project; pharmacotherapy

Corresponding author: Dr Wei Zhang, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3812, Durham, NC 27710, USA. Email: wei.zhang@duke.edu

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Psychopharmacological treatment algorithm for GAD

Introduction
Generalised anxiety disorder (GAD) is defined as excessive and uncontrollable worry and anxiety about everyday life situations. It is a chronic disorder and associated with substantial somatisation, high rates of comorbid depression and other anxiety disorders, and significant disability. The lifetime prevalence of GAD is estimated to be in the range of 2.8–6.6% among adults worldwide, and 12-month rates are in the range of 0.9–3.6% (Alonso and Lepine, 2007; Blazer, et al., 1991b; Carter, et al., 2001; Kessler, et al., 2005a,c; Offord, et al., 1996; Wittchen and Jacobi, 2005). The highest rates are often reported in the 45 to 55-year age group, with women twice as likely to have GAD as men (Carter, et al., 2001; Offord, et al., 1996; Wittchen, et al., 1994). In the elderly, one study found GAD to be the most common anxiety disorder, with a prevalence of 10.2% in this population (Beekman, et al., 1998). In primary care practice, GAD is often diagnosed by the International Classification of Disease (ICD) criteria, and is the most common anxiety disorder, with an 8% prevalence rate (Maier, et al., 2000). Patients with GAD are in fact more likely to consult with gastroenterologists than psychiatrists (Kennedy and Schwab, 1997), and a high proportion of difficult-to-treat high medical service users of hospital medical services have GAD (Lin, et al., 1991). GAD is linked to the overuse of medical services: emergency department visits, hospitalisations, diagnostic and laboratory tests, pharmacy costs and so on. Recognition of anxiety and depression in primary care is poor, with only 23% of pure anxiety cases being recognised compared with 56% of depression cases. The various stakeholders (patients, family members, employers and insurers) in a patient’s outcome may act in such a way as to complicate treatment of anxiety (Roy-Byrne and Wagner, 2004). GAD follows a chronic course in many cases and it is not uncommon to find that patients presenting for treatment have experienced active symptoms of the disorder for more than 10 years. Although it can remit spontaneously, rates of spontaneous remission over 5 years are less than 40% in the case of DSM-IIIR criteria (Yonkers, et al., 2000), and a waxing and waning course is more characteristic. Lifetime comorbidity with another Axis I disorder occurs in 90% of subjects with GAD, depression being found in over 60% (Wittchen, et al., 1994). When compared with chronic medical disorders, there is evidence that GAD is as disabling (Kessler, 2000). The evidence base for pharmacotherapy and psychotherapy has continued to grow, and a wide range of drug choices for GAD now exists. Current guidelines for GAD include those of 1) the British Association of Psychopharmacology (BAP) (http://www.BAP.org.uk) (Baldwin, et al., 2005); 2) the National Institute of Clinical Excellence (NICE) (http://www. nice.org.uk/CG022NICEguideline) and (http://www.nice.org. uk/CG022quickrefguide); 3) the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-

traumatic stress disorders (Bandelow, et al., 2002); 4) Consensus Statement on GAD from the International Consensus Group on Depression and Anxiety (Ballenger, et al., 2001a); 5) the Canadian guidelines (Swinson, et al., 2006); 6) the South African Primary Care Algorithms (http://www.mentalhealthsa.co.za/disclaimer.html); (7) the World Council of Anxiety Recommendations for the Long-Term Treatment of GAD (Allgulander, et al., 2003) and (8) the Singapore Ministry of Health guidelines (http://www.moh.gov.sg/mohcorp/publications.aspx?id=16364). These guidelines generally restrict themselves to presentation of the evidence for various treatments, but do not offer detailed discussion or recommendation of strategies beyond the first level of treatment. Thus, there is a lack of algorithmbased treatment guidelines for GAD. Our aim is, therefore, to present an algorithm for the psychopharmacologic management of GAD. It is important to recognise that two broad approaches are established, based on good evidence, for treating GAD – the pharmacological and the psychosocial methods of treatment. We are unaware of substantial evidence that the combination of the two adds any further benefit, but acknowledge that common clinical practice combines the two forms of treatment simultaneously or in sequence (Kuzma and Black, 2004). For decades, pharmacotherapy for generalised anxiety (previously called anxiety neurosis) was confined to the benzodiazepines (BZDs), following the introduction of chlordiazepoxide and diazepam in the late 1950s to early 1960s. However, drug treatments expanded with the development of the serotonin 5HT1a partial agonist buspirone in the 1980s. In the 1990s, the broad spectrum utility of the antidepressants became apparent, particularly the serotonergic agents, and these are now considered by many to be first line pharmacotherapy for GAD. Recent research is focusing on the development of drugs with novel mechanisms of action, as well as on various pharmacologic augmentation strategies with other psychotropic drug classes. In this algorithm, we provide a sequenced approach to the pharmacotherapy of GAD, taking into account salient symptomatology and comorbidity, and extent of response. Our recommendations are based on levels of evidence (LOE, see Table 2 and appropriate nodes in the text and flowchart) where this is available, or on informed clinical opinion where evidence is absent, as tends to be the case for augmentation or combination treatments, for example. We also cover special issues, including comorbidity, insomnia, suicidality, substance abuse, treatment adherence, pregnancy and lactation, crosscultural issues, use of medication in the elderly, psychosocial treatment (PST) and dosing issues. This approach is similar to one that we have previously taken with another anxiety disorder post-traumatic stress disorder (PTSD) [(Davidson, et al., 2005) and http://www.ipap.org/ptsd/]. In developing these algorithms, we have attempted to use many of the methods that are thought essential to guideline development, as described, for example, by the Appraisal of Guidelines Research and Evaluation (AGREE) instrument (AGREE, 2003) (e.g., defining

1993). How the algorithms are used depends on the nature of the question. Intended use and objectives of the algorithms The algorithms are intended for any clinician. with trend levels of significance on the primary scale. The group conducted its business via conference calls and emails. In some cases.. With regard to previous GAD guidelines. users who are interested in the complete picture may want to study the entire document from start to finish. has developed contacts in Europe. be found at the same place in the print version. versions of these algorithms exist in Chinese. ‘How do I manage a patient with GAD who is suicidal?’. using a range of levels. As noted above. We hope that these GAD algorithms and other guidelines can help to identify high-priority areas.. obtaining stakeholder involvement. case reports and uncontrolled trials. 1993). GAD used to be (in DSM-III) predominantly a disorder of autonomic.. that is. trazodone) become as effective or almost as effective. in which a draft document was circulated and repeatedly revised until agreement was reached on the final version.. This particular group of consultants was selected to represent all major regions of the world. Australia. It has been a moving target. with a focus on pharmacotherapy. with leading authorities participating from China. et al. et al. for example. the management of GAD with comorbid unipolar depression is identified at node 14 in the flowchart and text information can Node 1: Diagnosis of GAD No diagnostic category in psychiatry has changed as much over the past 25 years as GAD.. combination treatment. The flowchart serves as an easy way to locate the placement of a question in the text. Such an approach can also work well with the hard copy–printed document. to develop treatment algorithms. some provide no evidence categories. BZDs and other drug classes. in the short term (2 weeks) to BZDs than to antidepressants (Rickels. These symptoms may respond better. starting with level 1 (the most stringent) and ranging down to level 4 (the least rigorous). for example. we required more than one placebocontrolled study in which a sample size of 30 patients was enrolled. whereas others accept evidence based on significant differences between drug and placebo on important secondary measures. or ‘What recommendations are given about using a benzodiazepine in my patient?’ Some physicians may desire more information on the diagnosis of GAD by ICD-10 criteria. Its modular design on the IPAP website (http://www. for augmentation. 2007). ipap. who treats patients with GAD. from the standpoint of psychopharmacology. North America. Japan. Thus for these issues. An important change. The flowchart is also shown in Figure 1 in this review. for example. motor and other somatic manifestations of anxiety. regardless of experience. excessive worrying that is difficult to control and causes impairment. noting those (two) studies where we rely on a finding based on a secondary analysis of outcome. along with expertise in anxiety disorders. clarity and presentation.Psychopharmacological treatment algorithm for GAD 3 scope and purpose. et al. The International Psychopharmacology Algorithm Project (IPAP) is a not-for-profit organisation which. South America. much like STAR*D (Sequenced Treatment Alternatives to Relieve Depression) for depression (Fava. English and Spanish. more reliance is made on clinical opinion. Africa and Australia to help recruit faculty.g. and contains informational nodes with details described below. whereas others use somewhat different definitions. South America. in part. on the question of sleep pathology in a treatmentresistant case of GAD. Less evidence exists for third line approaches and beyond. or which class of drug to use first.org/gad/. This ‘psychic component’ of the disorder may respond better to antidepressants than BZDs (Rickels. These changes make GAD one of the more difficult disorders for making a psychopharmacology algorithm. and consensus does not exist as to how this should be done. our group adopted criteria that were essentially similar to those of other guidelines. we recognise that the evidence base is strongest for first and second line forms of monotherapy. applicability and editorial independence). for antidepressants. which need further study. primary care) or specialist (psychiatry). rigorous development. whether generalist (e. Currently. and can be downloaded at http://www. Asia. Europe and Africa. For example. although by week 8 the antidepressants (imipramine. For level 1. Others may find useful information. we followed the latter convention. for example. it has historically chosen experts.org/gad/) means that the algorithms can readily be used as isolated topics to inform a specific question. In our evaluation of evidence. the algorithm might be used for hypothesis generation and in the design of step-wise evaluation of treatment effectiveness and outcome for GAD. transcultural considerations and for situations where medical/psychiatric comorbidity is present. one disease at a time. 2003) and CATIE (Clinical Antipsychotic Trials in Intervention Effectiveness) for schizophrenia (Lieberman. The principal purpose of these algorithms is to facilitate clinical management of patients with GAD. et al. is the movement to the present criteria where the core problem is conceived to be chronic. The changes reflect. Existing guidelines define levels of scientific evidence in different ways. 1993).ipap. Some patients previously diagnosed with . and to interpret the studies we need to know which version of DSM was used for the particular study. Some accept results in which statistically significant treatment differences were found on the primary outcome. through years of networking. The GAD algorithm The GAD Algorithm Flowchart and Addenda are essential accompaniments to this article. or the management of GAD in the elderly. the results of psychopharmacological studies designed to improve the specificity of treatments for this disorder (Rickels.

