Continuing Education Article

Obsessive–Compulsive Disorder

Journal of Pharmacy Practice 2014, Vol. 27(2) 116-130 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014521996 jpp.sagepub.com

Gyula Bokor, MD1, and Peter D. Anderson, PharmD, BCPP2

Abstract Obsessive–compulsive disorder (OCD) is a common heterogeneous psychiatric disorder manifesting with obsessions and compulsions. Obsessions are intrusive, recurrent, and persistent unwanted thoughts. Compulsions are repetitive behaviors or mental acts that an individual feels driven to perform in response to the obsessions. The heterogeneity of OCD includes themes of obsessions, types of rituals, presence or absence of tics, etiology, genetics, and response to pharmacotherapy. Complications of OCD include interpersonal difficulties, unemployment, substance abuse, criminal justice issues, and physical injuries. Areas of the brain involved in the pathophysiology include the orbitofrontal cortex, anterior cingulate gyrus, and basal ganglia. Overall, OCD may be due to a malfunction in the cortico–striato–thalamo–cortical circuit in the brain. Neurotransmitters implicated in OCD include serotonin, dopamine, and glutamate. Numerous drugs such as atypical antipsychotics and dopaminergic agents can cause or exacerbate OCD symptoms. The etiology includes genetics and neurological insults. Treatment of OCD includes psychotherapy, pharmacotherapy, electroconvulsive therapy, transcranial magnetic simulation, and in extreme cases surgery. Exposure and response prevention is the most effective form of psychotherapy. Selective serotonin reuptake inhibitors (SSRIs) are the preferred pharmacotherapy. Higher doses than listed in the package insert and a longer trial are often needed for SSRIs than compared to other psychiatric disorders. Alternatives to SSRIs include clomipramine and serotonin/norepinephrine reuptake inhibitors. Treatment of resistant cases includes augmentation with atypical antipsychotics, pindolol, buspirone, and glutamate-blocking agents. Keywords obsessive–compulsive disorder, serotonin reuptake inhibitors, psychopharmacology, psychiatry, exposure and response prevention

Continuing Education Learning Objectives 1. Describe the clinical presentation and diagnostic criteria of obsessive–compulsive disorder (OCD). 2. Describe the pathophysiology of OCD. 3. Distinguish OCD from related conditions. 4. Name several drugs and medications that can produce or aggravate OCD symptoms. 5. Describe the pharmacology, side effects, and role of SSRIs in the treatment of OCD. 6. Describe the pharmacology of clomipramine. 7. Name several medications used as augmentation therapy with OCD. 8. Describe several types of nonpharmacological therapies for OCD.

Obsessive–compulsive disorder (OCD) is a heterogeneous disorder consisting of obsessions and compulsions.1 Obsessions are intrusive, recurrent, and persistent unwanted thoughts.2 Compulsions are repetitive behaviors or mental acts that an individual feels driven to perform in response to the obsessions.2 Examples of obsessions include preoccupation with germs, preoccupation with order and symmetry, fear of causing harm to others, excessive focus on religious ideas, or unwarranted fear of losing items. Examples of compulsions are excessive hand washing and excessive checking of locks, switches, or appliances. The prevalence of OCD in adults in the United States is approximately 1%.3

Diagnostic Criteria The Diagnostic and Statistical Manual of the Mental Disorders, Fifth Edition (DSM-5) lists formal criteria for diagnosis of OCD.2 In order to have a diagnosis of OCD, the presence

1 2

Staff Psychiatrist, Taunton State Hospital, Taunton, MA, USA Psychopharmacology Consultant, private practice, Randolph, MA, USA

Corresponding Author: Peter D. Anderson, 5308 Avalon Drive, Randolph, MA 02368, USA. Email: [email protected]

Bokor and Anderson Table 1. Examples of Obsessions. Germs Images of violent scenes Repugnant thoughts (eg, kicking a baby, shooting a coworker, etc) Fear of causing harm to oneself or others accidently or intentionally Fear of losing items that one may need Order and symmetry Religious and moral believes Intrusive sexual thoughts Superstitions

Table 2. Examples of Compulsions. Washing hands excessively Excessive cleaning of household items Washing a particular part of the body first when taking a shower Repeatedly checking that the doors are locked or that the stove is turned off Excessive rereading or rewriting

of obsessions, compulsions, or both is required. See Tables 1 and 2 for examples of obsessions and compulsions. The obsessions and compulsions must be time consuming such as taking more than an hour per day. The obsessions and compulsions must not be due to the pharmacological effects of a medication or a drug of abuse. For example, an obsession with obtaining more cocaine by an addict is not OCD. The disturbance must not be due to another psychiatric disorder such as paraphilic disorder, body dysmorphic disorder, or hoarding.2 There are several changes in the OCD criteria in DSM-5 from Diagnostic and Statistical Manual of the Mental Disorders, Fourth Edition (DSM-IV). For starters, in DSM-IV OCD was listed in the chapter on anxiety disorders.4,5 In DSM-5, OCD is in a chapter entitled ‘‘Obsessive-Compulsive and Related Disorders.’’2 In DSM-IV, the person (unless a child) must have recognized that the obsessions or compulsions are unreasonable or excessive. DSM-5 lacks this requirement. Nevertheless, DSM-5 does allow for a range of insight with good or fair, poor insight, or absent insight/delusional beliefs.5

