World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision

Figures & data

Table I.  Recent Guidelines on the Treatment of Anxiety Disorders, OCD and PTSD

Guideline	Source	Recommended minimum duration of pharmacotherapy
Royal Australian and New Zealand College of Psychiatrists: Australian and New Zealand Clinical Practice Guidelines for the Treatment of Panic Disorder and Agoraphobia	Andrews 2003	No recommendation
World Council on Anxiety: Recommendations for the long-term treatment of panic disorder	Pollack et al. 2003a	12–24 months
Generalized anxiety disorder Social phobia Obsessive-compulsive disorder in adults Post-traumatic stress disorder	Allgulander et al. 2003van Ameringen et al. 2003Greist et al. 2003Stein et al. 2003a	No recommendation due to lack of dataStein et al. 2003a12 months12–24 months12–24 months
Evidence-based Guidelines for the Pharmacological Treatment of Anxiety Disorders: recommendations from the British Association for Psychopharmacology	Baldwin et al. 2005	6 months after initial response to treatment
Canadian Psychiatric Association Clinical Practice Guidelines, Management of Anxiety Disorders	Canadian Psychiatric Association 2006	PD: 8–12 monthsGAD: no recommendationSAD: 12–24 monthsOCD: 12–24 months
National Institute for Health and Clinical Excellence (NICE). Anxiety (amended): management of anxiety (panic disorder, with or without agoraphobia, generalised anxiety disorder) in adults in primary, secondary and community care	NICE 2007	6 months after initial response to treatment
American Psychiatric Association: practice guideline for the treatment of patients with obsessive-compulsive disorder	Koran et al. 2007	12–14 months
National Institute for Clinical Excellence (NICE): obsessive compulsive disorder: core interventions in the treatment of obsessive compulsive disorder and body dysmorphic disorder.	NICE 2006	12 months or more
National Institute for Clinical Excellence (NICE): Post-Traumatic Stress Disorder. the management of PTSD in adults and children in primary and secondary care.	NICE 2005	12 months or more
Department of Veteran Affairs: post-traumatic stress disorder. clinical practice guidelines.	Veteran Affairs 2007	No recommendation
Institute of Medicine: treatment of PTSD: an assessment of the evidence. Report brief	Institute of Medicine 2007	No recommendation

Table II.  Categories of evidence. In Table VI, the Categories of Evidence are Given for all Recommended Drugs.

Category of evidence	Description
↑↑ A	Full evidence from controlled studies
	is based on: two or more double-blind, parallel-group, randomized controlled studies (RCTs) showing superiority to placebo (or in the case of psychotherapy studies, superiority to a “psychological placebo” in a study with adequate blinding) and one or more positive RCT showing superiority to or equivalent efficacy compared with established comparator treatment in a three-arm study with placebo control or in a well-powered non-inferiority trial (only required if such a standard treatment exists) In the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparator treatment), these must be outweighed by at least two more positive studies or a meta-analysis of all available studies that shows superiority to placebo and non-inferiority to an established comparator treatment. Studies must fulfill established methodological standards (Table III). The decision is based on the primary efficacy measure.
↑B	Limited positive evidence from controlled studies
	is based on: one or more RCTs showing superiority to placebo (or in the case of psychotherapy studies, superiority to a “psychological placebo”) or a randomized controlled comparison with a standard treatment without placebo control with a sample size sufficient for a non-inferiority trial. and no negative studies exist
(↑) C	Evidence from uncontrolled studies or case reports/expert opinion
C1	Uncontrolled studies
	is based on: one or more positive naturalistic open studies (with a minimum of five evaluable patients) or a comparison with a reference drug with a sample size insufficient for a non-inferiority trial and no negative controlled studies exist
C2	Case reports
	is based on: one or more positive case reports and no negative controlled studies exist
C3	Based on the opinion of experts in the field or clinical experience
↔ D	Inconsistent results Positive RCTs are outweighed by an approximately equal number of negative studies
↓ E	Negative evidence The majority of RCTs studies shows non-superiority to placebo (or in the case of psychotherapy studies, superiority to a “psychological placebo”) or inferiority to comparator treatment
? F	Lack of evidence Adequate studies proving efficacy or non-efficacy are lacking
Recommendation Grade	Based on:
1	Category A evidence and good risk-benefit ratio
2	Category A evidence and moderate risk-benefit ratio
3	Category B evidence
4	Category C evidence
5	Category D evidence

Table III.  Check list for Quality of Controlled Studies.

Study described as randomized*; method used to generate the sequence of randomization described and appropriate (e.g., computer-generated)* Use of standard diagnostic criteria (e.g., DSM or ICD) Study described as double-blind*; method of double-blinding described and appropriate* (identical placebo, dummy etc., or use of a “psychological placebo” control and assessment by a “blind” rater in the case of psychotherapy studies) Description of withdrawals and dropouts*; declaration of evaluation method (“intent to treat”/“according to protocol”) In the case of an active comparator: use of a comparator with established efficacy The only difference between groups is the treatment under investigation Use of parallel groups (instead of cross-over studies, wait list controls or “historical” comparisons) Adequate sample size, based on a-priori calculation Use of sensitive rating scales Declaration of the primary efficacy measure Use of appropriate statistical tests (e.g., control for baseline differences etc.); method of management of drop-outs described (e.g., last observation carried forward/LOCF, mixed model repeated measures analysis/MMRM) Fulfillment of good clinical practice (GCP) criteria Approval by properly-constituted ethics committee

*These points are part of the Jadad Score Jadad et al.

Table IV.  Short description of anxiety disorders as defined by ICD-10 (WHO 1991) and DSM-IV-TR (APA 2000)

Panic disorder (PD)

Panic disorder is characterized by recurrent panic attacks. Panic attacks are discrete periods of intense fear or discomfort, accompanied by at least four of 14 somatic and psychic symptoms (13 in DSM-IV). A panic attack reaches a peak within 10 minutes and lasts 30–45 minutes on average. Usually, the patient is afraid that he has a serious medical condition such as myocardial infarction.

Agoraphobia

About two-thirds of all patients with panic disorder suffer from agoraphobia, which is defined as fear in places or situations from which escape might be difficult or in which help may not be available in the event of having an unexpected panic attack. These situations include being in a crowd or standing in a line, being outside the home alone, or traveling in a bus, train or automobile. These situations are avoided or endured with marked distress.

Generalized anxiety disorder (GAD)

The main features of generalized anxiety disorder are excessive anxiety and worry. The patients suffer from somatic anxiety symptoms as well as from restlessness, irritability, difficulty concentrating, muscle tension, sleep disturbances and being easily fatigued. Patient may express constant worry that the patient or a relative will shortly become ill or have an accident.

Specific phobia

Specific phobia is characterized by excessive or unreasonable fear of single objects or situations (e.g., flying, heights, animals, seeing blood, etc.).

Social phobia (social anxiety disorder; SAD)

This disorder is characterized by marked, persistent, and unreasonable fear of being observed or evaluated negatively by others in social performance or interaction situations and is associated with somatic and cognitive symptoms. The feared situations are avoided or else are endured with intense anxiety or distress. These situations include fear of speaking in public, speaking to unfamiliar people or being exposed to possible scrutiny by others.

Obsessive-compulsive disorder (OCD)

OCD is characterized by recurrent obsessions or compulsions, or both, that cause impairment in terms of distress, time, or interference with functioning. Concerns involving contamination, harm, hoarding, and sexual, somatic and religious preoccupations are the most common obsessions. Compulsions include washing, checking, repeating, ordering, counting, hoarding and touching (rare).

Post-traumatic stress disorder (PTSD)

Post-traumatic stress disorder (PTSD) develops after a terrifying ordeal that involved physical harm or the threat of physical harm. The person who develops PTSD may have been the one who was harmed, the harm may have happened to a loved one, or the person may have witnessed a harmful event that happened to loved ones or strangers. The condition is characterized by recurrent and intrusive distressing recollections of the event, nightmares, a sense of reliving the experience with illusions, hallucinations, or dissociative flashback episodes, intense psychological or physiological distress at exposure to cues that resemble the traumatic event, avoidance of stimuli associated with the trauma, inability to recall important aspects of the trauma, loss of interest, estrangement from others, sleep disturbances, irritability, difficulty concentrating, hypervigilance, and exaggerated startle response. The full symptom picture must be present for more than 1 month.

Figure 1.  Anxiety Disorders, OCD and PTSD. Twelve-month and lifetime prevalence rates. Data from the National Comorbidity Survey Replication. *Kessler et al. 2005c; **Kessler et al. 2005a.

Table V.  Advantages and Disadvantages of Antianxiety Drugs.