Blue. assessment and evaluation. The flowchart is used by permission of the International Psychopharmacology Algorithm Project. http://www.org.ipap. Yellow. Green-.4 Psychopharmacological treatment algorithm for GAD Figure 1 International Psychopharmacology Algorithm Project (IPAP) Generalised Anxiety Disorder (GAD) Algorithm Flowchart. 12–16). second line treatment (Node 7b–11). first line treatment (Node 3–7a). . Purple. third line treatment (Node 7c.

et al.. Although DSM-IV specifies the minimal duration of 6 months and at least three associated symptoms. At the same time. which differs considerably from those of DSM-IV-TR (Text Revision).. as an anxiety condition. back pain. intake of caffeine. it is ‘free-floating’) b) Dominant symptoms including persistent nervousness. The current DSM-IV-Text Revision (TR) criteria for GAD (American Psychiatric Association. physical symptoms such as fatigue. 27% of whom met full criteria for GAD. http://www. and that clinicians may therefore Table 1 DSM-IV and ICD-10 criteria for generalised anxiety disorder Diagnostic code 300. Node 2: Consider diagnosis and other special issues at each evaluation At the initial assessment and at intervals during treatment. Ruscio. As noted by Stein (2001). as opposed to using them as a checklist. it is important to keep in mind the possibility that ongoing symptoms could be attributable to either separate psychiatric or medical morbidity or a disorder which is comorbid with GAD. 10th edition. DSM-IV. as the evidence is lacking for the creation of an algorithm based upon the ICD criteria. as well as assessment of current use of prescription and over-the-counter medications. the clinician should consider other issues relevant to the patient with GAD (as listed under ‘CONSIDER AT EACH STAGE’ in Figure 1). fatigability. 10th edition. In people with migraine. hyperthyroidism) a) Generalised and persistent anxiety not restricted to any particular environment (i. with attention to thyroid. glucose function. a drug of abuse. ICD-10 does not require minimal duration or number of symptoms.Psychopharmacological treatment algorithm for GAD 5 GAD would now be classified as having somatoform disorders in DSM-IIIR or IV.. 4th edition. 2002). alcohol and other drugs. the criteria became simpler. racing heart rate). palpitations. muscle tension and sleep disturbance d) Focus of the anxiety and worry not confined to another anxiety or somatoform disorder e) Significant distress or functional impairment because of the symptoms f) Symptoms not because of a substance (e. Subjects with GAD report a marked increase in the rate of peptic ulcer disease (Goodwin and Stein. . 1999). we recognise that the diagnostic criteria for DSM-IV GAD may be overly conservative (Kessler. et al. chest pain. 2005).g.1 a) Excessive anxiety and worry lasting at least 6 months b) Difficulty in controlling the worry c) Presence of 3 of the following 6 associated symptoms: restlessness. palpitations. apprehensive expectation (a sense of worry about everything in the future. 2005b. shorter and the disorder is now acknowledged to result in significant impairment. Castillo. muscle tension. with appropriate physical examination and laboratory testing. Diagnostic system DSM-IV ICD-10 F41.org.2% rate of GAD (Guillem.ipap. ICD-10 criteria place greater emphasis on the presence of somatic symptoms. With the extensive degree of psychiatric and medical comorbidity that is associated with GAD. epigastric discomfort and fears of impending illness or an accident c) Exclusion of neurasthenia Used by permission of the International Psychopharmacology Algorithm Project. diabetes and heart disease all make it more likely that the patient with GAD will make frequent visits to the doctor. dry mouth. et al. For example. sweating. Diagnostic and Statistical Manual of Mental Disorders.g. DSM-III or IIIR). and GAD was believed to produce no more than mild impairment. autonomic hyperactivity (sweating. GAD is often found in association with other medical conditions. Clinical judgment should also be used when applying the DSM criteria. lightheadedness.e.. difficulty concentrating. the relevant diagnostic criteria. muscular tension.. With subsequent editions of the DSM. tension headache. The concept of GAD was first described in DSM-III.02 Diagnostic criteria use their judgment in applying the current algorithm to patients who meet many. et al. are given in Table 1. the algorithm recommendations are based on DSM. An initial evaluation needs to include assessment for all relevant comorbid conditions. tension headaches and muscle pains secondary to tension and making people reactive and jumpy to sudden events). as well as hypertension. (1993) noted clinically significant GAD-like symptoms in 40% of patients with stroke. predicting negative outcomes for future events and occurrences – when this occurs primarily at night. but not all. There were sweeping restrictions as to the allowable coexistence of other Axis I disorders. it can lead to insomnia) and vigilance/ scanning (always looking for threats and problems). trembling. hyperventilation. To make the diagnosis required patients to experience at least 1 month of symptoms from three of four categories (motor tension often of the back or neck. a medication) or a general medical condition (e.. there was a 10. irritability. parathyroid. ICD-10. Because nearly all the evidence upon which our algorithms are based comes from studies which used DSM-IV (or in some cases. dizziness. Geneva: World Health Organisation). insomnia. 2004) and the ICD-10 criteria for GAD (International Statistical Classification of Diseases and Related Health Problems. International Statistical Classification of Diseases and Related Health Problems.

most particularly in panic disorder treated with high-dose clonazepam. a separate diagnosis of GAD is not made. suicidal behaviour and attention deficit and hyperactivity disorder (ADHD). which may declare an aspect of the patient’s life which is important for the understanding of their anxiety. bipolar disorder and undiagnosed medical illness. such as mirtazapine. et al. if the GAD symptoms occur exclusively during the course of any mood disorder (unipolar or bipolar). It should be noted that anxiety in the context of substance abuse may reflect intoxication or withdrawal symptoms (see below). 2003. for example. Although anxiety decreases when such agents are used to treat major depression.. should be titrated to its maximum dose. One benefit of considering PTSD in the differential diagnosis is that it necessitates obtaining a trauma history. other approaches might be considered. Among novel antiepileptic agents without proven thymoleptic properties.. Comorbid diagnosis Concomitant psychiatric or medical disorders can be present in patients who are being assessed for GAD and may complicate accurate diagnosis and treatment. et al. olanzapine (Bystritsky. 2005. 2005) (LOE 2). There is some evidence that pharmacotherapy for GAD may be associated with lower risk of developing secondary major depression. et al. Fineberg. et al. antidepressant therapy. Depressed patients with GAD (more severely ill) confined to the depressed periods and GAD not confined to the depressed periods were comparable on many parameters and differed from a pure depression control group (Zimmerman and Chelminski. and after a failed trial of treatment. For continuing depression. 2002). and hypervigilance is seen in both GAD and PTSD. 1998). endocrine (thyroid). but present the challenge of minimising switch risk when used in conjunction with a mood stabiliser.. valproate with sug- .. vulnerability or prognosis. albeit mixed. A number of newer antidepressants. the clinician should look for common coexisting conditions.. the findings do suggest that pharmacotherapy for GAD can confer a preventive effect against depression. 2003). Stein.. Initially. et al. quetiapine (Carey. McDougle. However. Although GAD with comorbid substance use disorder has not been well studied (see below). Kessler. 2001.. hostility during the course of BZD therapy. et al.. Reich. If it should occur during treatment of GAD.. 1990.ipap. As part of the initial diagnostic evaluation. In such a situation. if tolerated. 2003). 2001) is superior to placebo in subgroups with dual diagnoses of GAD and a secondary diagnosis of major depression. 2005. Zimmerman found that this hierarchical relationship may not be supported by the evidence. et al. Antidepressants from many classes have efficacy in the treatment of most anxiety disorders. et al.. et al. for example. evidence that a serotonergic antidepressant may be useful in either depressed or anxious patients with comorbid alcohol-related problems (Nunes and Levin. there are no prospectively designed trials published on the treatment of GAD with comorbid depression. assessment is recommended as to possible substance abuse or even abuse of the prescribed BZD. there is indirect.6 Psychopharmacological treatment algorithm for GAD Among the concomitant psychiatric disorders and symptoms to be included in the differential diagnosis are depression. et al. Schade. 2002) (LOE 3) and risperidone (Hamner. 1999) (LOE 3). 2004) (LOE 1). Denys. such as depression. et al. 2004. some selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have been shown to be effective in both GAD and major depression. the drug was superior to placebo in the full sample and in the subsample with GAD (Davidson. et al. Before introducing a drug for GAD. 2005) (LOE 1) and risperidone (Erzegovesi. pulmonary or cardiac disease. et al. et al.. 2004) (LOE 3) in PTSD. 2004. For bipolar disorder. and depression decreases when such agents are used to treat GAD. Silverstone and Salinas.. alcohol and substance use disorders. bipolar disorder. olanzapine (Butterfield. et al.. Although the two groups were only retrospectively randomised. No randomised controlled trials have been conducted in patients with bipolar disorder and any co-occurring anxiety disorder. Woodman and Noyes. 2003). or emergent. 2005... the patient should have a full psychiatric and medical history with appropriate consideration or referral for laboratory and physical examination. et al. There may be some circumstances where the use of a BZD has intensified depression or promoted its emergence as a side-effect. For ongoing. Shapira. lamotrigine (Hertzberg.. et al. 2004. In the case of GAD and other comorbid disorders such as ADHD. 87% of whom had concomitant GAD. Other relevant studies support the use of antidepressants.. et al. suggesting that they be used first-line when there is overlap. et al. other anxiety disorders. 1994) (LOE 4). evidence of anxiolytic efficacy from placebo-controlled trials exists for valproate in the treatment of panic disorder (Primeau. the clinician is advised to withdraw the offending agent. 2000) (LOE 1) as adjunctive treatment in SSRI-refractory obsessive-compulsive disorder and risperidone as augmentation to a SSRI in GAD (Brawman-Mintzer. alcohol problems. 2003. The GAD Algorithm Flowchart and Addenda are essential accompaniments to this article and can be downloaded at http://www. and appropriate action taken. PTSD is often associated with extensive somatisation (Andreski. SRI therapy is recommended if the symptoms are due to GAD or depression. et al. (2006) have similarly raised for discussion the importance of adequately treating both conditions. in this context (Goodnick. et al. It is often necessary to address the following issues as part of an adequate assessment in the diagnosis and treatment of GAD. based on a large population study (Goodwin and Gorman. it would be necessary to ensure adequate mood stabilisation because anxiety may reflect poor control of the mood disorder. In one small placebo-controlled study of chromium picolinate in patients with atypical depression. A study using post-hoc analysis from large controlled trials has shown that venlafaxine-XR (Goodman.org/gad/. which would normally be to either reduce the BZD dose or taper the drug towards discontinuation. Hollander.... Among agents with antimanic or mood-stabilising effects. We would note here that according to the DSM-IV criterion F. 1999).