Similar Conditions Conditions related to OCD include body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, substance/medicationinduced obsessive–compulsive and related disorder, and obsessive–compulsive and related disorder due to another medical condition.2 All of these conditions are listed in the chapter ‘‘Obsessive–Compulsive and Related Disorders’’ in the DSM-5.2 Body dysmorphic disorder is where the individual is preoccupied with one or more perceived flaws or defects in physical appearance that are not observable or minimal in others. Hoarding disorder is persistent difficulty with discarding possessions regardless of actual value. This results in accumulations of materials or items to the degree that it

117 clutters active living areas and impairs functioning. Trichotillomania (hair-pulling disorder) is manifested by recurrent pulling out of one’s hair, producing hair loss. Excoriation (skin-picking disorder) is recurrent skin picking resulting in skin lesions. Substance/medication-induced obsessive–compulsive and related disorder is where obsessions, compulsions, hairpulling, skin-picking, or other body-focused repetitive behaviors result from a medication or drug abuse.2 Amphetamines and cocaine are known to produce obsessive–compulsive symptoms. Methylphenidate has been reported to produce obsessive– compulsive symptoms.6,7 Atypical antipsychotics have also been reported to produce obsessive–compulsive symptoms.8-10 Dopamine agonists, especially agonists of the D3 receptor (eg, ropinirole, pramipexole, and pergolide), have been reported to produce obsessive–compulsive-like behaviors.11 Obsessive–compulsive and related disorder due to another medical condition manifests with obsessions, compulsions, preoccupations with appearance, hoarding, skin-picking, hair-pulling, and other body-focused repetitive behaviors, which is the result of a general medical disorder. Examples of medical illness that may produce obsessive–compulsive symptoms include Sydenham’s chorea and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Obsessive–compulsive symptoms that occur exclusively with delirium are not considered an obsessive–compulsive-related disorder due to another medical condition. Obsessive–compulsive personality disorder (OCPD) consists of a pervasive pattern of preoccupation with orderliness, perfectionism, and mental and interpersonal control to the degree that flexibility, openness, and efficiency are impaired.11 In OCPD, the individual is preoccupied with details, rules, order, lists, organization, or schedules to the extent that the major point of the activity is lost. Individuals with OCPD are overly rigid and stubborn. Unlike OCD, OCPD lacks true obsessions and compulsions.12 The manifestations of OCPD are egosyntonic, the affected individual finds the behavior suitable and correct. The manifestations of OCD are egodystonic, the affected individual finds the behavior inappropriate and stressful. Persons with OCPD usually obtain pleasure with organizing and controlling. Tic disorders and Tourette’s syndrome are a frequent comorbidity with OCD.4,13 Tics are sudden, brief, intermittent, involuntary, or semivoluntary movements or vocal sounds.14 Types of tics include simple motor tics, simple vocal tics, complex motor tics, and complex vocal tics.13,14 Simple motor tics include eye blinking, nose twitching, and head jerking. In theory, any skeletal muscle in the body could produce a tic. Complex tics involve several muscles. Examples of complex motor tics include head shaking, hair brushing, touching, rude gestures, and imitating gestures. Complex motor tics are stereotyped movements. Complex motor tics can be confused with compulsive behaviors.4 Vocal tics are also known as phonic tics. Examples of simple vocal tics include sniffing, throat clearing, grunting, humming, screaming, coughing, and blowing. In theory, any nonword vocal sound can be a vocal tic.15 Normal childhood

118 behavior often involves making various noises. The feature distinguishing tics from normal childhood behavior is the constancy, repetitive, and inappropriateness of the behavior. Complex vocal tics are linguistically meaningful utterances and verbalizations. Complex vocal tics include shorting of obscenities, profanity, repeating one’s own words, or imitating others. A diagnosis of Tourette’s disorder is based on the presence of multiple motor tics and at least 1 vocal tic.13 Over 50% of the patients with Tourette’s syndrome will have significant obsessive–compulsive symptoms and approximately 30% will have a diagnosis of OCD.16 Comorbidity of OCD with psychotic disorders including schizophrenia has been reported. OCD symptoms may occur in 8% to 26% of patients with schizophrenia.17 This comorbidity could represent a subtype of schizophrenia referred to as ‘‘obsessive–compulsive schizophrenia.’’18 Some patients with schizophrenia may have repetitive behavior in response to psychotic ideation.17 Repetitive behavior resulting from a paranoid delusion is not a compulsion. Other psychiatric disorders that can occur with OCD include posttraumatic stress disorder, generalized anxiety disorder, panic disorder, and social phobia. Neurological disorders that can occur with OCD include temporal lobe epilepsy, Huntington’s disease, multiple sclerosis, and possibly Parkinson’s disease.17 Strokes affecting the inferior parietal, basal ganglia, caudate, and/or posterior frontal lobe have been reported to produce OCD symptoms acutely.17 OCD may manifest with sexual obsessions. Conversely, OCD needs to be differentiated from paraphilias. A paraphilia is a condition where the person’s sexual arousal and gratification depend on fanaticizing and engaging in sexual behavior that is atypical and extreme.19 Paraphilias may involve objects or individuals. Alternatively, a paraphilia may revolve around a particular act such as exposing oneself or inflicting pain.20 Examples of paraphilias include voyeurism (peeping on others), exhibitionism (exposure of genitals), frotteurism (touching a nonconsenting individual), sexual masochism (sexual pleasure from pain or humiliation), sexual sadism (sexual pleasure from inflicting pain on others), pedophilia, and severe fetishes. Unlike patients with OCD, individuals with paraphilias obtain pleasure in the act and the main reason to resist the act is because of negative consequences such as criminal prosecution.