Substance	Advantages	Disadvantages
SSRIs	No dependency Sufficient evidence from clinical studies for all anxiety disordersRelatively safe in overdose	Latency of effect 2–6 weeks, initial jitteriness, nausea, restlessness, sexual dysfunctions and other side effects. Some risk of discontinuation syndromes.
SNRIs	No dependency Sufficient evidence from clinical studiesRelatively safe in overdose	Latency of effect 2–6 weeks, nausea, possible increase in blood pressure and other side effects. Some risk of discontinuation syndromes.
Pregabalin	No dependency Sufficient evidence from clinical studiesRapid onset of effect	Dizziness, sedation and other side effects
Quetiapine	No dependency Preliminary evidence from clinical studiesRapid onset of effect	Somnolence, weight gain and other side effects
TCAs	No dependency Sufficient evidence from clinical studies (exception: SAD, PTSD)	Latency of effect 2–6 weeks, anticholinergic effects, cardiac side effects, weight gain and other side effects, may be lethal in overdose
Benzodiazepines	Rapid onset of action Sufficient evidence from clinical studiesRelatively safe in overdose	Dependency possible; sedation, slow reaction time and other side effects. Paradoxical reactions in elderly patients.
Moclobemide	No dependency Benign side effect; relatively safe in overdose	Latency of effect 2–6 weeks, inconsistent study results in SAD, no efficacy proofs for other anxiety disorders
MAOIs	No dependency	Few supporting studies in PD and SAD; latency of effect 2–6 weeks; potentially dangerous side effects and interactions
Buspirone	No dependency Relatively safe in overdose	Latency of effect 2–6 weeks; efficacy proofs only for symptoms of GAD; lightheadedness, nausea and other side effects
Hydroxyzine	No dependency	Efficacy proofs only for GAD; sedation and other side effects; no experience with long-term treatment

TCA, tricyclic antidepressants; SSRI, selective serotonin reuptake inhibitors; SNRI, selective serotonin noradrenaline reuptake inhibitors; GAD, generalized anxiety disorder; PD, panic disorder; SAD, social anxiety disorder.

Table VI.  Recommendations for the Drug Treatment of Anxiety Disorders And OCD. Categories of Evidence are Only Based on Efficacy without Regard to Other Properties (e.g., Side Effects). Abbreviations: see Text. Category of Evidence: see Table II.

Diagnosis	Treatment	Examples	Category of evidence	Recommendation grade	Recommended daily dose for adults
Panic disorder and agoraphobia
	SSRIs, e.g.,	Citalopram	A	1	20–60 mg
		Escitalopram	A	1	10–20 mg
		Fluoxetine	A	1	20–40 mg
		Fluvoxamine	A	1	100–300 mg
		Paroxetine	A	1	20–60 mg
		Sertraline	A	1	50–150 mg
	SNRI	Venlafaxine	A	1	75–225 mg
	TCA, e.g.,	Clomipramine	A	2	75–250 mg
		Imipramine	A	2	75–250 mg
	Benzodiazepines, e.g.,	Alprazolam	A	2	1.5–8 mg
		Clonazepam	A	2	1–4 mg
		Diazepam	A	2	5–20 mg
		Lorazepam	A	2	2–8 mg
	MAOI	Phenelzine	B	3	45–90 mg
Generalized anxiety disorder
	SSRIs	Escitalopram	A	1	10–20 mg
		Paroxetine	A	1	20–50 mg
		Sertraline	A	1	50–150 mg
	SNRIs	Venlafaxine	A	1	75–225 mg
		Duloxetine	A	1	60–120 mg
	TCA	Imipramine	A	2	75–200 mg
	Calcium channel modulator	Pregabalin	A	1	150–600 mg
	Atypical antipsychotic	Quetiapine	A	1	50–300 mg
	Benzodiazepines, e.g.,	Diazepam	A	2	5–15 mg
		Lorazepam	A	2	2–8 mg
	Antihistamine	Hydroxyzine	A	2	37.5–75 mg
	Tricyclic anxiolytic	Opipramol	B	3	50–150 mg
	Azapirone	Buspirone	D	5	15–60 mg
Social anxiety disorder
	SSRIs	Escitalopram	A	1	10–20 mg
		Paroxetine	A	1	20–50 mg
		Sertraline	A	1	50–150 mg
		Fluvoxamine	A	1	100–300 mg
		Citalopram	B	3	20-40 mg
		Fluoxetine	D	5	20–40 mg
	SNRI	Venlafaxine	A	1	75–225 mg
	MAOI	Phenelzine	A	2	45–90 mg
	Benzodiazepines, e.g.,	Clonazepam	B	3	1.5–8 mg
	Anticonvulsant	Gabapentin	B	3	600–3,600 mg
	RIMA	Moclobemide	D	5	300–600 mg
Obsessive-Compulsive disorder
	SSRIs, e.g.,	Escitalopram	A	1	10–20 mg
		Fluoxetine	A	1	40–60 mg
		Fluvoxamine	A	1	100–300 mg
		Paroxetine	A	1	40–60 mg
		Sertraline	A	1	50–200 mg
		Citalopram	B	3	20–60 mg
	TCA	Clomipramine	A	2	75–300 mg
	NASSA	Mirtazapine	B	3	30–60mg
	MAOI	Phenelzine	D	5	45–90 mg
Post-traumatic stress disorder
	SSRIs, e.g.,	Fluoxetine	A	1	20–40 mg
		Sertraline	A	1	50–100 mg
		Paroxetine	A	1	20–40 mg
	SNRI	Venlafaxine	A	1	75–300 mg
	TCAs, e.g.,	Amitriptyline	B	3	75–200 mg
		Imipramine	B	3	75–200 mg
	NaSSA	Mirtazapine	B	3	30–60 mg
	Atypical Antipsychotic	Risperidone	B	3	0.5–6 mg
	Atypical Antipsychotic	Olanzapine (adjunctive)	B	3	2.5–20 mg
	Anticonvulsant	Lamotrigine	B	3	25–500 mg
	α1-Antagonist	Prazosin (only for nightmares)	B	3	1–10 mg
	MAOI	Phenelzine	D	5	45–90 mg

Table VII.  Panic Disorder: Open Trials and Case Reports

Disorder	Drugs	Authors	Efficacy
Panic disorder
	NaSSA mirtazapine	Carpenter et al. 1999	Yes (C1)
	SNRI milnacipran	Blaya et al. 2007	Yes (C1)
	5-HT3 antagonist ondansetron	Schneier et al. 1996	Yes (C1)
	norepinephrine-dopamine reuptake inhibitor bupropion	Simon et al. 2003	Yes, but not effective in DBPC studies (E)
	anticonvulsant valproate	Primeau et al. 1990; Keck et al. 1993; Woodman and Noyes 1994	Yes (C1)
	Selective GABA reuptake inhibitor anticonvulsant tiagabine	Zwanzger et al. 2001b	Yes (C1)
	Irreversible inhibitor of GABA transaminase vigabatrin	Zwanzger et al. 2001a	Yes (C1)
Panic disorder, treatment-resistant
	Olanzapine	Hollifield et al. 2005	Yes (C1)
	Addition of fluoxetine to a TCA/addition of TCA to fluoxetine	Tiffon et al. 1994	Yes (C1)
	Addition of olanzapine to an SSRI	Chao 2004; Etxebeste et al. 2000; Khaldi et al. 2003; Sepede et al. 2006	Yes (C1)
	Addition of lithium to clomipramine	Cournoyer 1986	Yes (C2)
	Valproate and clonazepam	Ontiveros and Fontaine 1992	Yes (C2)

Table VIII.  Summary of Recommendations for the Treatment of Panic Disorder

Recommendation grade	Category of evidence	Treatment
1	A	SSRIs (citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline) and the SNRI venlafaxine are the first-line treatment for panic disorder.
2	A	TCAs (clomipramine, imipramine), are equally effective, but they are less well tolerated than the SSRIs and may be potentially lethal in overdose. In treatment-resistant cases, benzodiazepines (alprazolam, clonazepam, diazepam, lorazepam) may be used when the patient does not have a history of dependency. Also, they can be combined with antidepressants in the first weeks of treatment before the onset of efficacy of the antidepressants.
3	B	Due to possible serious side effects and interactions with other drugs and food components, the irreversible MAOI phenelzine should only be prescribed when other first-line drugs have failed or not been tolerated.
4	C1	For mirtazapine, valproate and inositol, preliminary evidence is available, however, adequate RCTs are lacking
	C1	According to open studies, ondansetron, bupropion, tiagabine, vigabatrin, milnaciprane, combinations of SSRIs and TCAs, olanzapine monotherapy, augmentation of an SSRI with olanzapine, augmentation of SSRI treatment with pindolol or TCAs, a combination of valproate and clonazepam were effective In treatment-resistant cases, olanzapine, addition of fluoxetine to a TCA, addition of TCA to fluoxetine, or addition of olanzapine to an SSRI was effective according to open studies
	C2	In treatment-resistant cases, addition of lithium to clomipramine or a combination of valproate and clonazepam was effective according single case reports
5	D	Efficacy results with the RIMA moclobemide and the NARI reboxetine were inconsistent
Non-pharmacological treatment		CBT/exposure therapy for panic disorder/agoraphobia is more effective than a wait list condition and is superior to a psychological/pill placebo in the majority of studies A combination of CBT and medication is more effective than the monotherapies There is preliminary evidence for psychoanalytic treatment There is preliminary evidence for limited usefulness of aerobic exercise

Table IX.  GAD: Open Trials and Case Reports.