nice. et al. dependence and withdrawal issues (Freeman.. such as family psychiatric history. et al.ipap. and generalised anxiety disorder) in adults in primary. abstaining from products containing stimulants (coffee. 1) The British Association of Psychopharmacology (BAP) (http://www. Cipriani. http://www. 2005a)..org. when confounding factors are taken into account. secondary and community care (Clinical Guideline 22. In addition. especially in GAD... (2007) have observed that systematic reviews have reported an excess risk of suicide for children and adolescents with major depression treated with antidepressants (Hammad.. previous suicide attempt. 2005b). et al. Since 2005. et al. et al. 2002).co. There is evidence that subthreshold depression associated with GAD may increase the rate of attempted suicide (Balazs. 2006).. 2005).Psychopharmacological treatment algorithm for GAD 7 gested efficacy in panic disorder might be a candidate for the treatment of GAD comorbid with bipolar disorder (Keck.html). Suicidality Although the National Comorbidity Survey (NCS) did not find GAD to be significantly associated with suicidal ideation or attempts (Sareen. et al. Available at http://www. there is a limited evidence base specifically addressing comorbidity.. 2005). (6) The South African Primary Care Algorithms (http://www. There has been considerable attention to the nature of the relationship between use of antidepressants and emergence of suicidal thoughts and behaviours in adults who receive these drugs. particularly in the primary care setting. In summary. In one review. 2005. Freeman. 2006) (LOE 5). However.e. or suicidal ideation are seen in GAD among young adults aged 14–24 (Wunderlich. severity of illness. we consider that a rational treatment approach would be to institute an antidepressant drug and avoid the sole use of a BZD or other drug which is devoid of antidepressant effect.. as well as among an adult population in the Netherlands (Sareen. A careful assessment of whether the insomnia is a symptom of GAD.. et al. et al. et al. felt that antidepressants are best avoided for treating the anxiety disorders in these patients because of risk for ‘switch’ to hypomania and mania. Suicide is certainly a potential risk when patients with GAD have comorbid MDD. However. et al. and further studies are urged in this patient group. 2005). this risk abated considerably (Rubino. Insomnia Insomnia is a common and troubling feature of GAD and may be the presenting complaint.uk/CG022quickrefguide). BAP.. 2007). 2006).org. et al. The extent to which early agitation. 2007. APA guideline) should also be observed. et al. However. 3) The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety. they made favourable comments about using BZDs. relatively safe and well-tolerated. but not for adults (Gunnell.. Used by permission of the International Psychopharmacology Algorithm Project.org. diet. those who were without psychosis and hospitalised because of a suicide attempt) in one study (Rubino. the treatment of this component takes priority over treating GAD.. in this circumstance. et al. et al. activation or jitteriness plays an aetiological part in emergent suicidality. should be conducted early on.za/disclaimer. lifestyle issues such as exercise (especially in the morning). obsessivecompulsive and post-traumatic stress disorders (Bandelow. 2006) and among those who were prescribed with the index antidepressant for the first time according to a general practice research database (Rubino. et al. 5) The Canadian Guidelines (Swinson.uk/CG022NICEguideline and http://www. 2002). et al. they also caution that long-term use of BZD may be problematic because of tolerance.. 2) The National Institute of Clinical Excellence (NICE) (NHS National Institute of Clinical Excellence). the initial assessment and treatment should include attention to sleep hygiene. 2006). and most recently the warning has also expanded to include adults aged 18–24. et al..nice. In cases where suicide risk is considered to be serious. supplements such as . increased rates of attempted suicide Table 2 Level of evidencea 1 = More than one placebo-controlled trial having total sample sizes over 30 2 = One placebo-controlled trial (or active versus active drug comparison) with total sample size of 30 or greater 3 = One or more small (n < 30) placebo-controlled trial 4 = Case reports or open-label trials 5 = Expert clinical consensus without published evidence aTreatment Guidelines for generalised anxiety disorder include. 2007). et al. unless comorbidity was present. needs further exploration (Cipriani. Tiihonen. there are regional practice differences in respect of the role of antidepressants for patients with bipolar depression... a careful evaluation for comorbidity is needed before initiating treatment. as noted below (see node 11b). and preferred anxiolytic antimanics and atypical antipsychotics.. 2000).g. the Food and Drug Administration (FDA) has added to all antidepressant labels a warning of increased risk of suicidal thoughts and behaviour in children and adolescents who take antidepressants. et al. Although suicidal patients are excluded from almost all GAD trials. 1998). There is some evidence that venlafaxine may be associated with greater risk of suicide among highrisk subjects (i. with or without agoraphobia... et al. December 2004.org. OTC drugs with ephedra.mentalhealthsa. For GAD. 4) Consensus Statement on Generalised Anxiety Disorder from the International Consensus Group on Depression and Anxiety (Ballenger.. and the choice of treatment in GAD patients with comorbidity needs to be formulated with appropriate clinical judgment. or a separate disorder. The relevance of all these findings to a population suffering from GAD remains unclear. with inconclusive results (Gunnell. in that these agents are efficacious. Sleep difficulty may persist even after an otherwise good response to SRI drugs. General guidelines for assessment and treatment of suicide (e. Anxiety: Management of anxiety (panic disorder. 2001a). Tiihonen..uk) (Baldwin. et al.

which remit without medication intervention. myridia). 1994). In this group. it may be easier for them to stop the other misused drugs. or other sleep disorders. Discussion of ways in which antidepressants effect sleep appear in the review by Mayers and Baldwin (2005).. Patients with history of. Should the sequence of treatments for these ‘recreational’ users be any different from the standard approach? These frequently encountered patients have received little research attention and a prudent treatment approach thus involves reasonable and appropriate clinical judgment in managing such cases. and that it is difficult to confirm the diagnosis of GAD until after abstinence has been attained. Withdrawal from some substances can be prolonged. etc. and the residual effects of their presence can affect subsequent medication that may be given.8 Psychopharmacological treatment algorithm for GAD ginseng or Ma Huang. early use of SSRIs or other antidepressants may benefit these patients.g. the patient may not succeed in achieving this goal. Substance abuse Patients with current or recent substance dependence or abuse Individuals with GAD may misuse alcohol. et al. restless leg syndrome (RLS). The patient may have been recently detoxified. . substance dependence or abuse If the patient is not actively abusing or dependent upon substances presently. 2004). A group of patients not specifically addressed in this algorithm are individuals who use drugs of abuse. if this is not possible. If symptoms appear to be diminishing over the first week of sobriety. methadone has a halflife of about 2 days and its effects as an inhibitor of cytochrome P450 2D6 could therefore persist for more than a week. et al. and make a commitment to abstain from future use of these substances. Nunes and Levin (2004) have comprehensively reviewed antidepressant use in dual diagnosis patients with depression and substance use disorder. but sleepiness is found only rarely: when present. 2001). In the longer term. This would suggest that management of this problem would be at least as high a priority for treatment compared with treating their GAD. it is important to consider the possibility of sleep-related breathing disorder. Before beginning pharmacotherapy for comorbid GAD. the evidence is mixed from a pilot study of paroxetine in social anxiety disorder and comorbid alcohol use disorder (Randall. In the event of continued poor response. such as obstructive sleep apnea (OSA). et al. periodic limb movement disorder. the non-sedating agents including SSRIs and SNRIs often improve sleep as well. to allow the clinician to identify those mood syndromes. conservative and less complicated regimens are to be preferred. it seems reasonable to recommend that the patient should have completed withdrawal from his or her drug of abuse or dependence and from any drug used for withdrawal. as well as an evaluation of whether the sleep disturbance is caused or exacerbated by prescription medications such as some of the serotonergic antidepressants or stimulants. et al. except for the initial period of detoxification (LingfordHughes. it is reasonable to wait at least another week before initiating pharmacotherapy.pharmacotherapy) can be instituted. RLS. Although we are unaware of pharmacotherapy studies in GAD with comorbid alcohol use disorder. the treatment approach may require relapse prevention treatment. et al. and be abstinent for at least one additional week.. hoodia.. these include the sedative tricyclic antidepressants plus trazodone and mirtazapine. but who do not meet DSM-IV criteria for abuse or dependency. However. an SSRI should be considered. We recommend that patients with GAD first undergo withdrawal from his or her substance(s) of abuse or dependence. One important issue to consider in this group is the possible kindling effects of cocaine and amphetamine derivatives where the effect may be manifest as GAD symptoms. In time. The APA Guidelines advise delay in implementing antidepressant drugs by 1–4 weeks. but BZDs are generally contraindicated in this population. and there is no history of these symptoms before onset of the substance abuse/dependency or during previous periods of extended sobriety. possibly.continuous positive airways pressure (CPAP). for example. However. OSA. for example. energy drinks. Patients with GAD commonly endorse tiredness. However. but no current. In such circumstances. the initiation of treatment with an antidepressant. Some antidepressants have more immediate sleep promoting effects than others. As a general principle with these patients.. adequate treatment of GAD may ultimately produce better control of the substance abuse in many cases. For example. a side-effect of some antidepressants and sedating anxiolytics. be under unusual stress or may be experiencing strong cravings for his or her substance and therefore at high risk of relapse. Our recommendations below are consistent with those of Brady. a polysomnogram can be obtained if resources are available. cannabis or other substances in an effort to ameliorate their anxiety. (2007) noted that the symptoms of GAD are similar with those of alcohol withdrawal. Once the patient has shown a therapeutic response. 2007). such misuse may result in substance abuse or dependence. it suggests a comorbid primary sleep disorder or. If a sleep disorder is identified or diagnosed with a sleep study. Of course. Symptoms present after abstinence of less than 1 week may be due in part to the residual effects of the substance. (2007) and the American Psychiatric Association (APA) Guidelines (American Psychiatric Association. and compliance with the commitment to abstinence must be followed closely. Thus. they offer evidence that drinking outcomes improve less than does mood following antidepressants in patients with comorbid depression and alcohol dependence. then appropriate treatment (e. the guidelines endorse early use of antidepressants if there is a history of previous episodes. and if other symptoms are present to suggest these disorders. but has a history of such abuse or dependence. abstinence is important to achieve. probably secondary to their anxiolytic actions. Brady. A possible role exists for buspirone in patients with GAD and alcohol use disorder (Kranzler.