Complications of OCD The time consuming and oddness of the compulsions regularly strain social relationships with friends and family members.21 Quality of life and functional impairment occur.19 OCD can result in unemployment.22 Physical injuries can occur from certain rituals such as dermatological conditions from excessive hand washing.23 Criminal justice issues can result from OCD. Case in point, a man with OCD was washing and polishing his neighbors’ automobiles without permission. He was arrested but was later released when he explained to the officers that he had OCD. On his way out the station, he started cleaning the police cars.24 Substance abuse is another complication of

Journal of Pharmacy Practice 27(2) OCD. However, the association between substance abuse and OCD is less robust than with anxiety disorders.25 Suicidal behavior has been reported with OCD.26,27

Neurobiology of OCD Areas of the brain implicated in the pathophysiology include the orbitofrontal cortex, anterior cingulate gyrus, and caudate nucleus.28-30 The basis for this hypothesis is predominately structural and functional imaging studies.28,30 The parietal lobe, superior temporal gyrus, and hippocampus may also be involved in OCD.28,30 The basal ganglia may be the most relevant part of the brain in OCD. The basal ganglia functions in complex integrative motor and behavioral functions such as execution of learned behaviors.31 The basal ganglia is composed of striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, nuclear accumbens, and subthalamic nucleus. Lesions of the basal ganglia have been reported to produce acquired OCD.30,32 The neurotransmitters implicated in OCD include serotonin, dopamine, and glutamate.33-35 This is based on neuroimaging studies as well as pharmacological studies. The effectiveness of selective serotonin reuptake inhibitors (SSRIs) and clomipramine in treating OCD further suggests a role of serotonin in OCD.33,34 The contrasting improvement in or aggravation of OCD symptoms from atypical antipsychotics suggests dopamine and/or serotonin contributes to OCD.8-10 Dopamine agonists and reuptake inhibitors can cause or worsen OCD symptoms.6,7,11 Serotonin is a modulator for dopamine.36 More recent research examined glutamate as a cause of OCD.37 Evidence supporting the role of glutamate in OCD include genetic studies, neurochemical studies, animal models, pharmacological experiments, small clinical studies, and case reports with glutamate-altering drugs.37 Overall, OCD may be due to a malfunction in the cortico–striato–thalamo–cortical circuit in the brain.38-40 A key role for this network is maintaining self-control.

Causes of OCD OCD appears to be a hereditary condition.41 Due to the heterogeneity of the disorder, a single gene is not likely involved in all cases. Candidate genes for OCD include genes affecting serotonin, dopamine, and glutamate. Serotonergic genes include the 5-HTTLPR serotonin transporter, the 5HT1D beta receptor gene, 5HT2a serotonin receptor, and the serotonin 5HT2c receptor.42 Some studies suggest a repeat in the dopamine receptor type 4 (DRD4) gene. The D2 receptor gene has been found to be associated with OCD with tics but not with OCD without tics.42 Genes affecting catechol-O-methyltransferase and monoamine oxidase may be involved in OCD. The most likely glutaminergic gene associated with OCD is SLC1A1, the glutamate transporter gene.37 The SAPAP3 gene, which encodes for the ionotropic glutamate receptors, has been implicated in OCD.37 Other genes that may be involved with OCD include BDNF locus, SLITRK1, gamma-aminobutyric

Bokor and Anderson acid type receptor 1 (GABBR1), OLIG2, and myelin oligodendrocyte glycoprotein.42,43 One hypothesis is that exposure to group A beta hemolytic Streptococcus bacteria (GABHS) may cause some cases of OCD in children. The phrase for this phenomena is Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS).44 When the body is exposed to Streptococcus, antibodies develop. The antibodies then crossreact with nerve tissue including the basal ganglia, a mechanism similar to the cardiac effects produced from rheumatic fever. The onset of OCD or tics is sudden.44 Other symptoms that appear with PANDAS include personality changes, rage episodes, decline in academic performance, deterioration in handwriting, symptoms of attention-deficit hyperactivity disorder (ADHD), excessive sensory stimulation (eg, hypersensitivity to noises, light, etc), and frequent urination which differ from the typical clinical presentation of OCD.44-46 Children with OCD and PANDAS are more likely to have separation anxiety, urinary urgency, oppositional defiant disorder, and mood swings than a child with OCD only. A Streptococcus infection occurs prior to or at the time the OCD symptoms initially occur or abruptly increase in severity with an existing case of OCD. An increase in anti-Streptolysin O antibodies provides clinical evidence of PANDAS in an individual patient. However, no reliable biomarkers are currently available.45 The autoimmunity reaction from the Streptococcus is postulated to cause the OCD.44,45 The OCD is not a direct result from the infection with Streptococcus. The main criticism regarding the concept of PANDAS is the difficulty with documenting an association of a new Streptococcus infection with and exacerbations of tics/OCDlike behavior.45 Another criticism of the PANDAS model is the lack of other features found with rheumatic fever.45 Furthermore, both GABHS infections and OCD are common conditions so that co-occurrence may be a random coincidence.47 Strictly speaking, even if PANDAS is proven, it would not technically be a cause of OCD. Obsessive–compulsive behavior due to a medical condition is classified as obsessive–compulsive and related disorder due to another medical condition by the DSM-5.2 PANDAS has many similarities and many differences from Sydenham Chorea (SC), a neurological disorder of childhood resulting from infection with GABHS. SC consists of rapid, irregular, and aimless involuntary movements of the extremities, trunk, and facial muscles.48 Symptoms of OCD may occur with SC.48 Other manifestations of SC include muscle weakness, incoordination, poor handwriting, and emotional instability.48 The etiology of SC may involve antibodies cross reacting with cellular material in the basal ganglia.47 Certain cases of OCD may be caused by psychological traumatic events.49,50 Fontenelle and colleagues proposed a posttraumatic subtype of OCD.51 Features of posttraumatic subtype of OCD include a higher rate of self-injurious behavior, history of suicide plans, panic disorder with agoraphobia, and compulsive buying.51