Disorder	Drugs	Authors	Efficacy
Generalized anxiety disorder	Paroxetine vs. imipramine vs. chlordemethyl-diazepam	Rocca et al. 1997	all equally effective (C1)
	Selective GABA reuptake inhibitor anticonvulsant tiagabine	Rosenthal 2003	As effective as paroxetine. Not effective in DBPC study (E)
	Azapirone buspirone	Feighner 1987	yes (1 year). Inconsistent results in RCTs (D)

Table X.  Summary of Recommendations for the Treatment of GAD.

Recommendation grade	Category of evidence	Treatment
1	A	The drugs recommended as the first-line treatment for GAD are the SSRIs (escitalopram, paroxetine, and sertraline), the SNRIs (venlafaxine and duloxetine), and the calcium channel modulator pregabalin Results with the atypical antipsychotic quetiapine were positive; however, the results are preliminary
2	A	The TCA imipramine is effective in GAD, but its potential lethality in case of overdose, as well as the lower tolerability, puts it as a second-line option. In treatment-resistant cases, benzodiazepines (alprazolam, diazepam) may be used when the patient does not have a history of dependency. Also, they can be combined with antidepressants in the first couple of weeks of treatment before the onset of efficacy of the antidepressants The antihistamine hydroxyzine was effective in placebo- and comparator-controlled studies; however, the drug has sedating properties
3	B	For opipramol and valproate, limited positive evidence is available In treatment-refractory GAD patients, augmentation of SSRI treatment with atypical antipsychotics (risperidone or olanzapine) may be used
5	D	Efficacy results with buspirone were inconsistent
Non-Pharmacological Treatment		CBT is more effective than a wait list control and a “psychological placebo”

Table XI.  Social Anxiety Disorder (SAD): Open Trials and Case Reports.

Disorder	Drugs	Authors	Efficacy
Social phobia
	SSRI citalopram	Bouwer and Stein 1998	Yes. Effective in DBPC study (B)
	SSRI fluvoxamine	DeVane et al. 1999	Yes. Effective in DBPC studies (A)
	SSRI fluoxetine	Gorman et al. 1987; van Ameringen et al. 1993	Yes. Inconsistent results in DBPC studies (D)
	TCA imipramine	Simpson et al. 1998	No (E)
	MAOI tranylcypromine	Versiani et al. 1988	Yes. Effective in DBPC studies (A)
	Anticonvulsant tiagabine	Dunlop et al. 2007	Yes (C1)
	Anticonvulsant topiramate	Van Ameringen et al. 2004	Yes (C1)
	Anticonvulsant levetiracetam	Simon et al. 2004	Yes (C1)
Social phobia, treatment-resistant
	SNRI venlafaxine	Altamura et al. 1999	Yes (C1)
	Addition of buspirone to an SSRI	van Ameringen et al. 1996	Yes (C1)
	SSRI escitalopram	Pallanti and Quercioli 2006	Yes (C1)
Social phobia in children and adolescents
	SSRI escitalopram	Isolan et al. 2007	Yes. Effective in DBPC studies (A)

Table XII.  Summary of Recommendations for the Treatment of SAD.

Recommendation grade	Category of evidence	Treatment
1	A	The drugs recommended as the first-line treatment for SAD are the SSRIs (escitalopram, fluvoxamine, paroxetine and sertraline) and the SNRI venlafaxine
2	A	The MAOI phenelzine is effective in SAD, but is less well tolerated than other antidepressants
3	B	In treatment-resistant cases, benzodiazepines (clonazepam) may be used when the patient does not have a history of dependency. Also, they can be combined with antidepressants in the first weeks of treatment before the onset of efficacy of the antidepressants. For citalopram and gabapentin, preliminary positive evidence is available
4	C1	For olanzapine, tranylcypromine, tiagabine, topiramate and levetiracetam, preliminary evidence is available, but adequate RCTs are lacking In treatment-resistant cases, addition of buspirone to an SSRI was effective according to an open study
5	D	Efficacy results with moclobemide were inconsistent
Non-pharmacological treatment		CBT/exposure is more effective than a wait list control condition, and more effective than a psychological/pill placebo in some, but not all studies The efficacy of exposure therapy for social anxiety disorder could be enhanced by augmentation with d-cycloserine

Table XIII.  Summary of Recommendations for the Treatment of Specific Phobia.

Recommendation grade	Category of evidence	Treatment
1	B	The SSRI paroxetine was effective in treating specific phobia
Non-pharmacological treatment		Exposure therapy is effective

Table XIV.  Obsessive Compulsive Disorder (OCD): Open Trials and Case Reports

Disorder	Drugs	Authors	Efficacy
OCD
	Citalopram	Koponen et al. 1997; Thomsen 1997	Yes. Effective in DBPC study (B)
	SSRI escitalopram	Galvao-de Almeida et al. 2007	Yes. Effective in DBPC studies (A)
	SNRI venlafaxine, SSRI fluoxetine	Kocabasoglu et al. 2004	Venlafaxine = fluoxetine
	SNRI venlafaxine, TCA clomipramine	Albert et al. 2002	Lower response rate with venlafaxine than with clomipramine. Incosisten results in DBPC studies (D)
	Addition of gabapentin to an SSRI	Onder et al. 2008	No (E)
	Aripiprazole	Connor et al. 2005	Yes (C1)
	Hallucinogen psilocybin	Moreno et al. 2006	Yes (C1)
	Nicotine chewing gum	Lundberg et al. 2004	Yes (C1)
	Naloxone infusion	Keuler et al. 1996	No (E)
	Cyproterone acetate	Casas et al. 1986	Yes (C1)
	rTMS	Greenberg et al. 1997; Mantovani et al. 2006	Yes/partially (C1)
OCD in children
	Citalopram	Thomsen 1997; Mukaddes et al. 2003	Yes. Effective in DBPC study (B)
	Paroxetine	Rosenberg et al. 1999	Yes. Effective in DBPC studies (A)
	Sertraline	Wagner et al. 2003	Yes. Effective in DBPC studies (A)
	Glutamate antagonist riluzole	Grant et al. 2007	Yes (C1)
OCD, treatment-resistant
	SSRI citalopram	Marazziti et al. 2001	Yes (C1)
	Glutamate antagonist riluzole	Coric et al. 2005	Yes (C1)
	NMDA receptor antagonist memantine	Pasquini and Biondi, 2006; Poyurovsky et al. 2005	Yes (C2)
	Gonadotropin-releasing hormone analogue triptorelin	Eriksson 2007	Yes (C1)
	Naltrexone	Gade et al. submitted	Yes (C2)
	SSRI citalopram + NARI reboxetine	Fontenelle et al. 2005	Yes (C2)
	Addition of clomipramine to an SSRI	Pallanti et al. 1999	Yes (C1)
	Addition of an SSRI to clomipramine	Ravizza et al. 1996	Yes (C1)
	Adding lithium to clomipramine*	Rasmussen 1984	Yes (C1)
	Addition of buspirone to an* SSRI	Jenike et al. 1991b; Markovitz et al. 1990	Yes (C1)
	Addition of topiramate to an SSRI	Hollander and Dell'Osso, 2006; Van Ameringen et al. 2006	Yes (C1)
	Addition of N-acetylcysteine to an SSRI	Lafleur et al. 2006	Yes (C2)
	Addition of atypical antipsychotics aripiprazole olanzapine,perospirone, quetiapine, or risperidone, to an SSRI or clomipramine	Agid and Lerer 1999; Atmaca et al. 2002; Bogan et al. 2005; Bogetto et al. 2000; da Rocha and Correa 2007; Dell'Osso et al. 2006; Francobandiera, 2001; Friedman et al. 2007b; Kawahara et al. 2000; Koran et al. 2000; Marazziti and Pallanti 1999; Marazziti et al. 2005; Mohr et al. 2002; Otsuka et al. 2007; Pfanner et al. 2000; Ravizza et al. 1996; Saxena et al. 1996; Stein et al. 1997; Storch et al. 2008; Weiss et al. 1999; Yoshimura et al. 2006	Yes (C1)
	Addition of l-tryptophan to clomipramine or to SSRI + pindolol	Blier and Bergeron 1996; Rasmussen 1984	Yes (C1)
	Addition of inositol to an SSRI	Seedat and Stein 1999	No (E)
	Electroconvulsive therapy	Gruber 1971; Husain et al. 1993; Khanna et al. 1988; Maletzky et al. 1994; Mellman and Gorman 1984	Yes (C1)
OCD in children, treatment-resistant
	Adding clonazepam or risperidone to an SSRI	(Leonard et al. 1994)	Yes (C2)
	Adding risperidone to an SSRI	(Fitzgerald et al. 1999)	Yes (C2)