Clinicians seldom order routine pregnancy tests.. et al. (1993) have reported that GAD subjects with impulsiveness.Psychopharmacological treatment algorithm for GAD 9 If the patient’s problem is with alcohol. 2005). 21. et al. Non-adherence to medication is higher in patients who view their symptoms from a nonmedical perspective. In a large prospective longitudinal study of a community sample of 8323 pregnant women in England. It is likely that similar rates might hold true for patients with GAD. Increased risk of pulmonary hypertension with SSRI in pregnancy has been reported and should be considered when advising patients about risk-benefit issues (Chambers. 2005) or topiramate (Johnson. (d) do not stop taking medication without checking with the prescribing physician. the clinician may then return to the GAD algorithm. et al. et al. selfreported anxiety and increased impulsivity as well as lower scores on the subtests of the WISC-R in 14 to 15-year-old children (Van den Bergh and Marcoen. The primary issues in women of childbearing potential are best addressed at initial treatment planning. novelty seeking traits and who show dislike of regimentation are more likely to drop out of medication trials.. improvement of symptoms. The following educational messages to patients may prove helpful: (a) take medication daily. the physician is encouraged to approach the clinical decision as if the woman may be pregnant. et al. sertraline. Disulfiram may be of value for prevention of relapse in cocaine-dependent individuals (Carroll. fluoxetine.. et al. Urine pregnancy tests neither rule out early pregnancy (1–3 weeks gestation) nor does a recent or current menses. et al. Sholomskas. Because it is not possible to ensure that all women are with reproductive capacity are not pregnant. and provides one explanatory model by which the effects of psychotropic medication can be understood (Hoehn-Saric. The clinician’s vigilance towards detecting comorbid substance abuse needs to be continued throughout treatment.. Similarly. As such. there is sparse information regarding the incidence and course of anxiety disorders during pregnancy and the post-partum period.. 2004. 2004) (LOE 2 for index disorder.. A recent prospective study reported that maternal depression and anxiety during pregnancy predicted higher rates of conduct disorder in children (Kim-Cohen. 1990). 2003). Metz. A strong treatment alliance and credible rationale are called for. James. evidence-supported pharmacotherapy options could include naltrexone (Srisurapanont and Jarusuraisin. also apply to GAD. (1995) have suggested a number of strategies to enhance treatment adherence in depression. 1996. there is a significant correlation between maternal antenatal anxiety (12–22 weeks gestation) with ADHD.. all of which. 2005). et al. even after controlling for the presence of antenatal depression. If the patient with a history of substance abuse has been assessed and treated (if appropriate). Despite the B category rating. Somatically focused patients are often reluctant to consider a psychiatric diagnosis and psychotropic medication. 2003). Furthermore. LOE 5 for GAD). (c) continue taking medication even when feeling improved. 1988. et al. Nonadherence rates to antidepressants in depression can be as high as 50% within the first 3 months (Lin. and include side effects.. Reasons for non-adherence are myriad... 2002. 2005). All pharmacotherapy options for substance abuse/dependence seem to work best in the context of ongoing intensive. as well as ambivalence about treatment and the stigma associated with taking psychotropic medication. Treatment non-adherence Clear explanation about the expected effects of medication and how to deal with problems which arise is essential at the initiation of pharmacotherapy. 1994) with evidence of a either worsening or new onset in the post-partum period (Cohen. in older children aged 8–9. LOE 5 for GAD). The recent FDA pregnancy category change for paroxetine to category D must be included in treatment decisions. et al.. Issues relevant to women of childbearing potential Despite the prevalence of anxiety disorders in women. et al. Maternal anxiety during pregnancy has been associated with behavioural problems at 4 and 6 years of age (O’Connor.. et al. structured psychotherapeutic treatment focused on abstinence. In cases. . citalopram. paroxetine). particularly in the 15 to 25-year age group. 1994.... et al. Most of the women (64%) who reported elevated levels of anxiety during pregnancy also reported elevated levels of anxiety after delivery. Lin. 2004. et al. although the incidence and course of GAD is not well studied in women during pregnancy and the post-partum period. 2004) (All LOE 1 for the index disorder. The patient may require a detailed rationale about the relationship between physical symptoms and mode of action of the medication. et al. antenatal anxiety predicted postpartum depression at 8 weeks and 8 months. in our view. The course of panic disorder during pregnancy has also received attention (Cohen. 1994. This includes: 1) documentation of method of birth control for all women of reproductive capacity at all visits. Wingerson. lack of efficacy..g. there is a dearth of information for buspirone during pregnancy and/or lactation. 2006). Northcott and Stein. (e) instructions on how to deal with side effects or to resolve other questions about medication and (f) schedule pleasant activities..9% of the women had clinically significant symptoms of anxiety (Heron. acamprosate (Verheul. there is clear evidence that untreated anxiety may pose a significant risk for the mother in the post-partum period and potentially affect the developmental trajectory of the infant. et al. 1993). 1987. 1995. George. 2004). 2) over 50% of pregnancies are unplanned. 1995). The literature on somatic vigilance and selective attention is relevant in this regard. et al. the treatment should be conducted with the medications with the majority of obstetrical outcome data (e. (b) antidepressants (but not BZDs) may take some weeks to work. compliance and relapse-prevention (O’Malley. where medications are indicated. Van den Bergh. There is mounting evidence that maternal anxiety during pregnancy and the post-partum period potentially poses significant risk to the child. and may therefore constitute a high-risk group for treatment non-adherence. et al. as well as with the addition of any new medication.

Although cohort studies have failed to show this increased risk. A study which compared sertraline. characterised by CNS or respiratory signs. 35% met criteria for GAD. a meta-analysis (Altshuler. with benefit (LOE 2) (Schuurmans. 2005) (LOE 2 for the entire sample). However. Node 3: Treatment An initial treatment choice may be made as to whether medication. which tend to be more prolonged among premature newborns. Appropriate medical work-up is recommended when evidence suggests that other disorders may be present.. the optimum duration of treatment . et al. as well as the greater risk of hyponatremia in response to SSRI drugs in older patients (Jacob and Spinler. et al. 2006. GAD in the elderly GAD is more likely to be seen in the elderly than are other anxiety disorders. hip fracture.. Because GAD is a chronic. Flint. found that both active treatments were superior to WL. that is. et al. Similarly. 2004) found that the number of patients with GAD who sought medical treatment is less than 17% and that subjects tend to see their tension and excessive worry as being normal reactions to negative life events. et al. Of all entered subjects.. Early discontinuation is associated with higher relapse rates. Cognitive therapy for GAD has been adapted to the elderly.. Earlier reports with diazepam and chlordiazepoxide suggested a higher rate of cleft lip. et al. et al. not simply the continuation of a long-standing problem (Blazer. relapsing condition. 1990) (LOE2). Oslin. A review of the potential for pregnancy and/or urine pregnancy test should be considered at any juncture in the algorithm that adds adjunctive pharmacotherapy (node 9–17). BZD use in the elderly is problematic. a history of use in children with status epilepticus. 2006). 1996) indicated a small but significant risk of birth defects with BZDs. in almost all cases of pharmacotherapy. 1987. cognitive behavioural therapy (CBT) and a waiting list (WL) control in a mixed anxiety population age 60 and older (LOE2 for aggregated diagnoses of anxiety. Stanley and Novy.. This information regarding the approach to women in their reproductive years should influence the algorithm at all points that include use of BZD. 1989). 2001b. it is also important to consider relevant medical aetiologies. withdrawal difficulties and increased risk of cognitive impairment (Bogunovic and Greenfield. useful to consider patients’ explanatory model of their illness. mainly GAD (Lenze. 2000). 2004. is recommended for a minimum of 1 year. and has a reported prevalence rate that ranges from 0. Krasucki. Clonazepam has a better pregnancy rating (category C) relative to other BZDs. including GAD). assuming some degree of response. in particular the greater likelihood of accumulation of those drugs. 1999). it is. and to use standard diagnostic criteria and good clinical judgment. There is also a positive placebocontrolled study of citalopram in elderly patients with anxiety disorders. medication side effects or drug–drug interactions.. Although it has been argued that somatisation varies in prevalence across different cultures. Theories of illness are influenced by cultural factors and patients’ beliefs should be discussed and carefully accommodated. as for example the intolerance which was found in one study of venlafaxine-extended release in frail elderly subjects. Maier. with only a low rate of spontaneous remission. 1994. et al. One study has found buspirone to show greater benefit than placebo in patients over age 65 with GAD (Bohm. including any pertinent cultural aspects. In addition. when used. PST or both will be given. this allows the clinician to understand the meaning of the symptoms for them. et al. as well as iatrogenic causes. an internet survey in Japan (Tajima.7 to 10. there are pharmacokinetic and pharmacodynamic considerations to be kept in mind. For example. The primary and/or adjunctive use of BZDs is generally not recommended in treating GAD during pregnancy.. et al. 2006. Retrospectively derived pooled data (LOE2) from five studies report efficacy of venlafaxine-extended release in patients with GAD who are age 65 and older (Katz. However. given their higher incidence of falls. which are metabolised by oxidation and which have longer half-lives. 1991a). Side effects of antidepressants are of greater concern in the elderly. with the pattern of results generally suggesting a more robust effect for sertraline over CBT (Schuurmans.. lorazepam has the advantages of multiple routes of administration. to ensure that a valid diagnosis is made.. About onehalf of all elderly subjects with GAD report that their condition is of recent onset. drugs with shorter half-lives may produce more severe withdrawal if used in the long-term. 2003). et al. et al. often for long-term treatment. Elderly people are more likely to be taking other medications. BZDs are considered ‘contra-indicated’ in breast feeding according to American Academy of Paediatrics committee on medications in breast feeding report 2002.2% (Copeland. and a pathway of metabolism that does not require the foetal/neonatal liver. There is a need to screen for GAD with appropriate questions.. et al.10 Psychopharmacological treatment algorithm for GAD Retrospective cohort review by Ferreira. et al.. Similarly.. for example. however. (2007) suggests that use of SSRI and venlafaxine during the third trimester of pregnancy is associated in many cases with a brief neonatal withdrawal state. In formulating a treatment plan. and thus are at more risk for drug–drug interactions. 2000). Should BZDs be required during pregnancy and/or lactation – the preferred agents would include clonazepam and lorazepam. 45% for panic disorder and 20% other forms of anxiety. 2002). and to negotiate an agreed upon treatment accordingly. et al. In elderly patients who present with new onset anxiety. Lindesay. GAD is often accompanied by depression and somatisation in different populations. Cultural issues There may be significant differences in reporting of GAD symptoms in different cultures (Ballenger..