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Rating Scales The most common rating scale used in OCD clinical trials is the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). It is a 10-question semistructured questionnaire. Each item of the Y-BOCS has a 5-point scale, ranging from zero to 4. The zero is least symptomatic and 4 being the most symptomatic. The possible total range is from zero to 40. A children’s version of the Y-BOCS is also available. Many clinical trials define a response to pharmacotherapy as a 25% or a 35% reduction in the Y-BOCS score. Other studies only examine the total decrease in score. An individual is still able to have severe symptoms despite a 35% decrease. Other rating scales used for OCD include the National Institute of Mental Health General Obsessive-Compulsive Scale, Maudsley Obsessive-Compulsive Inventory, and the Leyton Obsession Inventory. The clinical global impression scale, severity of illness, and the clinical global impression and improvement are commonly used but are not specific to OCD. Rating scales for measuring depression (eg, Hamilton Depression Rating Scale) and anxiety are also used in OCD clinical trials.

Nonpharmacological Treatment of OCD The most common nonpharmacological treatment of OCD is cognitive behavioral therapy (CBT).52 CBT is a psychotherapeutic approach that addresses dysfunctional emotions, maladaptive behaviors, and cognitive processes through a variety of goal-orientated, explicit procedures. A key element of CBT is to differentiate rational and irrational thoughts as well as change maladaptive thinking. There are many types of CBT, the most effective for OCD is ‘‘Exposure and Response Prevention’’ (ERP).53 The exposure in ERP deals with confronting the images, thoughts, objects, and events that make a person with OCD anxious.52 The ‘‘Response Prevention’’ in ERP refers to selecting an option not to do a compulsive act such as coming into contact with the objects or situations that make a person anxious.52 Numerous studies and meta-analyses support the use of ERP for treating OCD.52 Transcranial magnetic stimulation (TMS) is a procedure that uses magnetic fields to depolarize or hyperpolarize neurons in the brain. TMS has been studied in OCD.54 Two brain areas show promise for improvement in OCD, the supplementary motor area and the orbitofrontal cortex.55 Stimulation of the dorsolateral prefrontal cortex appears to be ineffective for treating OCD.55 A rare but potentially serious adverse reaction to TMS is seizures.56 TMS is not a routine treatment for OCD.53 The literature for electroconvulsive therapy for OCD is limited to case reports.57-60 Brain surgery is a rarely used treatment for refractory OCD.61 Targets for surgical intervention of OCD include the anterior limb of internal capsule, the anterior cingulate gyrus, and nucleus accumbens.61 Deep brain stimulation for treating OCD received the Food and Drug Administration (FDA) approval in 2009 under a humanitarian device

120 exception.62 Deep brain stimulation electrodes are implanted in the anterior limbs of the internal capsule or in the white matter projections from the anterior cingulate. The electrodes are attached to a pulse generator implanted either in the abdomen or near the clavicle.