Table XV.  Summary of Recommendations for the Treatment of OCD

Recommendation grade	Category of evidence	Treatment
1	A	SSRIs (escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline) are the first-line treatment for OCD.
2	A	The TCA clomipramine is equally effective, but is less well tolerated than the SSRIs
3	B	Citalopram and mirtazapine were effective in a DBPC studies In treatment-resistant cases, intravenous clomipramine was more effective than oral clomipramine, and the combination of the antipsychotics haloperidol, quetiapine, olanzapine and risperidone with an SSRI was more effective than SSRI monotherapy
4	C1	According to open studies, the following treatments were effective: aripiprazole and some experimental treatments such as cyproterone acetate, the hallucinogen psilocybin, and nicotine chewing gum In treatment resistant cases, the following medications were successful: the glutamate antagonist riluzole, the NMDA receptor antagonist memantine, and the gonadotropin-releasing hormone analogue triptorelin, SSRI citalopram + NARI reboxetine, addition of clomipramine to an SSRI or vice versa, adding lithium to clomipramine, addition of buspirone to an SSRI, addition of topiramate to an SSRI, and addition of l-tryptophan to clomipramine or to SSRI + pindolol
5	D	Efficacy results with the MAOI phenelzine, the SNRI venlafaxine, and the second messenger precursor inositol were inconsistent
Non-pharmacological treatment		CBT/ERP is more effective than a wait list condition and superior to a psychological/pill placebo The usefulness of a combination of CBT/ERP and medications was not clearly supported or rejected. Electroconvulsive therapy may be effective in some patients, but should be restricted to carefully selected treatment-refractory sufferers from OCD. It may be helpful in treating some relevant symptoms in specific patients, i.e. incapacitating depression, catatonia, etc. Results with repetitive transcranial magnetic stimulation (rTMS) were mostly negative Neurosurgery and deep brain stimulation (DBS) were only tried in uncontrolled studies in a few patients. The results were mixed. However, these procedures may represent a potentially effective alternative for a few carefully selected patients with very severe OCD. Some authors find that the risk-benefit-ratio of neurosurgery for OCD is not acceptable.

Table XVI.  Post-Traumatic Stress Disorder (PTSD): Open Trials and Case Reports.

Disorder	Drugs	Authors	Efficacy
PTSD
	SSRI citalopram	Seedat et al. 2000; Seedat et al. 2001	Yes (C1)
	SSRI escitalopram	Robert et al. 2006	Yes (C1)
	SSRI fluvoxamine	Davidson et al. 1998; Escalona et al. 2002; Marmar et al. 1996; Neylan et al. 2001	Yes. Effective in DBPC study (C1)
	SSRI paroxetine	Marshall et al. 1998	Yes. Effective in DBPC studies (A)
	TCA desipramine	Reist et al. 1989	No (E)
	Moclobemide	Neal et al. 1997	Yes (C1)
	Trazodone	Warner et al. 2001	Effect on nightmares; no report on overall symptomatology
	Quetiapine	Hamner et al. 2003a	Yes (C1)
	Olanzapine	Petty et al. 2001	Yes (C1)
	Anticonvulsant phenytoin	Bremner et al. 2004	Yes (C1)
	Anticonvulsant carbamazepine	Lipper et al. 1986	Moderate (C1)
	Anticonvulsant gabapentin	Hamner et al. 2001	Yes (C1)
	Anticonvulsant lamotrigine	Berlant and van Kammen 2002	Yes. Effective in DBPC study (B)
	Anticonvulsant topiramate	Berlant and van Kammen 2002; Berlant 2001	Yes (C1)
	Anticonvulsant valproate	Fesler 1991	Moderate. Not effective in DBPC study (E)
	NMDA receptor antagonist memantine	Battista et al. 2007	Yes (C1)
	Fluoxetine, moclobemide, or tianeptine	Onder et al. 2006	Yes, all equal (C1)
	Fluoxetine vs. amitriptyline	Cavaljuga et al. 2003	Response 70% with amitriptyline, 60% with fluoxetine (C1)
	Propranolol and hypnotics	Pastrana Jiménez et al. 2007	Yes
	Addition of triiodothyronine (T3) to an SSRI	Agid et al. 2001	Yes (C2)
	Addition of quetiapine to venlafaxine	Sattar et al. 2002	Yes (C2)
	Imipramine + clonidine	Kinzie and Leung 1989	Yes (C1)
	Addition of gabapentin to an SSRI	Malek-Ahmadi 2003	Yes (C2)
	Addition of levetiracetam to antidepressant therapy	Kinrys et al. 2006	Yes (C1)
	Non-benzodiazepine zolpidem	Dieperink and Drogemuller 1999	Effect on insomnia
PTSD, treatment-resistant
	SNRI venlafaxine	Hamner and Frueh 1998	Yes, but inconsistent results in DBPC studies (D)
	α1-Antagonist prazosin	Peskind et al. 2003; Raskind et al. 2000; Raskind et al. 2002; Taylor and Raskind 2002	Only effective in nightmares (C1)
Prevention of PTSD
	Beta-blocker propranolol	Taylor and Cahill 2002; Vaiva et al. 2003	Yes. Not effective in DBPC study (E)
Prevention of PTSD in children
	Beta-blocker propranolol	Famularo et al. 1988	Partly. Not effective in DBPC study (E)

Table XVII.  Summary of Recommendations for the Treatment of PTSD

Recommendation grade	Category of evidence	Treatment
1	A	SSRIs (fluoxetine, paroxetine, sertraline) and the SNRI venlafaxine are the first-line treatments for PTSD
3	B	Amitriptyline, imipramine, mirtazapine, risperidone, and lamotrigine were effective in DBPC trials. Prazosin may reduce nightmares In treatment-resistant cases, adjunctive olanzapine or risperidone were successful Acute intravenous administration of hydrocortisone was superior to placebo in preventing emergence of post-traumatic symptoms in intensive care patients
4	C1	According to open studies, the following treatments were effective: citalopram, escitalopram, fluvoxamine, moclobemide, tianeptine, quetiapine, olanzapine, phenytoin, carbamazepine, gabapentin, lamotrigine, topiramate, memantine, addition of triiodothyronine (T3) to an SSRI, and imipramine + clonidine In treatment-resistant cases, venlafaxine and prazosin were successful
	C2	In single cases, addition of quetiapine to venlafaxine ort addition of gabapentin to an SSRI were effective
5	D	Efficacy results with the MAOI phenelzine were inconsistent
Non-pharmacological treatment		CBT was superior to wait list control conditions and to a psychological placebo; however, a few studies did not show differences to placebo conditions Exposure therapy showed positive results in some, but a deterioration in some other studies The usefulness of a combination of both modalities cannot be clearly supported or rejected due to lack of data. “Debriefing” is contraindicated There is only limited evidence showing that the effects of EMDR are superior to attention effects rTMS was effective in one controlled study

Table XVIII.  Efficacy of medications in children and adolescents with anxiety disorders and OCD in RCTs. Categories of evidence: see Table II.

Drug	GAD	SAD	Separation anxiety disorder	Overanxious disorder	Avoidant disorder	OCD
Fluvoxamine	RUPPASG 2001 (B)	RUPPASG 2001 (B)	RUPPASG 2001 (B)			Riddle et al. 1996; Riddle et al. 2001 (A)
Fluoxetine	Birmaher et al. 2003 (B)	Birmaher et al. 2003 (B)	Birmaher et al. 2003 (B)			Geller et al. 2001; Liebowitz et al. 2002b; Riddle et al. 1992 (A)
Paroxetine		Wagner et al. 2004 (B)				Geller et al. 2003; Geller et al. 2004 (D)
Sertraline	Rynn et al. 2001					March et al. 1998; Pediatric OCD Treatment Study Group 2004(A)
Venlafaxine	Rynn et al. 2007b (D)
Clomipramine						DeVeaugh-Geiss et al. 1992; Flament et al. 1985 (A)
Alprazolam				Simeon et al. 1992 (E)	Simeon et al. 1992 (E)

Andrews G. Australian and New Zealand clinical practice guidelines for the treatment of panic disorder and agoraphobia. Aust NZ J Psychiatry 2003; 37: 641–656

 Google Scholar

Pollack MH, Allgulander C, Bandelow B, Cassano GB, Greist JH, Hollander E, et al. WCA recommendations for the long-term treatment of panic disorder. CNS Spectrums 2003a; 8: 17–30

 PubMed Web of Science ®Google Scholar

Greist JH, Bandelow B, Hollander E, Marazziti D, Montgomery SA, Nutt DJ, et al. WCA recommendations for the long-term treatment of obsessive-compulsive disorder in adults. CNS Spectrums 2003; 8: 7–16

 PubMed Web of Science ®Google Scholar

Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2005; 19: 567–596

 PubMed Web of Science ®Google Scholar

Canadian Psychiatric Association. 2006. Clinical practice guidelines. Management of anxiety disorders. Can J Psychiatry 51:9S–91S.