Davidson. Of the above three medications. 1989). This is perhaps more likely if comorbid panic disorder is also present.Psychopharmacological treatment algorithm for GAD 11 varies from one patient to another. et al. we recommend BZDs as second line treatments. venlafaxineextended release and duloxetine. et al. form of nefazodone (Serzone) has been discontinued. and these data support BZD for all the recent DSM iterations of GAD. we recommend the use of an SSRI or SNRI for treating the somatic symptoms of GAD. 2000. et al. et al. 1999). In general. Psychotherapeutic treatments include CBT and relaxation therapy (although there is little evidence base for the latter). long-half life BZDs may hold merits or advantages in anxiety disorders except in the elderly because of their relatively low risk of inter-dose rebound anxiety and withdrawal symptoms compared with those with short-half life. However. 2006. Rynn.. et al. as well as social treatments include problem solving might also be helpful (Catalan. to be chosen after intolerance has been established to antidepressants.. 2007. 1996) and fluoxetine in children and adults (LOE 2 for children and for adults) (Birmaher. 2002). 2001. First line treatment antidepressants Following a DSM-IV diagnosis of GAD. Varia and Rauscher. Schweizer and Rickels (1997) propose that BZD are appropriate first line choices in two circumstances: 1) short-duration GAD type reactions in response to stress and 2) where somatic symptoms are more prominent than psychic symptoms (Rickels.. Their rapid onset of efficacy. However. et al. Role of non-antidepressant drugs in GAD Although it is acknowledged that many practitioners use the following drugs as first line treatment. and we are unaware of any reliable predictors of who is at most at risk for relapse. at a rate determined by tolerability. we recommend their use only as a second line form of monotherapy after intolerance to a series of antidepressants. including one long-term 6month study of extended-release venlafaxine. Although the branded . 1993). Benzodiazepines A solid body of level 1 evidence supports the short-term efficacy of BZD drugs for GAD. sertraline (Allgulander. nefazodone (LOE 4) (Hedges... Although antidepressants may have a slower onset of action than BZDs. et al. 2003. Rickels. et al. beginning with DSM-III. Other antidepressants (imipramine and trazodone) have been reported to show greater efficacy than placebo in one study of DSM-III–based GAD (level 2) (Rickels. Level 1 evidence supports the SNRI drugs.. 2006). 2007). et al. based upon their proven efficacy on this symptom cluster. as well as in GAD with concomitant major depressive disorder (Goodnick. 1984). impatience. There is no evidence that combined use of CBT with drug therapy enhances CBT alone. 1999. and a satisfactory effect is usually obtained. Recommended doses of each medication are provided in Table 3. sertraline would be the best option for women of reproductive years. et al. 2001. et al. from the perspective of the extent of safety data in pregnancy and lactation. Rickels. Level 1 evidence supports the following SSRI drugs for DSM-IV diagnosed GAD: escitalopram (Davidson. 1993). 1982. these medications are looked upon with disfavour because of their abuse potential and association with dependence. 2007. Hartford. paroxetine-immediate release (Pollack. early in treatment for marked agitation or severe sleep disturbances. 2005).. et al. they are eventually as effective. (2005).. et al. Some evidence exists for citalopram (LOE 2) (Blank. as reviewed by Mitte. if not more so.... 1984). in other quarters. the recommended first line choice will be an SSRI or SNRI drug. in patients who met DSMIV criteria for GAD (Allgulander. Nevertheless... 2003). In this regard. et al. 2005. Lower levels of evidence (LOE 4) support the use of mirtazapine in GAD (Gambi.. Node 5: Monotherapy with SSRI or SNRI: 4 to 6-week evaluation with adequate dosing Please refer to Table 3 for initial prescribing and dose titration strategies. bupropion was equivalent to escitalopram in treating GAD (LOE 3) (Bystritsky. et al. et al. although we recommend that the drug should be generally avoided because of liver toxicity. generic forms of this drug are still available. although acknowledging that antidepressants typically have a greater benefit on psychic than somatic symptoms... Koponen. Rickels and Schweizer (1996) have noted that serotonergic drugs may be more effective in this situation (LOE 4). et al. to be followed by a persistent but carefully managed upward dose titration.. et al. but CBT in combination with a sub-therapeutic dose of diazepam produces a greater effect than the same dose of diazepam alone (Power.. et al. et al. et al. Many authorities suggest the use of BZDs in the early phases of treatment with SSRIs or other antidepressants to achieve some symptomatic relief until the antidepressant has had time to work (generally about 2–3 weeks) and to protect against the occasional early worsening of anxiety seen at the beginning of antidepressant therapy.. Lenze. et al. 2004).. In a head-to-head comparison trial of bupropion and escitalopram. 2001) (LOE 1). but some patients with GAD are sensitive to medication side-effects and may require low initial starting doses. 2006).. Pollack. irritability and impulsivity. but these are not recommended as first choice treatments because of poorer tolerability and higher risk of potentially serious side effects. BZD are not recommended where GAD is characterised by substantial hostility. There is also a place for these drugs in augmentation (see below Nodes 9–17) or on occasion. reasonable side-effect profile and good tolerability make them appealing drugs for many clinicians. which can sometimes be made worse by BZDs (Rosenbaum.. et al. et al.. Fewer authorities advise that BZDs should be avoided whenever possible Node 4: Psychosocial treatment Cognitive behavioural treatment is efficacious for GAD (Borkovec and Ruscio. 2004).

5 mg every 3–4 days 1–2 mg every week 5 mg after 4–7 days. for approved non-psychosis indications (i.75–1. increase to 200 mg 20 mg every 2–3 days 50 mg after 1–3 days 25 (HS) 100 300 15 (HS) 50 (HS) 100 0. we note a limited literature (LOE 1 for imipramine.25–0. aAll maximum doses are according to US package insert. Doses may be reduced in the elderly or those with significant medical conditions at the discretion of the treating clinicians. The large SSRI (e.5 25 30 37. http://www. et al..g.5 200 40 50 45 400 400 4 6 40 6 60 60 100 600 16 1. may then increase in 50 mg increments 15 mg every 1–2 weeks 50 mg every 3–4 days 100 mg every 4–7 days 0. there- .5 mg every 1–2 weeks 50 mg after 3–4 days. (Woods. not exclusively for generalised anxiety disorder). venlafaxine-XR) databases suggest that the psychological components of the Hamilton Anxiety Scale are more responsive to each drug. et al. 1999).5–75 20 10 20 20 25 50 60 75 60 20 60 50 75 200 120 225 20 mg every 2 weeks 5–10 mg every 1–2 weeks 10–20 mg every 2 weeks 10–20 mg every 2 weeks 12.5 TID) 1–2 (1 BID) 5–15 (5 TID) 1–2 (1 BID) 10–15 (5 BID-TID) 15–30 (5–10 TID) 50 (25 BID) 150 (75 BID) 4 (2 BID) 0. escitalopram) and SNRI (e. et al.. with food 50 30 100 150 1. some patients are used to BZDs. Hoehn-Saric. albeit more slowly and to a lesser degree. at least in the short term. et al.c Paroxetine-CR Sertralineb Duloxetinec Venlafaxine-IR/ERc TCA’s Imipramine Other antidepressants Mirtazapine Trazodone Bupropion IR/SR/XL Benzodiazepines Alprazolamc Clonazepam Diazepamc Lorazepamc Azapirones Buspironec Tandospirone Other anxiolytics Hydroxyzinec Pregabalin Anticonvulsants Tiagabine Antipsychotics Fluphenthixol Sulpiride Ziprasidone Other drugs Riluzole 20 5–10 10 10–20 12.12 Psychopharmacological treatment algorithm for GAD Table 3 Drug Medication dosing recommendations for treating generalised anxiety disorder Starting dose (mg/day) Minimal target dose (mg/day) Maximum dosea (mg/day) Dose increments SSRI/SNRI Citalopramb Escitalopramb. then increase by 25–50 mg every 1–2 weeks Increase by 30 mg after 1–2 weeks Increase to 75 mg within 1 week. buspirone or hydroxyzine. given that some patients benefit from and do not abuse them (Osser. et al.. 10 mg every week 1–2 mg every week 5 mg every 3 days 15 mg every 2–4 weeks 50 mg every week 150 mg every 4–7 days 2–4 mg every week 0. whereas imipramine was more effective for dysphoria and anticipatory thinking.. 1988. LOE 2 for paroxetine). Antidepressants versus BZDs In deciding upon the comparative merits of antidepressants and BZD. after 1 week. 1992).. 1997). bAvailable in liquid formulation. Rickels. then increase by 37.. when at 100 mg. 1993.5(0.org.c Fluoxetineb Paroxetine-IRb.5 2 15 2 20 30 50 200 4 0.5 50 40 (20 BID). which finds a superior effect for antidepressants (Hoehn-Saric.5–25 mg every 1–2 weeks Increase to 50 mg within 1 week. Because of the chronic nature of GAD. BZDs are better for sleep and can be used as hypnotics.5–75 mg every 2 weeks 25 mg every 4 days. (1988) (LOE2) noted that alprazolam was more effective for somatic symptoms. Rocca.5 200 160 100 Used by permission of the International Psychopharmacology Algorithm Project.. et al..ipap. but the somatic items do respond.g. cUS Food and Drug Administration (FDA) approved for generalised anxiety disorder or its equivalent diagnoses.e.