Pharmacotherapy Selective Serotonin Reuptake Inhibitors The SSRIs are the primary drugs for treating OCD.53,63-65 Paroxetine (Paxil1), sertraline (Zoloft1), fluoxetine (Prozac1), and fluvoxamine (Luvox1) have FDA approval for treating OCD. Citalopram (Celexa1) and escitalopram (Lexapro1) do not have FDA approval for treating OCD.66,67 A Cochrane database analysis confirmed that SSRIs are more effective than placebo for treating OCD.68 No convincing evidence was found that any particular SSRI is more effective than another SSRI with regard to OCD.68 Often, higher doses of SSRIs are needed for treating OCD than depression or anxiety disorders.69 A meta-analysis of dose response found higher doses of SSRI to be more effective in treating OCD than lower doses.70 In addition, the response of OCD is slower than depression so a longer trial of 10 to 12 weeks in duration is needed.71 SSRIs are the best choice for pharmacotherapy of OCD in children and adolescents.72 The first SSRI to be studied in clinical trials for OCD was fluvoxamine. Perse et al conducted a double-blind, placebocontrolled crossover study that was published in 1987.73 Twenty outpatients were studied. All patients received placebo initially for 2 weeks. The subjects then received either placebo or fluvoxamine for 8 weeks. On weeks 11 and 12, all patients received placebo. Patients then received the opposite treatment for the next 8 weeks. Of the 16 subjects, 13 showed improvement. Of the 16 patients, 9 showed major improvement. A crossover study may not be the best design for OCD studies for a variety of reasons. The 2-week washout period may have been adequate for the drug to eliminate from the body but not enough for changes in receptor downregulation. Two years later, Goodman and colleagues published findings from a double-blind, placebo-controlled study with fluvoxamine.74 In all, 21 patients received fluvoxamine and 21 patients received placebo. Fluvoxamine was started at 50 mg every hour of sleep. The dose was increased to 50 mg twice daily after 3 days unless severe side effects were present. After 2 weeks of treatment, the dose could be increased to 50 mg every 3 to 4 days up to a maximum of 300 mg per day. The Y-BOCS and the Clinical Global Impression Scale for Improvement evaluated treatment response. At 6 weeks of treatment, the fluvoxamine group had a decrease in Y-BOCS scores from 25 at baseline to 19.4 at week 6. The placebo group had no significant changes at 6 weeks. A ‘‘responder’’ was defined as ‘‘a score of much improved or very improved on the Clinical Global Impression Severity of Illness item.’’ Partial responders were defined as ‘‘minimally improved’’ and were considered nonresponders. Seven partial responders to fluvoxamine were present at the

Journal of Pharmacy Practice 27(2) 6-week interval. Of the 7 partial responders, 5 became full responders by week 8. None of the partial responders in the placebo group improved from week 6 to week 8. Of the 21 subjects, 9 became responders. Extended-release fluvoxamine was found to increase quality-of-life measures in 12-week, placebo-controlled trial.75 Fluvoxamine was found to be more effective than placebo but less effective than behavioral therapy in a group of Japanese subjects.76 Fluvoxamine demonstrated similar efficacy but superior tolerability over clomipramine in a group of 227 patients.77 A multicenter study also reported comparable effectiveness of fluvoxamine and clomipramine but better tolerability with the former.78 Fluvoxamine has demonstrated effectiveness in children and adolescents with OCD.79 Numerous other studies support the use of fluvoxamine for treating OCD. The effectiveness of fluoxetine in OCD was first documented in open-label trials reported in 1990.80 Placebo-controlled studies were later done to confirm its effectiveness.81 Fluoxetine has FDA approval for treatment of OCD in children over 8 years of age. Published studies also support the use of fluoxetine for younger children with OCD.82,83 Fluoxetine demonstrated comparable efficacy to clomipramine.84 Fluoxetine has an active metabolite, norfluoxetine.85 Fluoxetine is also a potent inhibitor of cytochrome P-450 (CYP) 2D6.85 Numerous clinical trials support the effectiveness of sertraline for OCD.86-88 Sertraline does not have FDA approval for children or adolescents. Clinical studies support the use of sertraline for pediatric OCD.89,90 Paroxetine also works for OCD.91,92 Paroxetine has several disadvantages over other SSRIs. Paroxetine is more likely to cause birth defects and has category D rating by the FDA.93 Paroxetine produces more withdrawal reactions compared to other SSRIs.94 Antimuscarinic activity is greater with paroxetine than with other SSRIs.94 Paroxetine is also a strong inhibitor of CYP 2D6. Citalopram lacks a labeled indication for OCD. A number of studies document the efficacy of citalopram.82,95 Only 1 placebo-controlled study was found with a Medline search.95 Clinical trials include the use of citalopram in combination studies with clomipramine and quetiapine. 96,97 Escitalopram also lacks FDA approval for OCD. Studies of escitalopram are in the literature.98-100 Citalopram and escitalopram have minimal inhibitory activity on the CYP, which is an advantage over other SSRIs.101 Citalopram and escitalopram can produce QTc prolongation, especially in overdose.102 Torsades de pointes is a life-threatening development of a prolonged QTc interval. This promoted FDA to issue a warning letter regarding citalopram, with the key point of not using citalopram in doses above 40 mg.103 Many clinicians disagree with this recommendation.102 Sheeler et al suggest obtaining an electrocardiogram if doses about 40 mg are used. Patients should be accessed for other risk factors for QTc prolongation including bradycardia, hypokalemia, and hypomagnesemia. Interestingly, the FDA has not issued a warning for escitalopram. QTc prolongation has been reported with escitalopram.104-106 The Medicines and Healthcare Products