 PubMedGoogle Scholar

Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry 2007; 164: 5–53

 PubMed Web of Science ®Google Scholar

NICE 2006. National Institute for Clinical Excellence (NICE): Obsessive compulsive disorder: Core interventions in the treatment of obsessive compulsive disorder and body dysmorphic disorder.

 Google Scholar

Veteran Affairs . 2007. Department of Veteran Affairs: Post-Traumatic Stress Disorder. Clinical Practice Guidelines.

 Google Scholar

Institute of Medicine. 2007. Treatment of PTSD: An Assessment of the Evidence. Report Brief [ www.iom.edu].

 Google Scholar

WHO . 1991. World Health Organisation. Tenth Revision of the International Classification of Diseases, Chapter V (F): Mental and Behavioural Disorders (including disorders of psychological development) Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organisation.

 Google Scholar

APA . 2000. Diagnostic and statistical manual of mental disorders. 4th ed. Text Revision (DSM-IV-TR®). Washington, DC: American Psychiatric Press.

 Google Scholar

Carpenter LL, Leon Z, Yasmin S, Price LH. Clinical experience with mirtazapine in the treatment of panic disorder. Ann Clin Psychiatry 1999; 11: 81–86

 PubMedGoogle Scholar

Blaya C, Seganfredo AC, Dornelles M, Torres M, Paludo A, Heldt E, et al. The efficacy of milnacipran in panic disorder: an open trial. Int Clin Psychopharmacol 2007; 22: 153–158

 PubMed Web of Science ®Google Scholar

Schneier FR, Garfinkel R, Kennedy B, Campeas R, Fallon B, Marshall R, et al. Ondansetron in the treatment of panic disorder. Anxiety 1996; 2: 199–202

 Google Scholar

Simon NM, Emmanuel N, Ballenger J, Worthington JJ, Kinrys G, Korbly NB, et al. Bupropion sustained release for panic disorder. Psychopharmacol Bull 2003; 37: 66–72

 PubMedGoogle Scholar

Primeau F, Fontaine R, Beauclair L. Valproic acid and panic disorder. Can J Psychiatry 1990; 35: 248–250

 PubMed Web of Science ®Google Scholar

Keck PE, Taylor VE, Tugrul KC, McElroy SL, Bennett JA. Valproate treatment of panic disorder and lactate-induced panic attacks. Biol Psychiatry 1993; 33: 542–546

 PubMedGoogle Scholar

Woodman CL, Noyes R. Panic disorder: treatment with valproate. J Clin Psychiatry 1994; 55: 134–136

 Google Scholar

Zwanzger P, Baghai TC, Schule C, Minov C, Padberg F, Möller HJ, et al. Tiagabine improves panic and agoraphobia in panic disorder patients. J Clin Psychiatry 2001b; 62: 656–657

 PubMed Web of Science ®Google Scholar

Zwanzger P, Baghai T, Boerner RJ, Möller HJ, Rupprecht R. Anxiolytic effects of vigabatrin in panic disorder. J Clin Psychopharmacol 2001a; 21: 539–540

 PubMedGoogle Scholar

Hollifield M, Thompson PM, Ruiz JE, Uhlenhuth EH. Potential effectiveness and safety of olanzapine in refractory panic disorder. Depress Anxiety 2005; 21: 33–40

 PubMed Web of Science ®Google Scholar

Tiffon L, Coplan JD, Papp LA, Gorman JM. Augmentation strategies with tricyclic or fluoxetine treatment in seven partially responsive panic disorder patients. J Clin Psychiatry 1994; 55: 66–69

 Google Scholar

Chao IL. Olanzapine augmentation in panic disorder: a case report. Pharmacopsychiatry 2004; 37: 239–240

 Google Scholar

Etxebeste M, Aragüés E, Malo P, Pacheco L. Olanzapine and panic attacks. Am J Psychiatry 2000; 157: 659–60

 PubMed Web of Science ®Google Scholar

Khaldi S, Kornreich C, Dan B, Pelc I. Usefulness of olanzapine in refractory panic attacks. J Clin Psychopharmacol 2003; 23: 100–101

 Google Scholar

Sepede G, De Berardis D, Gambi F, Campanella D, La Rovere R, D'Amico M, et al. Olanzapine augmentation in treatment-resistant panic disorder: a 12-week, fixed-dose, open-label trial. J Clin Psychopharmacol 2006; 26: 45–49

 PubMed Web of Science ®Google Scholar

Cournoyer J. Reponse rapide a l'addition du carbonate de lithium d'un trouble: panique resistant aux antidepresseurs tricycliques [Rapid response of a disorder to the addition of lithium carbonate: panic resistant to tricyclic antidepressants]. Can J Psychiatry 1986; 31: 335–338

 Google Scholar

Ontiveros A, Fontaine R. Sodium valproate and clonazepam for treatment-resistant panic disorder. J Psychiatry Neurosci 1992; 17: 78–80

 Web of Science ®Google Scholar

Rocca P, Fonzo V, Scotta M, Zanalda E, Ravizza L. Paroxetine efficacy in the treatment of generalized anxiety disorder. Acta Psychiatr Scand 1997; 95: 444–450

 PubMed Web of Science ®Google Scholar

Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control. J Clin Psychiatry 2003; 64: 1245–1249

 PubMed Web of Science ®Google Scholar

Feighner JP. Buspirone in the long-term treatment of generalized anxiety disorder. J Clin Psychiatry (Suppl) 1987; 48: 3–6

 PubMed Web of Science ®Google Scholar

Bouwer C, Stein DJ. Use of the selective serotonin reuptake inhibitor citalopram in the treatment of generalized social phobia. J Affect Disord 1998; 49: 79–82

 PubMed Web of Science ®Google Scholar

DeVane CL, Ware MR, Emmanuel NP, Brawman-Mintzer O, Morton WA, Villarreal G, et al. Evaluation of the efficacy, safety and physiological effects of fluvoxamine in social phobia. Int Clin Psychopharmacol 1999; 14: 345–351

 PubMed Web of Science ®Google Scholar

Gorman JM, Liebowitz MR, Fyer AJ, Goetz D, Campeas RB, Fyer MR, et al. An open trial of fluoxetine in the treatment of panic attacks. J Clin Psychopharmacol 1987; 7: 329–332

 PubMed Web of Science ®Google Scholar

van Ameringen M, Mancini C, Streiner DL. Fluoxetine efficacy in social phobia. J Clin Psychiatry 1993; 54: 27–32

 PubMed Web of Science ®Google Scholar

Simpson HB, Schneier FR, Campeas RB, Marshall RD, Fallon BA, Davies S, et al. Imipramine in the treatment of social phobia. J Clin Psychopharmacol 1998; 18: 132–135

 PubMed Web of Science ®Google Scholar

Versiani M, Mundim FD, Nardi AE, Liebowitz MR. Tranylcypromine in social phobia. J Clin Psychopharmacol 1988; 8: 279–283

 PubMed Web of Science ®Google Scholar

Dunlop BW, Papp L, Garlow SJ, Weiss PS, Knight BT, Ninan PT. Tiagabine for social anxiety disorder. Hum Psychopharmacol 2007; 22: 241–244

 PubMed Web of Science ®Google Scholar

Van Ameringen M, Mancini C, Pipe B, Oakman J, Bennett M. An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry 2004; 65: 1674–1678

 PubMed Web of Science ®Google Scholar

Simon NM, Worthington JJ, Doyle AC, Hoge EA, Kinrys G, Fischmann D, et al. An open-label study of levetiracetam for the treatment of social anxiety disorder. J Clin Psychiatry 2004; 65: 1219–1222

 PubMed Web of Science ®Google Scholar

Altamura AC, Pioli R, Vitto M, Mannu P. Venlafaxine in social phobia: a study in selective serotonin reuptake inhibitor non-responders. Int Clin Psychopharmacol 1999; 14: 239–245

 PubMed Web of Science ®Google Scholar

van Ameringen M, Mancini C, Wilson C. Buspirone augmentation of selective serotonin reuptake inhibitors (SSRIs) in social phobia. J Affect Disord 1996; 39: 115–121

 PubMed Web of Science ®Google Scholar

Pallanti S, Quercioli L. Resistant social anxiety disorder response to Escitalopram. Clin Pract Epidemiol Ment Health 2006; 2: 35

 PubMedGoogle Scholar

Isolan L Pheula G Salum GA, Jr Oswald S Rohde LA Manfro GG 2007. An open-label trial of escitalopram in children and adolescents with social anxiety disorder. J Child Adolesc Psychopharmacol 17:751–760.