et al. particularly among primary care doctors. Non-response: less than 25% better or reduction in symptoms from baseline. et al. An open label trial suggested benefit for ziprasidone (LOE 4) (Snyderman. In the United Kingdom. Pande. a feeling that they are being observed (LOE5).. 2006). et al. improved. previous medication experience should be taken into account. we recommend that the clinician re-evaluate according to Node 7 (see below). buspirone may have some role as an initial pharmacotherapy of GAD. but on some secondary analyses there was separation in favour of drug (Pollack. et al. 2004).. Sulpiride is also used in similar situations (Bruscky. This drug is available in some countries for adjunctive treatment of epilepsy (LOE 1) (Arroyo.. hydroxyzine is a widely used anxiolytic. 2005. 2005. 2005). These response categories are generally defined as follows:     Remission: at least 70% better or reduction in symptoms from baseline (Sheehan.. has shown promise in a small open-label study (LOE 4) (Mathew. 2005). Although we are aware of ongoing interest in the use of atypical antipsychotics for GAD. we would recommend switch to a different treatment. 2005.. Improved: at least 50% better or reduction in symptoms from baseline (Pollack.. 1995. 2006. et al. Pohl. and the lack of efficacy in recent BDZ users [although not all findings are consistent in this respect (Delle Chiaie. and the results of a double-blind. Others The α2 δ calcium channel antagonist. et al. 2004) and fibromyalgia (LOE 1) (Crofford. to our knowledge.. flupenthixol is approved for the use of depression. Rosenstock. mild symptoms of GAD and not exposed to BZDs. and lack of efficacy for comorbid disorders.. Beydoun. 1995).. et al. in patients with GAD comorbid with other disorders. 2005. but we recommend its use as a second line agent in view of its side-effect profile. as well as treating chronic pain associated with diabetes (LOE 1) (Lesser.. or placebo among subjects with refractory GAD (Wurthmann.. but is widely used to treat GAD-like states. and lack of efficacy for comorbid disorders. Most published evidence is limited to depression... Azapirones Buspirone is a partial 5HT1a agonist with shortterm efficacy in GAD (LOE 1). at least 25% symptom reduction from baseline) has occurred after 4–6 weeks of adequate trial. Node 6: Assessment for initial response Response to treatment after a trial period is described as remitted. a presynaptic glutamate release inhibitor. et al. For antidepressants. However. et al. Montgomery. 2003. for GAD. et al. if there is no response or the response is less than 25%.. there was one controlled study that showed flupenthixol was superior to amitriptyline. we do not know of any such reviews for GAD and would avoid recommending too short a treatment trial. Chen. Tiagabine (LOE 2) did not separate from placebo on the primary measure in a large GAD study.. et al. et al. French. et al. In patients with ICD-10 diagnosed. but recently it was launched in China. Antihistamines The H1 antihistaminic drug. The drug was approved for a wider indication mainly based on ICD-9 criteria of neurosis. clotiazepam. non-placebo–controlled. Evidence for antipsychotic monotherapy in GAD is very meager. is widely used for mild anxious-depressive symptoms. et al.. et al. et al. et al. et al.. 2005). partial response or non-response after 4– 6 weeks. Although no data exist. 2001). et al... et al. especially among primary care physicians. Richter. et al. 1974. pregabalin. 1994). herpes zoster (LOE 1) (Dworkin. 2004). 2005). 2003. hydroxyzine. et al. Llorca. 2003). Rickels. Riluzole. 1995) (LOE 2)]. et al. Elger. However. although it may take over 12 weeks before remission occurs (Bielski. or chronic pain related to diabetes. Sabatowski. we do not recommend it as a first-line agent for GAD in view of the relative lack of experience to date. for example. fibromyalgia or post-herpetic neuralgia. 2003.e. many of which were conducted in samples diagnosed with DSM-III or IIIR criteria.. at this point we remain sufficiently concerned about their tolerability and safety profile that we would not recommend them as first-line agents. and of which the effect size relative to placebo was acceptable in eight.. Freynhagen. is effective (LOE 1) in studies that have been conducted for as long as 12 weeks in DSM-IV GAD (Ferreri. 2005). randomised.. 2004. which was launched in Japan in 1996. 2005).. However. Tandospirone. variable tolerability and its overall lack of benefit against other comorbid disorders (except possibly for alcohol use disorder). 2005. 2004. the drug might be considered as a treatment option (LOE 5) for GAD with comorbid epilepsy. trial of buspirone and tandospirone showed similar efficacy and safety for both treatments in GAD (Zhan. This was a proof-of-concept trial. et al.. short-duration. if at least partial response (i. There have been 10 studies referred to by Mitte. It is approved in some European countries. because of its slow onset of action.Psychopharmacological treatment algorithm for GAD 13 fore. (2005). In some countries. we in general do not recommend this drug as a first line treatment for DSM-IV GAD. et al. 2002). 1998. et al.. is also effective in the short-term treatment of GAD (LOE 1) (Feltner.. et al. et al. Although reviews for schizophrenia and depression show that response often appears before 4 weeks. . in that many patients need longer to benefit. et al. Lader and Scotto. Partial response: 25–49% better or reduction in symptom severity from baseline. but not in the United States.. The latter drug may be useful in patients who have a mild paranoid element... and the drug has significant tolerability concerns.

alcohol and other substance use. 1959). and even beyond 6 months in the case of remission (Bielski. with the possible exception of azapirones and fluoxetine. A score of 4 represents no change. many patients will experience improvement. 1983). time spent with the patient. behavioural or other mental changes. along a 7 point scale. diagnostic process. sleep disruption. excess caffeine usage especially late in the day. although their evidence as hypnotics is weak and their side effects can be more problematic. sleep hygiene. Node 8: Assessment for partial response When there is only partial response to an initial trial after 4– 6 weeks of adequate dosing. The SDS comprises of three self-rated items (work. A CGI-I score of 1 or 2 is typically considered to indicate ‘response’. Other sedating anxiolytic or antidepressant drugs can be used. exercise) (see above. but has been since used widely among general population as well as the psychiatrically and medically ill populations. but are rarely encountered. of the therapy for at least a year in GAD. 1983) for assessing functional impairment. with at least 50% reduction in symptoms. The CGI-I rates degree of overall improvement from the start of treatment. For other drug groups. if the maximal dose had not been used. etc. but not necessarily remission. The HAMA is a clinician-rated scale that consists of 14 items (scoring 0–4 per item) that assesses a variety of psychological and physiological symptoms of anxiety. can be used. Once a good response to SRI therapy has been determined. to augment or to switch to another drug class. 2) adequate trial and non-response: go to node 11. Although data are not available. 2005. zaleplon or eszopiclone. 4) failure to give an adequate trial: go back up to node 5 for an adequate trial of an alternative agent. we recommend maintenance treatment at the same dose which it took to achieve response. et al. 10) or (c) switch to a different treatment (see below node 11). it is also important to evaluate lifestyle issues that can impact on sleep (i. although data do not exist on this topic as far as we know. 2. Failure to achieve remission should constitute a signal for the clinicians to either increase the dose to maximal or supramaximal levels.14 Psychopharmacological treatment algorithm for GAD We note that this is a clinical recommendation. for 1) adequate trial and good response: go to node 7a. the self-rated Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith. 2000. Because withdrawal from most anti-anxiety medications can be distressing.. 2003). et al. Scores of 5 (minimally worse). such as hostility or impulsivity. it is possible that less severe cases of GAD are found as compared with psychiatric settings. and look forward to data that will help support it. we recommend that the clinician re-evaluate and consider either (a) further increase of the dose. and randomised controlled trials showing relapse after short-term maintenance treatment. Stocchi. such as BZD and antihistamine. the dose may be lowered. 6 (much worse) and 7 (very much worse) represent degrees of worsening. et al. investigator bias. An exception to this recommendation can be made where late emerging side effects occur. (b) augmentation where there has been some response to monotherapy (see below node 9. such as weight gain. A number of scales exist for assessing GAD. sexual difficulty. in GAD.. The role of non-pharmacologically specific response may be considered in partial responders. Further studies of the Node 7: Remission and relapse prevention After 8–12 weeks of treatment. Node 9: For partial response with persistent insomnia Although pharmacologic intervention may be indicated. Continued treatment over 8 months or longer is associated with a reduction in the risk of relapse (LOE 1) (Allgulander. there is little published data on time until remission. family life) on a 10-point visual analogue scale. social life. discontinued or antidote medicine used. we recommend continuation . When considering pharmacotherapeutic options..e. although HAMA is less-likely to be used in clinical practice because of the length and time it takes to administer the scale. However. according to clinical judgment. zolpidem.. In these cases. 1976). then drug augmentation may be of very limited benefit. 3) adequate trial and partial response: go to node 8. Node 2). The most widely used and well-validated scale in GAD research is probably the Hamilton Anxiety Rating Scale (HAMA) (Hamilton. Stocchi. where improvement can partly be due to the care. If the physician determines that these factors are significant. See node 5 for further information on definitions of response and remission. and that the required dose may be lower. 2006. very much improvement. et al. 3. although neither CGI nor SDS assess the symptomatology of GAD per se. designed to measure the extent of impairment in patient’s life. much improvement and 1. Among the simpler and best-established are the physician-rated Clinical Global Impressions of Improvement (CGI-I) (Guy. In summary. or even rate of remission. for example. In primary care. augmentation with proven non-BZD GABAergic hypnotic drugs (LOE 1). there is evidence from two studies that response and remission rates continue to increase beyond 2 months. BZD drugs can also be considered for sleep enhancement because they have beneficial effects in GAD. The HADS contains 14 items rated on a 4-point Likert-type scales and was initially designed to screen for mood disorders among the medically ill patients. 2003).. empathic support. et al. Gelenberg. given the chronicity of symptoms. minimal improvement. and the self-rated Sheehan Disability Scale (SDS) (Sheehan. that are part of the interaction with the patient. but which have unproven anxiolytic effects (LOE 5). we recommend a slow taper when the decision has been made to stop medication. diet. No data exist to our knowledge on the efficacy of continued treatment with a BZD or antihistamine in GAD. but Schweizer and Rickels (1997) state that 3–4 weeks treatment at a diazepam equivalent dose of 40 mg/ day constitutes an adequate BZD trial..