Bokor and Anderson Regulatory Agency of the United Kingdom issued a warning for both citalopram and escitalopram.107 A retrospective review was conducted on 374 citalopram and 421 escitalopram overdose cases. The study conclusions are that escitalopram is less toxic than citalopram in acute overdose.108 Citalopram overdose does have higher seizure potential than escitalopram overdose.108 Side effects of the SSRIs include nausea, nervousness, dizziness, tiredness, insomnia, reduced sexual drive, erectile dysfunction, weight changes, dry mouth, vomiting, and diarrhea. When starting a patient on an SSRI, the possibility of starting a manic episode needs to be considered. Activation of a manic episode has been reported with the SSRIs.109 Signs of a manic episode include delusions of grandeur, a rapid rate of speech, unusual and excessive happiness, spending sprees, hypersexual behavior, aggression or agitation, and prolonged insomnia without fatigue. A potential complication of SSRI therapy is serotonin syndrome.110 The most common cause of serotonin syndrome is drug interactions. SSRIs are contraindicated with monoamine oxidase inhibitors. Serotonin syndrome can also result from combining SSRIs with lithium, psychostimulants (eg, cocaine and the amphetamines), and dextromorphan.110 Pharmacokinetic interactions can cause serotonin syndrome such as administrating sertraline with erythromycin.111 The serotonin syndrome is characterized by the triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities.111,112 Specific signs and symptoms include agitation, mydriasis, hyperthermia, tachycardia, fluctuating blood pressure, mutism, tremor, muscle rigidity, hyperreflexia, and seizures.112 Leadpipe rigidity of the muscles is more likely to be due to neuroleptic malignant syndrome than serotonin syndrome.112

Clomipramine Clomipramine (Anafranil1) was the first drug to obtain FDA approval for treating OCD. It was developed in the early 1960s by Geigy which is now Novartis.113 Clomipramine is a tricyclic antidepressant with nearly an identical structure to imipramine. A chlorine atom is substituted for hydrogen at position 3 on the ring structure.113 This simple change created a potent inhibitor of serotonin reuptake. Imipramine has minimal serotonin activity. In contrast to SSRIs, clomipramine also inhibits the reuptake of norepinephrine.114 Clomipramine also has dopamine-blocking effects.115 Desmethylclomipramine is the primary metabolite and is active on the norepinephrine transporter.116 The first open-label study of clomipramine was done in the 1960s.117 Clomipramine did not receive FDA approval for OCD until 1989. Meta-analyses suggested that clomipramine is more effective than SSRIs.118,119 Criticisms of the meta-analyses include that clomipramine studies were conducted years earlier than SSRIs.65 Many of the clomipramine studies consisted of treatment-naive patients. Many of the SSRIs included patients with a history of pharmacotherapeutic interventions.65 Headto-head studies of SSRIs and clomipramine have found similar efficacy.77,84

121 Clomipramine has many disadvantages over SSRIs. Clomipramine has the potential for cardiac toxicity including QTc prolongation.120-122 Antimuscarinic side effects are also common with clomipramine and include dry mouth, constipation, urinary retention, and tachycardia.123,124 Another drawback with clomipramine is the potential for orthostatic hypotension.125 Similar to the SSRIs, serotonin syndrome can result from clomipramine.126,127 Due to its dopamine antagonist activity, it has been argued that clomipramine can cause neuroleptic malignant syndrome.126 Clomipramine has the potential to activate a manic episode in patients with underlying bipolar disorder.128 Clomipramine causes greater weight gain than SSRIs.129 The main enzyme involved in clomipramine metabolism is CYP 2D6 so dosage reductions are likely needed for patients receiving potent inhibitors of CYP 2D6 such as paroxetine or fluoxetine. Clomipramine is also metabolized by CYP 2C19.130 Clomipramine is not commercially available as an intravenous formulation in the United States but is available in Europe. Intravenous clomipramine may have a faster onset than oral clomipramine. Onset may be a matter of days rather than weeks.131

Serotonin Norepinephrine Reuptake Inhibitors Serotonin norepinephrine reuptake inhibitors (SNRIs) include venlafaxine, duloxetine, milnacipran, and levomilnacipran. None of the SNRIs have FDA approval for treatment of OCD. Numerous case reports, open-label studies, and 3 controlled double-blind studies support the efficacy of venlafaxine for OCD.132 Albert et al conducted a study comparing clomipramine to venlafaxine.133 The response rate for venlafaxine was 36%, which was less than clomipramine with a response rate of 50%.133 The study only had 13 subjects in each group, therefore strong conclusions cannot be made. Venlafaxine produces a withdrawal syndrome greater than the SSRIs.134 Hypertension is a common adverse reaction to venlafaxine.135,136 Duloxetine has also been used for treating OCD but data are limited to a handful of case reports.137-139 Sansone and Sansone suggest SNRIs may be a reasonable second-line agent after SSRIs.132 Milnacipran (Savella1) is another SNRI. The only labeled indication for milnacipran is fibromyalgia. Data for milnacipran are limited to 1 study in laboratory mice and case reports.132 The latest SNRI to enter the US market is levomilnacipran extended release (Fetzima1). Levomilnacipran is the active enantiomer of the racemic milnacipran and is the most selective of the SNRIs for norepinephrine. It has 17 times the selectivity for norepinephrine compared to venlafaxine and 27 times the selectivity compared to duloxetine.140 The FDA approved levomilnacipran for major depressive disorder. To the best of our knowledge, no studies have been done for levomilnacipran for OCD.