 PubMed Web of Science ®Google Scholar

Koponen H, Lepola U, Leinonen E, Jokinen R, Penttinen J, Turtonen J. Citalopram in the treatment of obsessive-compulsive disorder: an open pilot study. Acta Psychiatr Scand 1997; 96: 343–346

 PubMed Web of Science ®Google Scholar

Thomsen PH. Child and adolescent obsessive-compulsive disorder treated with citalopram: findings from an open trial of 23 cases. J Child Adolesc Psychopharmacol 1997; 7: 157–166

 PubMed Web of Science ®Google Scholar

Galvao-de Almeida A, Quarantini LC, Gois CR, Santos-Jesus R, Miranda-Scippa AM, de Oliveira IR, et al. Obsessive-compulsive disorder: an open-label pilot trial of escitalopram. CNS Spectrums 2007; 12: 519–524

 PubMedGoogle Scholar

Kocabasoglu N, Corapcioglu A, Yargic I, Erdogan A. Venlafaxine versus fluoxetine in the treatment of obsessive-compulsive disorder: A preliminary single-blind, 12 week, controlled study [abstract]. Eur Neuropsychopharmacol 2004; 14(Suppl 3)S304

 Google Scholar

Albert U, Aguglia E, Maina G, Bogetto F. Venlafaxine versus clomipramine in the treatment of obsessive-compulsive disorder: a preliminary single-blind, 12-week, controlled study. J Clin Psychiatry 2002; 63: 1004–1009

 PubMed Web of Science ®Google Scholar

Onder E, Tural U, Gokbakan M. Does gabapentin lead to early symptom improvement in obsessive-compulsive disorder?. Eur Arch Psychiatry Clin Neurosci 2008; 258: 319–23

 Google Scholar

Connor KM, Payne VM, Gadde KM, Zhang W, Davidson JR. The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients. J Clin Psychiatry 2005; 66: 49–51

 PubMed Web of Science ®Google Scholar

Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry 2006; 67: 1735–1740

 PubMed Web of Science ®Google Scholar

Lundberg S, Carlsson A, Norfeldt P, Carlsson ML. Nicotine treatment of obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1195–1199

 PubMed Web of Science ®Google Scholar

Keuler DJ, Altemus M, Michelson D, Greenberg B, Murphy DL. Behavioral effects of naloxone infusion in obsessive-compulsive disorder. Biol Psychiatry 1996; 40: 154–156

 PubMed Web of Science ®Google Scholar

Casas M, Alvarez E, Duro P, Garcia-Ribera C, Udina C, Velat A, et al. Antiandrogenic treatment of obsessive-compulsive neurosis. Acta Psychiatr Scand 1986; 73: 221–222

 PubMed Web of Science ®Google Scholar

Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE, Altemus M, et al. Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study. Am J Psychiatry 1997; 154: 867–869

 PubMed Web of Science ®Google Scholar

Mantovani A, Lisanby SH, Pieraccini F, Ulivelli M, Castrogiovanni P, Rossi S. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive–compulsive disorder (OCD) and Tourette's syndrome (TS). Int J Neuropsychopharmacol 2006; 9: 95–100

 PubMed Web of Science ®Google Scholar

Mukaddes NM, Abali O, Kaynak N. Citalopram treatment of children and adolescents with obsessive-compulsive disorder: a preliminary report. Psychiatry Clin Neurosci 2003; 57: 405–408

 PubMedGoogle Scholar

Rosenberg DR, Stewart CM, Fitzgerald KD, Tawile V, Carroll E. Paroxetine open-label treatment of pediatric outpatients with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 1999; 38: 1180–1185

 PubMed Web of Science ®Google Scholar

Wagner KD, Cook EH, Chung H, Messig M. Remission status after long-term sertraline treatment of pediatric obsessive-compulsive disorder. J Child Adolesc Psychopharmacol 2003; 13(Suppl 1)S53–60

 PubMedGoogle Scholar

Grant P, Lougee L, Hirschtritt M, Swedo SE. An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. J Child Adolesc Psychopharmacol 2007; 17: 761–767

 PubMed Web of Science ®Google Scholar

Marazziti D, Dell'Osso L, Gemignani A, Ciapparelli A, Presta S, Nasso ED, et al. Citalopram in refractory obsessive-compulsive disorder: an open study. Int Clin Psychopharmacol 2001; 16: 215–219

 PubMedGoogle Scholar

Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry 2005; 58: 424–428

 PubMed Web of Science ®Google Scholar

Pasquini M, Biondi M. Memantine augmentation for refractory obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1173–1175

 PubMed Web of Science ®Google Scholar

Poyurovsky M, Weizman R, Weizman A, Koran L. Memantine for treatment-resistant OCD. Am J Psychiatry 2005; 162: 2191–2192

 PubMed Web of Science ®Google Scholar

Eriksson T. Anti-androgenic treatment of obsessive-compulsive disorder: an open-label clinical trial of the long-acting gonadotropin-releasing hormone analogue triptorelin. Int Clin Psychopharmacol 2007; 22: 57–61

 Google Scholar

Gade K Häußinger C Bandelow B submitted. Anorexia due to obsessive-compulsive disorder in a male patient successfully treated with naltrexone.

 Google Scholar

Fontenelle LF, Mendlowicz MV, Miguel EC, Versiani M. Citalopram plus reboxetine in treatment-resistant obsessive-compulsive disorder. World J Biol Psychiatry 2005; 6: 57–59

 PubMed Web of Science ®Google Scholar

Pallanti S, Quercioli L, Paiva RS, Koran LM. Citalopram for treatment-resistant obsessive-compulsive disorder. Eur Psychiatry 1999; 14: 101–106

 PubMed Web of Science ®Google Scholar

Ravizza L, Barzega G, Bellino S, Bogetto F, Maina G. Therapeutic effect and safety of adjunctive risperidone in refractory obsessive-compulsive disorder (OCD). Psychopharmacol Bull 1996; 32: 677–682

 PubMedGoogle Scholar

Rasmussen SA. Lithium and tryptophan augmentation in clomipramine-resistant obsessive-compulsive disorder. Am J Psychiatry 1984; 141: 1283–1285

 PubMed Web of Science ®Google Scholar

Jenike MA, Baer L, Buttolph L. Buspirone augmentation of fluoxetine in patients with obsessive compulsive disorder. J Clin Psychiatry 1991b; 52: 13–14

 PubMed Web of Science ®Google Scholar

Markovitz PJ, Stagno SJ, Calabrese JR. Buspirone augmentation of fluoxetine in obsessive-compulsive disorder. Am J Psychiatry 1990; 147: 798–800

 PubMed Web of Science ®Google Scholar

Hollander E, Dell'Osso B. Topiramate plus paroxetine in treatment-resistant obsessive-compulsive disorder. Int Clin Psychopharmacol 2006; 21: 189–191

 PubMed Web of Science ®Google Scholar

Van Ameringen M, Mancini C, Patterson B, Bennett M. Topiramate augmentation in treatment-resistant obsessive-compulsive disorder: a retrospective, open-label case series. Depress Anxiety 2006; 23: 1–5

 PubMed Web of Science ®Google Scholar

Lafleur DL, Pittenger C, Kelmendi B, Gardner T, Wasylink S, Malison RT, et al. N-Acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berlin) 2006; 184: 254–256

 PubMed Web of Science ®Google Scholar

Agid O, Lerer B. Risperidone augmentation of paroxetine in a case of severe, treatment-refractory obsessive-compulsive disorder without comorbid psychopathology. J Clin Psychiatry 1999; 60: 55–56

 PubMed Web of Science ®Google Scholar

Atmaca M, Kuloglu M, Tezcan E, Gecici O. Quetiapine augmentation in patients with treatment resistant obsessive-compulsive disorder: a single-blind, placebo-controlled study. Int Clin Psychopharmacol 2002; 17: 115–119

 PubMed Web of Science ®Google Scholar

Bogan AM, Koran LM, Chuong HW, Vapnik T, Bystritsky A. Quetiapine augmentation in obsessive-compulsive disorder resistant to serotonin reuptake inhibitors: an open-label study. J Clin Psychiatry 2005; 66: 73–79

 PubMed Web of Science ®Google Scholar

Bogetto F, Bellino S, Vaschetto P, Ziero S. Olanzapine augmentation of fluvoxamine-refractory obsessive-compulsive disorder (OCD): a 12-week open trial. Psychiatry Res 2000; 96: 91–98

 PubMed Web of Science ®Google Scholar

da Rocha FF, Correa H. Successful augmentation with aripiprazole in clomipramine-refractory obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1550–1551

 Google Scholar

Dell'Osso B, Mundo E, Altamura AC. Quetiapine augmentation of selective serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a six-month follow-up case series. CNS Spectrums 2006; 11: 879–883

 PubMed Web of Science ®Google Scholar

Francobandiera G. Olanzapine augmentation of serotonin uptake inhibitors in obsessive-compulsive disorder: an open study. Can J Psychiatry 2001; 46: 356–358