to the atypical neuroleptics risperidone and olanzapine. In atypical major depression with comorbid GAD. et al. stable bipolar disorder or other anxiety disorder (panic. Node 10: Augmentation strategies for partial response with general symptom persistence Almost all clinical trials of GAD have tested the efficacy of monotherapy. Other augmentation strategies. (2006) (LOE2). An antidepressant could be added to any of the aforementioned drugs.. have not been studied in GAD. et al. It is also important to be mindful that in some instances treatment of GAD may also exacerbate sleep disturbance. Thus. Monoamine oxidase inhibitor (MAOI) therapy may also be tried at this stage (LOE 1 for depression and LOE 5 for GAD). and there is evidence that a SNRI can be effective in cases where patients have failed a number of previous medication trials. social anxiety. We consider that augmentation with an atypical antipsychotic drug has a good foundation based on short-term efficacy data (rather than long-term safety data). and when. we recommend switching to an SNRI. 2002). However. For severe depression with GAD. then the following steps are recommended. Alternatively. 1990. a BZD. Node 12: Assessment for response See Node 6. although no trials have been done to address this. et al. firstly with an antihistamine or BZD. have examined the effects of this strategy in GAD. There is little systematic guidance as which strategy is preferable. in situations where the patient has been treated. should be used with caution in those with a seizure history or predisposition.. LOE 5 for GAD). a sedating antihistamine such as hydroxyzine can be added (LOE 1 for GAD). PTSD. LOE 3 for GAD) or an atypical antipsychotic. to our knowledge... to our knowledge. In a study by Pollack. SSRI to SSRI or SSRI to SNRI). 2001). buspirone or tiagabine (LOE 5 each) could be added to an antidepressant. therefore our recommendations are largely extrapolations from monotherapy trials of the recommended product. each as monotherapy). 2005). we recommend the addition of a drug from other classes to the primary drug already being given to the patient. In elderly patients.. while effective in depression (LOE 1) (Carvalho. whose effects in GAD are modest at best. despite adequate treatment with a variety of antidepressant or non-antidepressant drugs for GAD.5 mg/day was associated with further improvement (LOE 2) (Brawman-Mintzer. for example. et al. who showed persistence of the full symptom complex. If there has been intolerance to at least two different antidepressants. antihistamine. et al. but there are data in MDE that a second SSRI can be effective in approximately 50% of cases when there is failure on the first. it is possible that ECT would be indicated for the depressive component (LOE 1 for depression. OCD or specific phobia). 2003). For partial responders to an SSRI. 2007).Psychopharmacological treatment algorithm for GAD 15 dose/response/side-effects relationships with antidepressants used as hypnotics are needed.. chromium picolinate showed greater effect than placebo on symptoms of both conditions (LOE3) (Davidson. such as risperidone or olanzapine (LOE 2 for GAD).. Node 11: Switch strategies for partial response or nonresponse with general symptom persistence An alternative strategy for partial response would be to switch to another antidepressant. No studies . but there is arguably greater rationale for switching than for augmentation when response to the first medication is zero or below 25%. In addition. although there is no current evidence to support a potentiating effect of CBT to ongoing pharmacotherapy in GAD (LOE5) (Power. Node 13: Evaluate for comorbidity If inadequate response is found to be associated with comorbid depression. Tolerance to the sedation from diphenhydramine 50 mg twice daily was complete by day 3 of a placebocontrolled study (Richardson. then switching to BZD seems reasonable (LOE 5). et al. but the more recent studies of another antihistamine are not encouraging. Tiagabine.g. augmentation of fluoxetine with olanzapine yielded better response than did augmentation with placebo only on some secondary outcome measures: failure to separate on the primary measure was most likely because of underpowering of the study. the addition of risperidone up to 1. many clinicians may prefer to use drugs that are not associated with risks of metabolic changes or abnormal involuntary movements. bupropion (Trivedi. However. 1989). LOE1 for GAD and MDD. We do not generally recommend switching from an SSRI/ SNRI to a BZD on the grounds of non-response. Trivedi. but its hypnotic effects are also unproven. The evidence is mixed. they could be considered with the expectation that they might benefit the depressive component. if other measures have failed.. Notable exception applies. if there were two failed trials with SSRIs. et al. we recommend use of maximum tolerated dose antidepressant drugs or augmentation of an SSRI or SNRI with buspirone (Robinson. et al. however. such as lithium and tri-iodothyronine. 2006) (LOE 1 for MDD as monotherapy and augmentation.. CBT could be added. major cognitive impairment was found in 426 patients given diphenhydramine (Agostini. et al. Imipramine (LOE 2) may also be a consideration for non-responders to SSRI/SNRI. either within the same class or in a different one (e. et al. Node 14: GAD with persisting unipolar depression For GAD with persisting unipolar depression. 2006) (LOE 2 for augmentation of depression.. In that case.

2006). Node 17: Inadequate response without comorbidity In the case of inadequate response (non-response or partial response) to the drug combination chosen at Node 9–11. backed by substantial long-term data of antidepressants being associated with lower mortality over 50 years follow-up when used with a mood stabiliser or antipsychotic. for example. 2002). some mood stabilisers and antipsychotics may need periodic laboratory monitoring. LOE 2 for SSRI augmentation in GAD)..g. et al. 3) The initial evaluation should include a thorough psychiatric assessment. Preliminary evidence (LOE 3) from a small trial in atypical depression. Of note. Latest data suggest avoiding antidepressants: only 16% respond and many experience a mood switch (Leverich. 2003). Hollander.. without significant comorbidity. as compared with treatment without an antidepressant (Angst. these criteria may be especially useful. SNRI (LOE 1 for all anxiety disorders except OCD). PST can also be added at this stage (LOE 5). 2003. et al. 2003. referral for laboratory or medical evaluation. et al. and fasting lipid profile and fasting blood sugar for some antipsychotics.. which was comorbid with GAD in the majority of subjects. Node 19: Diagnostic re-evaluation Non-response or partial response at this stage would call for diagnostic re-evaluation. adding a third drug of a different class to the two already in use. Hamner.. 1999. or when there is loss of previous response. 2001. 2005. psychotic or bipolar symptoms. found benefit for monotherapy with chromium picolinate (LOE 3) (Davidson. where appropriate. 2005) in SAD. although evidence from studies of triple therapy is lacking. et al. et al. and LOE 5 for GAD) or atypical antipsychotic (LOE 1 for bipolar disorder. for all anxiety disorders.. 2002). lithium) (LOE 1 for bipolar disorder. et al. et al. There are some regional differences in respect to the use of antidepressants in patients with bipolar depression. SSRIs (LOE 1) are effective. as well as medication side effects. or At initial and repeated evaluation: 1) GAD is common and often passes unrecognised. Stein. 2004. Reich. valproic acid and lithium.. 2004. assess for key symptoms that may change management (e. et al. et al. of which one drug should be a serotonergic antidepressant (SSRI. a second treatment can be added. et al. et al. et al.. et al. Similarly. LOE 1 for clomipramine. care should be taken that it does not exacerbate the bipolar disorder (Leverich. other comorbid disorders may need to be stabilised before attempting to treat . Thus.. augmentation with this agent may be useful (LOE 5) in refractory GAD. 4) Initially and at subsequent points of non-response. Butterfield. we would want to rule out uncontrolled mood instability. 2004) and levetiracetam (LOE 3) (Zhang.. Summary General principles of GAD treatment We recommend the following general principles be considered in the diagnosis and treatment of GAD:  Node 16: GAD with other anxiety disorders For GAD with other anxiety disorders. augmentation with risperidone or olanzapine in OCD (LOE 1) (Bystritsky. TCA (LOE 1 for imipramine or clomipramine in PD. a BZD (alprazolam or clonazepam) may be used (LOE 1). 2004) and PTSD (LOE 1 or 2) (Bartzokis. lifestyle issues. There is some evidence to support olanzapine monotherapy for SAD (LOE 3) (Barnett. LOE 2 for imipramine in PTSD. substance use) introduction of other medications and treatment nonadherence. Shapira. with US physicians preferring not to recommend their use. et al.16 Psychopharmacological treatment algorithm for GAD Node 15: GAD with bipolar spectrum disorder If the symptom picture suggests bipolar spectrum disorder that coexists with GAD. medical history and.. 2006). so in the event that an antidepressant is used. blood levels of carbamazepine. an SRI or BZD.. however. we recommend the use of treatments that are beneficial for both states. Nevertheless. et al. Node 18: Assessment for response See Node 6. 2) The initial evaluation should adhere to DSM-IV or ICD-10 criteria. 2000.. for example. Li. 2005. It is possible that in combination with established treatments. we recommend switching to another combination. et al. SNRI). although there are regional differences in the approach to using antidepressants for bipolar depression. 2003.. For panic disorder.. Monnelly.. has used DSM-IV. and pharmacotherapy in particular. not all data is consistent.. et al. 5) Patients with bipolar disorder should already be stabilised before introducing antidepressant treatment for GAD.. has failed to adequately treat the comorbid disorder. Those in Europe. use them more often in practice. MAOI monotherapy could also be considered at this stage (LOE5). McDougle. noradrenergic and specific serotonergic antidepressant (NaSSa) or serotonergic TCA. If monotherapy with. There are data to support use of pregabalin (LOE 1) (Pande. Attention should also be added to sleep hygiene. suicidality. in OCD) may be beneficial. 1985). We recommend addition of a drug with mood stabilising properties such as an anticonvulsant (divalproex sodium.. Given that the most research on GAD.