Augmentation Therapy The percentage of responders in placebo-controlled studies is typically 40% to 60%.141 As discussed earlier, a decrease in

122 25% to 35% in the Y-BOCS is often used to define a response to treatment. Even with a 35% response rate, the patient may have remaining significant symptoms. Treatment resistance can be defined as failed a single trial of a serotonin reuptake inhibitor and treatment refractory can be defined as having failed 2 adequate trials of serotonin reuptake inhibitors.141 Readers should bear in mind that definitions of treatment resistance and treatment refractory vary from study to study. Treatment options for resistant OCD include combining an SSRI with clomipramine.141 Other options include adding pindolol, mirtazapine, lithium, buspirone, and antipsychotics to an SSRI. Haloperidol was studied in a placebo-controlled study in patients with fluvoxamine-refractory OCD.142 Subjects were titrated to a dose of 300 mg/d of fluvoxamine and received this dose for 7 weeks. Patients were considered refractory to fluvoxamine by an improvement of less than 35% in the Y-BOCS and or a total score of 16. The refractory patients were entered into either the placebo or the haloperidol arm. Haloperidol was started at 2 mg/d for 3 days. The dose was increased by 2 mg every 3 days to a maximum of 10 mg. Benztropine was administered for prophylaxis of extrapyramidal symptoms. A statistical significant difference was shown after 4 weeks of therapy with haloperidol. Tics as a comorbidity was shown to be predictor of positive response to haloperidol. More studies have evaluated the use of atypical antipsychotics (second generation) than typical antipsychotics (first generation). A number of studies have examined risperidone (Risperdal1) for augmentation therapy of OCD.143-145 Risperidone was found to be more effective than aripiprazole in a group of 41 patients resistant to SSRIs.144 Risperidone demonstrated comparable effectiveness to olanzapine in a group of 91 patients.145 Positron emission tomography revealed that improvement from risperidone was associated with increased metabolic activity in the striatum, cingulated gyrus, and in the orbital region of the prefrontal cortex.146 Only 2 placebocontrolled studies support the use of risperidone as an augmenting agent for OCD.147,148 Risperidone was compared to exposure and ritual prevention therapy as augmentation therapy for OCD. Exposure and ritual prevention therapy was found to be more effective than risperidone.149 A pilot trial of paliperidone, an active metabolite of risperidone, did not show statistical difference compared to placebo in treatment of resistant OCD.150 Olanzapine (Zyprexa1) has also been studied as a treatment for OCD. Olanzapine has been compared to placebo conducted at the Neuropsychiatric Institute and Hospital.150 Olanzapine could be dosed up to 20 mg but the average dose was 11.2 mg. Of the 13 subjects in the olanzapine group, 6 have a 25% reduction in the Y-BOCS score. Limitations include a small patient group and a short duration of 6 weeks. A 6-week, placebo-controlled trial of olanzapine add-on therapy to fluoxetine was conducted at the University of Florida.151 Subjects first received an open-label trial of fluoxetine for 8 weeks. Partial or nonresponders received olanzapine of up to 10 mg per day. Olanzapine demonstrated no benefit over

Journal of Pharmacy Practice 27(2) placebo. The fluoxetine regimen was limited to 40 mg per day, and the olanzapine dose was limited to 10 mg a day. Earlier open-label studies were conducted with olanzapine. Weiss et al had a mean dose of 7.3 mg of olanzapine per day.152 Common complaints with olanzapine include sedation and weight gain.150,152 Potential long-term effects of olanzapine include metabolic abnormalities such as elevated triglycerides and glucose (including type 2 diabetes mellitus). To varying degrees metabolic effects occur with other second-generation antipsychotics. Korton et al conducted a placebo-controlled study of quetiapine (Seroquel1) augmentation therapy to serotonin reuptake inhibitors.153 Patients received serotonin reuptake inhibitor for at least 12 weeks. Subjects then received up to 400 mg of quetiapine for 6 weeks. The quetiapine dose could be increased to 600 mg for the next 6 weeks. Quetiapine showed no benefit over placebo. The study was limited to 40 patients. An earlier placebo-controlled study by Fineberg and colleagues did not find a statistically significant difference between quetiapine and placebo.154 Furthermore, quetiapine demonstrated no benefits over placebo in another study.155 Only 1 study with placebo comparison found quetiapine to be effective.156 Quetiapine was found to be more effective than clomipramine for add-on therapy in patients with inadequate response to SSRIs.157 This study was limited to 10 patients with clomipramine and 11 with quetiapine. Ziprasidone (Geodon1) was introduced in 2001.158 No placebo-controlled studies of ziprasidone were found with a Medline search. A retrospective analysis was done comparing ziprasidone to quetiapine in OCD.159 The review included 15 patients on quetiapine and 9 with ziprasidone. Quetiapine was found more effective than ziprasidone. Two placebo-controlled studies found aripiprazole (Abilify1) more effective than placebo.160,161 Risperidone was found to be more effective than aripiprazole in head-to-head study of 23 patients.144 Other open-label studies support the use of aripiprazole for OCD.162 Clozapine (Clozaril1) is not effective for treating OCD.163 Clozapine has been reported to induce obsessive–compulsive symptoms.8,164 Interestingly, olanzapine, aripiprazole, paliperidone, and quetiapine have also been reported to cause OCD symptoms.9,10,165-167 No literature was found for iloperidone (Fanapt1), lurasidone (Latuda1), or asenapine (Saphris1) either as a treatment of or as a cause of OCD. The apparently opposite effects from atypical antipsychotics in different patients further document the heterogeneity of OCD. Case reports from the 1980s suggested that lithium is effective for refractory OCD.168 However, these reports were before serotonergic drugs became available. A controlled study on lithium augmentation versus placebo found no benefit of lithium.169 Pindolol (Visken1) is a nonselective beta blocker with partial agonist activity at the beta receptors. Pindolol has been used as an augmentation agent for OCD.170 One placebocontrolled, double-blind study found pindolol more effective than placebo for patients refractory to paroxetine.170