 PubMed Web of Science ®Google Scholar

Friedman S, Abdallah TA, Oumaya M, Rouillon F, Guelfi JD. Aripiprazole augmentation of clomipramine-refractory obsessive-compulsive disorder. J Clin Psychiatry 2007b; 68: 972–973

 PubMedGoogle Scholar

Kawahara T, Ueda Y, Mitsuyama Y. A case report of refractory obsessive-compulsive disorder improved by risperidone augmentation of clomipramine treatment. Psychiatry Clin Neurosci 2000; 54: 599–601

 PubMedGoogle Scholar

Koran LM, Ringold AL, Elliott MA. Olanzapine augmentation for treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry 2000; 61: 514–517

 PubMed Web of Science ®Google Scholar

Marazziti D, Pallanti S. Effectiveness of olanzapine treatment for severe obsessive-compulsive disorder. Am J Psychiatry 1999; 156: 1834–1835

 PubMed Web of Science ®Google Scholar

Marazziti D, Pfanner C, Dell'Osso B, Ciapparelli A, Presta S, Corretti G, et al. Augmentation strategy with olanzapine in resistant obsessive compulsive disorder: an Italian long-term open-label study. J Psychopharmacol 2005; 19: 392–394

 PubMed Web of Science ®Google Scholar

Mohr N, Vythilingum B, Emsley RA, Stein DJ. Quetiapine augmentation of serotonin reuptake inhibitors in obsessive-compulsive disorder. Int Clin Psychopharmacol 2002; 17: 37–40

 PubMed Web of Science ®Google Scholar

Otsuka T, Togo T, Sugiyama N, Uehara K, Yoshimi A, Karashima A, et al. Perospirone augmentation of paroxetine in treatment of refractory obsessive-compulsive disorder with depression. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 564–566

 Google Scholar

Pfanner C, Marazziti D, Dell'Osso L, Presta S, Gemignani A, Milanfranchi A, et al. Risperidone augmentation in refractory obsessive-compulsive disorder: an open-label study. Int Clin Psychopharmacol 2000; 15: 297–301

 PubMed Web of Science ®Google Scholar

Saxena S, Wang D, Bystritsky A, Baxter LR. Risperidone augmentation of SRI treatment for refractory obsessive-compulsive disorder. J Clin Psychiatry 1996; 57: 303–306

 PubMed Web of Science ®Google Scholar

Stein DJ, Bouwer C, Hawkridge S, Emsley RA. Risperidone augmentation of serotonin reuptake inhibitors in obsessive-compulsive and related disorders. J Clin Psychiatry 1997; 58: 119–122

 PubMed Web of Science ®Google Scholar

Storch EA, Lehmkuhl H, Geffken GR, Touchton A, Murphy TK. Aripiprazole augmentation of incomplete treatment response in an adolescent male with obsessive-compulsive disorder. Depress Anxiety 2008; 25: 172–174

 Web of Science ®Google Scholar

Weiss EL, Potenza MN, McDougle CJ, Epperson CN. Olanzapine addition in obsessive-compulsive disorder refractory to selective serotonin reuptake inhibitors: an open-label case series. J Clin Psychiatry 1999; 60: 524–527

 PubMed Web of Science ®Google Scholar

Yoshimura R, Kaneko S, Shinkai K, Nakamura J. Successful treatment for obsessive-compulsive disorder with addition of low-dose risperidone to fluvoxamine: implications for plasma levels of catecholamine metabolites and serum brain-derived neurotrophic factor levels. Psychiatry Clin Neurosci 2006; 60: 389–393

 PubMed Web of Science ®Google Scholar

Blier P, Bergeron R. Sequential administration of augmentation strategies in treatment-resistant obsessive-compulsive disorder: preliminary findings. Int Clin Psychopharmacol 1996; 11: 37–44

 Google Scholar

Seedat S, Stein DJ. Inositol augmentation of serotonin reuptake inhibitors in treatment-refractory obsessive-compulsive disorder: an open trial. Int Clin Psychopharmacol 1999; 14: 353–356

 PubMed Web of Science ®Google Scholar

Gruber RP. ECT for obsessive-compulsive symptoms (possible mechanisms of action). Dis Nerv Syst 1971; 32: 180–182

 PubMedGoogle Scholar

Husain MM, Lewis SF, Thornton WL. Maintenance ECT for refractory obsessive-compulsive disorder. Am J Psychiatry 1993; 150: 1899–1900

 PubMed Web of Science ®Google Scholar

Khanna S, Gangadhar BN, Sinha V, Rajendra PN, Channabasavanna SM. Electroconvulsive therapy in obsessive-compulsive disorder. Convuls Ther 1988; 4: 314–320

 PubMedGoogle Scholar

Maletzky B, McFarland B, Burt A. Refractory obsessive compulsive disorder and ECT. Convuls Ther 1994; 10: 34–42

 PubMedGoogle Scholar

Mellman LA, Gorman JM. Successful treatment of obsessive-compulsive disorder with ECT. Am J Psychiatry 1984; 141: 596–597

 Web of Science ®Google Scholar

Leonard HL, Topol D, Bukstein O, Hindmarsh D, Allen AJ, Swedo SE. Clonazepam as an augmenting agent in the treatment of childhood-onset obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 1994; 33: 792–794

 PubMed Web of Science ®Google Scholar

Fitzgerald KD, Stewart CM, Tawile V, Rosenberg DR. Risperidone augmentation of serotonin reuptake inhibitor treatment of pediatric obsessive compulsive disorder. J Child Adolesc Psychopharmacol 1999; 9: 115–123

 PubMed Web of Science ®Google Scholar

Seedat S, Stein DJ, Emsley RA. Open trial of citalopram in adults with post-traumatic stress disorder. Int J Neuropsychopharmacol 2000; 3: 135–140

 PubMedGoogle Scholar

Seedat S, Lockhat R, Kaminer D, Zungu-Dirwayi N, Stein DJ. An open trial of citalopram in adolescents with post-traumatic stress disorder. Int Clin Psychopharmacol 2001; 16: 21–25

 PubMed Web of Science ®Google Scholar

Robert S, Hamner MB, Ulmer HG, Lorberbaum JP, Durkalski VL. Open-label trial of escitalopram in the treatment of posttraumatic stress disorder. J Clin Psychiatry 2006; 67: 1522–1526

 PubMed Web of Science ®Google Scholar

Davidson JR, Weisler RH, Malik M, Tupler LA. Fluvoxamine in civilians with posttraumatic stress disorder. J Clin Psychopharmacol 1998; 18: 93–95

 Google Scholar

Escalona R, Canive JM, Calais LA, Davidson JR. Fluvoxamine treatment in veterans with combat-related post-traumatic stress disorder. Depress Anxiety 2002; 15: 29–33

 PubMed Web of Science ®Google Scholar

Marmar CR, Schoenfeld F, Weiss DS, Metzler T, Zatzick D, Wu R, et al. Open trial of fluvoxamine treatment for combat-related posttraumatic stress disorder. J Clin Psychiatry 1996; 57(Suppl 8)66–70

 PubMedGoogle Scholar

Neylan TC, Metzler TJ, Schoenfeld FB, Weiss DS, Lenoci M, Best SR, et al. Fluvoxamine and sleep disturbances in posttraumatic stress disorder. J Trauma Stress 2001; 14: 461–467

 Web of Science ®Google Scholar

Marshall RD, Schneier FR, Fallon BA, Knight CB, Abbate LA, Goetz D, et al. An open trial of paroxetine in patients with noncombat-related, chronic posttraumatic stress disorder. J Clin Psychopharmacol 1998; 18: 10–18

 PubMed Web of Science ®Google Scholar

Reist C, Kauffmann CD, Haier RJ, Sangdahl C, DeMet EM, Chicz-DeMet A, et al. A controlled trial of desipramine in 18 men with posttraumatic stress disorder. Am J Psychiatry 1989; 146: 513–516

 PubMed Web of Science ®Google Scholar

Neal LA, Shapland W, Fox C. An open trial of moclobemide in the treatment of post-traumatic stress disorder. Int Clin Psychopharmacol 1997; 12: 231–237

 PubMed Web of Science ®Google Scholar

Warner MD, Dorn MR, Peabody CA. Survey on the usefulness of trazodone in patients with PTSD with insomnia or nightmares. Pharmacopsychiatry 2001; 34: 128–131

 PubMed Web of Science ®Google Scholar

Hamner MB, Deitsch SE, Brodrick PS, Ulmer HG, Lorberbaum JP. Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol 2003a; 23: 15–20

 PubMed Web of Science ®Google Scholar

Petty F, Brannan S, Casada J, Davis LL, Gajewski V, Kramer GL, et al. Olanzapine treatment for post-traumatic stress disorder: an open-label study. Int Clin Psychopharmacol 2001; 16: 331–337

 PubMed Web of Science ®Google Scholar

Bremner DJ, Mletzko T, Welter S, Siddiq S, Reed L, Williams C, et al. Treatment of posttraumatic stress disorder with phenytoin: an open-label pilot study. J Clin Psychiatry 2004; 65: 1559–1564