other anxiogenic prescription. 2) Both approaches have been found efficacious for GAD. we suggest the following: i) educational material should be provided regarding the treatment to patients and their care-takers. diazepam at 5 mg three times daily. One expects at least partial response by 4–6 weeks with adequate dosing. recommend switching treatment where an adequate trial has failed to elicit at least 25% improvement. dizziness.e. 3) Antipsychotic drugs are associated with metabolic and general cardiovascular side-effects. stress coping ability) can be useful. there is greater likelihood that a patient with GAD will be taking other medication over the long term. in most cases. psychotherapy.com. 1996). 4) Occasionally patients with GAD experience exacerbation of anxiety or jitteriness with onset of SRI treatment.   Choice of treatment: medication. for example.. Appropriate monitoring of metabolic profile is recommended in accordance with current standards. we do not believe that persistence with drug will produce greater improvement. depressed mood and somatic symptoms such as headache. however. quality of life. vivid dreams and insomnia (Coupland. or fail to respond. and the SDS. may be used for easier administering in the case of an unusually low dose or difficulty swallowing. Some hold that under these circumstances a medication switch would be preferable to augmentation. As a general guide to management. ii) a gradual taper is recommended (with an even slower taper in the elderly and medically ill population) when a decision is made to discontinue a medication and iii) liquid form. 5) BZD is relatively contraindicated in those with a history of substance use problems. 2) When patients respond partially. Early withdrawal is associated with greater relapse risk. encouraged to familiarise themselves with the more common types of interactions that could occur with each psychotropic drug. switch or wait longer when there has been partial response. as has been suggested in the depression literature. nausea. we cannot say whether it is better to increase dose. over the counter treatments or the need for diagnostic re-evaluation. 6) The patient who has shown an excellent response to pharmacotherapy should generally be treated for at least 1 year. With increased rates of comorbid medical illness. 7) Many scales are available to measure symptom severity and function in GAD. abdominal obesity. or the combination. Clinicians may wish to keep their options open as to the preferred approach. In addition. we recommend either lowering of dose to minimal starting levels and then increase in small steps. treatment non-adherence. or co-prescribe a BZD for a short period of time. There may be greater risk of developing type II diabetes or worsening of previously controlled diabetes. and if there has not been adequate response after 4–6 weeks.genelex. and it is assumed that the clinician will progressively titrate the dose upwards according to tolerability of the drug. as reviewed by Oesterheld J. irritability. the result of side effects. or if insomnia is a dominant symptom. Only if rapid response is needed. psychosocial or both 1) The initial treatment of GAD can be either with medication. Their relative merits and limitations are beyond the scope of this report. Osser DN and Sandson N at http://www. augment. 2) The response time to an antidepressant drug in GAD is generally 4–12 weeks. Comorbidity and previous response to treatment are also important considerations.  Managing side effects 1) Patients with an anxiety disorder are often more sensitive than other patients to medication side-effects and may need lower starting dose and incremental titration over a longer time than might be the case when treating depression. Medications and adequacy of response 1) Patients with GAD who are going to be treated with medication should. although there are no data to inform on the matter. The role of the placebo response may be considered in partial responders.. treatment for both conditions can be instituted simultaneously. increased triglycerides or total and LDL cholesterol. it is important to consider if this represents inadequate medication benefit. function and resiliency (i. On other occasions. where . paresthesia. We do. 5) Typical SSRI/SNRI discontinuation (or ‘withdrawal’) symptoms include worsening of anxiety. if available. receive an SSRI or SNRI as first line monotherapy. 6) Standardised rating scales for symptom severity. We do not know to what extent this is the case for GAD or how it would best be managed. tremor. but three simple and well validated scales include the CGI-I. therefore. substances. et al. Clinicians are. concomitant use of alcohol. for example.  Placebo response Sometimes an initial rapid response that fades may be indicative of a ‘placebo’ or ‘non-specific’ response. 3) In our current state of knowledge. Response to BZDs is usually faster than for antidepressants. would a concomitant BZD be recommended for brief treatment. HAMA has been widely used in GAD and other anxiety disorders research. Patient preference and therapist skill will be important determinants of the choice.Psychopharmacological treatment algorithm for GAD 17 GAD. 4) There is the possibility of untoward drug interactions brought about by the inhibitory properties of some antidepressant drugs on the CYP 450 isoenzyme system. weight gain. In such instances. HADS.

Montgomery. DJ. Bristol Myers Squibb. David Osser: None applicable. Shionogi. GlaxoSmithKline. Lundbeck. Bandelow. Roche. Inc. etc. et al. Inc. Dan Stein: Research grants and/or consultancy honoraria: Astrazeneca. Esteve. LS. Eli Lilly. 2004. Lepine. J (1996) Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Organon. Dean Hartley.. Phamacia. ReckittBenkiser. Allgulander. Upjohn. Parke Davis. Bristol Myers Squibb. Asahi. which should be a consideration in drug selection. DC: American Psychiatric Association. Wyeth Pederle. Takeda. PL. C. Fayyad. Drugs supplied for other studies from Eli Lilly. GlaxoSmithKline. Solvay Pharmaceuticals. Lichtwer Pharma. it is prudent for the clinician to prefer the less expensive product. L. Wyeth Ayerst Pharmaceutical Company. Pfizer Inc. Washington. Pfizer. diagnosis. Boots.. Eli Lilly.. King Pharmaceuticals. C. Int J Neuropsychopharmacol 9: 495–505. Text Revision. Jazz Pharmaceuticals. Pfizer. American Psychiatric Association. Kathryn Connor: Grants and Research Support: Eli Lilly. Stock holding: No. Florea. Hollander. Aché. Pfizer. However. Servier. Cephalon. similar toxicity and similar acceptability to the patient. Consultancies: Cephalon. Altshuler. Passion for Life. Sanofi-Synthelabo. Servier. Inc. J Clin Psychiatry 68(Suppl. Speaking honoraria (in addition to above): Wyeth. Pharmacia. Otsuka. M. Alexza. Osamu Tajima: Speakers Bureau: Meiji. Inc. Astra Zeneca. (2003) WCA recommendations for the longterm treatment of generalized anxiety disorder. Forest. et al. Eli Lilly and Co. Merck. Janssen. AA. Bristol-Myers. Wyeth Pharmaceuticals. Qual Saf Health Care 12: 18–23. However. Johnson and Johnson. Because of the variability in medication costs from one country to another. Pharmacia. Related is the issue of riskbenefit. Wei Zhang: Grants and Research Support: AstraZeneca. Inouye. Huusom. Merck.. that are part of the interaction with the patient. Research Triangle Institute. 6) Cost-benefit considerations Cost is often an important consideration in drug selection. Martin Dunitz. Eli-Lilly. Therasci. Pfizer.. Pfeizer. David Penniman and Oakley Ray as consultants for the project. Servier. Grants and Research Support: MSD. C. consulting. MP. Yves Lecrubier: Advisory boards. Agostini. investigator bias. Inc. Other Financial or Material Support: Dr Wilmar Schwabe. Forest Laboratories. Leo-Summers. E. D. Wyeth. (2004) Efficacy of sertraline in a 12-week trial for generalized anxiety disorder. which bring additional cost-burdens. Cohen. C. 2): S3–S9. GlaxoSimithKline. Roche. Glaxo SmithKline. Br J Psychiatry 179: 15–22. Allergan.. and there is a big difference in cost. American Psychiatric Association (2004) Diagnostic and Statistical Manual of Mental Disorders. Fabre. Royalties from MultiHealth Systems Inc. Current Medical Science. Pfizer. Novartis. Pure World Botanicals. Cypress. Consultancies: Solvay. Janssen. Austin. JA. Nordic Naturals.. UCB. Speakers Bureau: Ortho McNeil. PureWorld. Sumitomo. SA. Inc. Solvay. Orion. PureWorld. B. Astellas.. Pfizer. Sogaard. VK. Schwarz Pharma Inc. UCB. Inc. cost of medication must be viewed more broadly as part of a cost-benefit equation because ‘cheaper’ drugs may have more problematic side-effects. Jianlin Ji: None applicable. Eli Lilly. Taylor and Francis.. Jazz. Organon. R. AGREE (2003) Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Alexander Macfarlane: Grants and Research Support: Pfizer. Thanks also to Paul Nordstrom August. if at any node in the algorithm there are two or more options of apparently equal efficacy. Forest. Forest Laboratories. Cephalon.. Organon. A. Alonso.. Dahl. Morris. Predix Pharmaceuticals. Hackett. empathic support.18 Psychopharmacological treatment algorithm for GAD improvement can partly be due to the care. Inc. Pfizer Inc. Nutrition 21. Burt. Novartis. sponsored trials: Sanofi. Boehringer Ingelheim. Stock Holding: GlaxoSmithKline. Okasha. MSD. Solvay. GlaxoSmithKline. Mintz. Gitlin. Novartis. Advisory Board for Solvay. Jansen. Ancile. SK (2001) Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Research Support from Pfizer. Janssen. GlaxoSmithKline. Nutrition 21. Solvay. American Psychiatric Association. Solvay Pharmaceuticals. Arch Intern Med 161: 2091–2097. JV. Janssen. Am J Psychiatry 161: 1642–1649. Astra Zeneca. Forest Laboratories. Cephalon Pharmaceuticals.. Inc. Inc. Inc. Nutt. CNS Spectr 8: 53– 61. taking into account what is available on the formulary in the country or locale of practice. MedTap. Salinas. MediciNova. Yamanouchi. Sumitomo. GlaxoSmithKline. Guilford Publications. Novartis. P. Schwabe. Lilly. Inc. time spent with the patient. JP (2007) Overview of key data from the European Study of the Epidemiology of Mental Disorders (ESEMeD). UCB. and Wyeth. Penguin Putnam Publishers. AK (2006) Prevention of relapse in generalized anxiety disorder by escitalopram treatment. Inc. Organon. Marcio Versiani: Research grants and/or consultancies: Pfizer. Forest. Organon Inc. Allgulander. Lundbeck. Allgulander. References Disclosure statements Jonathan RT Davidson: Speaker for Solvay Pharmaceuticals. Consultancies: Ortho McNeil. Janssen. I. Glaxo SmithKline. Am J Psychiatry 153: 592– 606. 4th edition. we do not make any specific recommendations about this issue. Lundbeck. . E (2001) Venlafaxine extended release (ER) in the treatment of generalised anxiety disorder: twenty-four-week placebo-controlled dose-ranging study. Lundbeck. GlaxoSmithKline. Wyeth. LL. Inc. Ken Jobson: None applicable. C. Cephalon Pharmaceuticals. Szuba. Asahi-Kasei. Cephalon. Johnson and Johnson. J. Pfizer. Inc. Wyeth. David Nutt: Consultancies: Pfizer (W-L). Allgulander..  Acknowledgements This project is supported by a grant from the International Psychopharmacology Algorithm Project (IPAP).

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