 Google Scholar

Lipper S, Davidson JR, Grady TA, Edinger JD, Hammett EB, Mahorney SL, et al. Preliminary study of carbamazepine in post-traumatic stress disorder. Psychosomatics 1986; 27: 849–854

 PubMed Web of Science ®Google Scholar

Hamner MB, Brodrick PS, Labbate LA. Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy. Ann Clin Psychiatry 2001; 13: 141–146

 PubMedGoogle Scholar

Berlant J, van Kammen DP. Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry 2002; 63: 15–20

 PubMed Web of Science ®Google Scholar

Berlant JL. Topiramate in posttraumatic stress disorder: Preliminary clinical observations. J Clin Psychiatry 2001; 62: 60–63

 PubMed Web of Science ®Google Scholar

Fesler FA. Valproate in combat-related posttraumatic stress disorder. J Clin Psychiatry 1991; 52: 361–364

 PubMed Web of Science ®Google Scholar

Battista MA, Hierholzer R, Khouzam HR, Barlow A, O'Toole S. Pilot trial of memantine in the treatment of posttraumatic stress disorder. Psychiatry 2007; 70: 167–174

 PubMed Web of Science ®Google Scholar

Onder E, Tural U, Aker T. A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake. Eur Psychiatry 2006; 21: 174–179

 Google Scholar

Cavaljuga S, Licanin I, Kapic E, Potkonjak D. Clomipramine and fluoxetine effects in the treatment of panic disorder. Bosn J Basic Med Sci 2003; 3: 27–31

 PubMedGoogle Scholar

Pastrana Jiménez JI, Catalina Romero C, García Diéguez N, López-Ibor Aliño JJ. Pharmacological treatment of acute stress disorder with propranolol and hypnotics. Actas Esp Psiquiatr 2007; 35: 351–358

 Google Scholar

Agid O, Shalev AY, Lerer B. Triiodothyronine augmentation of selective serotonin reuptake inhibitors in posttraumatic stress disorder. J Clin Psychiatry 2001; 62: 169–173

 PubMed Web of Science ®Google Scholar

Sattar SP, Ucci B, Grant K, Bhatia SC, Petty F. Quetiapine therapy for posttraumatic stress disorder. Ann Pharmacother 2002; 36: 1875–1878

 PubMed Web of Science ®Google Scholar

Kinzie JD, Leung P. Clonidine in Cambodian patients with posttraumatic stress disorder. J Nerv Ment Dis 1989; 177: 546–550

 PubMed Web of Science ®Google Scholar

Malek-Ahmadi P. Gabapentin and posttraumatic stress disorder. Ann Pharmacother 2003; 37: 664–666

 Google Scholar

Kinrys G, Wygant LE, Pardo TB, Melo M. Levetiracetam for treatment-refractory posttraumatic stress disorder. J Clin Psychiatry 2006; 67: 211–214

 PubMed Web of Science ®Google Scholar

Dieperink ME, Drogemuller L. Zolpidem for insomnia related to PTSD. Psychiatr Serv 1999; 50: 421

 PubMed Web of Science ®Google Scholar

Hamner MB, Frueh BC. Response to venlafaxine in a previously antidepressant treatment-resistant combat veteran with post–traumatic stress disorder. Int Clin Psychopharmacol 1998; 13: 233–234

 PubMedGoogle Scholar

Peskind ER, Bonner LT, Hoff DJ, Raskind MA. Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder. J Geriatr Psychiatry Neurol 2003; 16: 165–171

 PubMed Web of Science ®Google Scholar

Raskind MA, Dobie DJ, Kanter ED, Petrie EC, Thompson CE, Peskind ER. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry 2000; 61: 129–133

 Google Scholar

Raskind MA, Thompson C, Petrie EC, Dobie DJ, Rein RJ, Hoff DJ, et al. Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder. J Clin Psychiatry 2002; 63: 565–568

 PubMed Web of Science ®Google Scholar

Taylor F, Raskind MA. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. J Clin Psychopharmacol 2002; 22: 82–85

 PubMed Web of Science ®Google Scholar

Taylor F, Cahill L. Propranolol for reemergent posttraumatic stress disorder following an event of retraumatization: a case study. J Trauma Stress 2002; 15: 433–437

 PubMedGoogle Scholar

Vaiva G, Ducrocq F, Jezequel K, Averland B, Lestavel P, Brunet A, et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry 2003; 54: 947–949

 PubMed Web of Science ®Google Scholar

Famularo R, Kinscherff R, Fenton T. Propranolol treatment for childhood posttraumatic stress disorder, acute type. A pilot study. Am J Dis Child 1988; 142: 1244–1247

 PubMedGoogle Scholar

RUPPASG 2001. Fluvoxamine for the treatment of anxiety disorders in children and adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group. New Engl J Med 344:1279–1285.

 Google Scholar

Riddle MA, Claghorn JL, Gaffney G, Griest JH, Holland AD, Landbloom R, et al. A controlled trial of fluvoxamine for obsessive-compulsive disorder in children and adolescents. Psychopharmacol Bull 1996; 32: 399

 Google Scholar

Riddle MA, Reeve EA, Yaryura-Tobias JA, Yang HM, Claghorn JL, Gaffney G, et al. Fluvoxamine for children and adolescents with obsessive-compulsive disorder: a randomized, controlled, multicenter trial. J Am Acad Child Adolesc Psychiatry 2001; 40: 222–229

 PubMed Web of Science ®Google Scholar

Birmaher B, Axelson DA, Monk K, Kalas C, Clark DB, Ehmann M, et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 2003; 42: 415–423

 PubMed Web of Science ®Google Scholar

Geller DA, Hoog SL, Heiligenstein JH, Ricardi RK, Tamura R, Kluszynski S, et al. Fluoxetine treatment for obsessive-compulsive disorder in children and adolescents: a placebo-controlled clinical trial. J Am Acad Child Adolesc Psychiatry 2001; 40: 773–779

 PubMed Web of Science ®Google Scholar

Liebowitz MR, Turner SM, Piacentini J, Beidel DC, Clarvit SR, Davies SO, et al. Fluoxetine in children and adolescents with OCD: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2002b; 41: 1431–1438

 PubMed Web of Science ®Google Scholar

Riddle MA, Scahill L, King RA, Hardin MT, Anderson GM, Ort SI, et al. Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 1992; 31: 1062–1069

 PubMed Web of Science ®Google Scholar

Wagner KD, Berard R, Stein MB, Wetherhold E, Carpenter DJ, Perera P, et al. A multicenter, randomized, double-blind, placebo-controlled trial of paroxetine in children and adolescents with social anxiety disorder. Arch Gen Psychiatry 2004; 61: 1153–1162

 PubMed Web of Science ®Google Scholar

Geller DA, Biederman J, Stewart SE, Mullin B, Farrell C, Wagner KD, et al. Impact of comorbidity on treatment response to paroxetine in pediatric obsessive-compulsive disorder: is the use of exclusion criteria empirically supported in randomized clinical trials?. J Child Adolesc Psychopharmacol 2003; 13(Suppl 1)S19–29

 Google Scholar

Geller DA, Wagner KD, Emslie G, Murphy T, Carpenter DJ, Wetherhold E, et al. Paroxetine treatment in children and adolescents with obsessive-compulsive disorder: a randomized, multicenter, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2004; 43: 1387–1396

 PubMed Web of Science ®Google Scholar

Rynn MA, Siqueland L, Rickels K. Placebo-controlled trial of sertraline in the treatment of children with generalized anxiety disorder. Am J Psychiatry 2001; 158: 2008–2014

 PubMed Web of Science ®Google Scholar

March JS, Biederman J, Wolkow R, Safferman A, Mardekian J, Cook EH, et al. Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. J Am Med Assoc 1998; 280: 1752–1756

 PubMed Web of Science ®Google Scholar

Rynn M, Riddle MA, Yeung PP, Kunz NR. Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: two placebo-controlled trials. Am J Psychiatry 2007b; 164: 290–300

 PubMed Web of Science ®Google Scholar

DeVeaugh-Geiss J, Moroz G, Biederman J, Cantwell D, Fontaine R, Greist JH, et al. Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder – a multicenter trial. J Am Acad Child Adolesc Psychiatry 1992; 31: 45–49

 PubMed Web of Science ®Google Scholar

Flament MF, Rapoport JL, Berg CJ, Sceery W, Kilts C, Mellstrom B, et al. Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study. Arch Gen Psychiatry 1985; 42: 977–983

 PubMed Web of Science ®Google Scholar

Simeon JG, Ferguson HB, Knott V, Roberts N, Gauthier B, Dubois C, et al. Clinical, cognitive, and neurophysiological effects of alprazolam in children and adolescents with overanxious and avoidant disorders. J Am Acad Child Adolesc Psychiatry 1992; 31: 29–33

 PubMed Web of Science ®Google Scholar