Bokor and Anderson

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Table 3. American Psychiatric Association (APA) Practice Guidelines: Obsessive–Compulsive Disorder, Key Points. First-line treatment of OCD is either a CBT or an SSRI CBT, consisting of exposure and response prevention, is recommended for a patient who lacks major depression, anxiety, and is not too severely impaired to cooperate with the treatment actions If psychotherapy is tried first, then it should involve exposure and response prevention If pharmacotherapy is tried first then an SSRI should be used before clomipramine Higher doses of SSRIs than the maximum doses listed in the package insert may be needed for some patients Patients with a partial response to an SSRI can be considered for augmentation therapy such as combining an SSRI with antipsychotics or combining CBT with an SSRI Patients with no response to an SSRI then a trial of different SSRI can be considered For cases that do not respond to SSRIs with antipsychotics then augmentation of SSRIs with clomipramine, buspirone, pindolol, riluzole, or once weekly morphine sulfate Successful medication treatment should be continued for 1 to 2 years before considering a gradual taper. This taper should be 10% to 25% every 1 or 2 months Abbreviations: CBT, cognitive behavioral therapy; OCD, obsessive–compulsive disorder; SSRIs, selective serotonin reuptake inhibitors.

Preliminary studies suggest 5-HT3 antagonists may be an effective augmentation agent for OCD.171 A single blind study used ondansetron (Zofran1) as augmentation for patients that failed a prior regimen of SSRIs and antipsychotics. Of the 14 patients, 9 experienced a greater than 25% reduction in the Y-BOCS rating scale.171 Granisetron (Kytril1) was investigated as add-on therapy for fluvoxamine.172 A study compared 20 subjects with placebo to 19 subjects with granisetron for patients not responding to fluvoxamine. A response (ie, >25% reduction in Y-BOCS scores) was seen after 6 weeks in 100% of the granisetron group and 35% in the placebo group. An open-label study consisting of ondansetron as monotherapy for OCD reported that 3 of the 6 patients received a 35% or greater improvement in the Y-BOCS scores.173 Two studies examined the addition of buspirone (BuSpar1) to SSRIs in the treatment of OCD.174,175 Both studies had only 14 patients. Neither study found buspirone effective compared to placebo. Another small study found buspirone ineffective as adjuvant therapy to clomipramine.176 However, there may be isolated cases where patients do respond to buspirone.177 Data with mirtazapine (Remeron1) as a treatment for OCD are limited. One study found mirtazapine speeds up the time period to response with citalopram.178 However, this study included mirtazapine at the initiation of citalopram rather than studying treatment nonresponders to citalopram. After 12 weeks, mirtazapine provided no additional benefit to citalopram. An open-label study showed some efficacy of mirtazapine as monotherapy for OCD.179 In summary, there is no compelling evidence to support a drug of choice for refractory OCD. However, there is more evidence with certain atypical antipsychotics than other classes.

Glutamate Antagonists Glutamate may play a role in the pathophysiology of OCD.37 This led to research on glutamate antagonists as a potential treatment of OCD including as monotherapy and add-on therapy. An open-label study found riluzole (Rilutek1), a glutamate antagonist, effective for OCD in children.180 Another open-label study reported riluzole effective as augmentation therapy.181 A clinical

trial is currently investigating riluzole compared to placebo as add-on therapy for serotonin reuptake inhibitors.182 A small placebo-controlled study found that lamotrigine (Lamictal1) augmentation of serotonin reuptake inhibitors reduced OCD symptoms.183 Lamotrigine is an anticonvulsant that inhibits the release of glutamate. Ketamine (Ketalar1) has been studied as a treatment for OCD but should be considered for research interest rather than clinical interest at this point.184,185

Practice Guidelines for OCD The American Psychiatric Association has a series of practice guidelines for treating OCD in adults.186 The highlights of the guidelines are given in Table 3. The American Academy of Child and Adolescent Psychiatry (AACAP) developed practice guidelines for treating OCD in pediatric patients.187 One major difference between the adult and the pediatric guidelines is that CBT is preferred over pharmacotherapy in children and adolescents with mild to moderate OCD.187 The AACAP has stronger language to discourage the use of clomipramine over SSRIs for treating OCD. The AACAP guidelines specifically address comorbid OCD and ADHD. When both OCD and ADHD are present, the OCD should be treated first. Obsessions impair attention, and treatment of OCD may improve attention.187 Furthermore, psychostimulants may exacerbate obsessions.187 The AACAP deemphasizes augmentation therapy with the exception of combining psychotherapy with SSRIs.

Measurement of Outcomes Ideally, outcomes should be measured with a rating scale such as the Y-BOCS. Other measurements of outcomes include occupational functioning and a decrease in OCD-related physical illness (eg, skin conditions secondarily to excessive cleaning). Side effects of medications should also be assessed.

Conclusions The heterogeneity of OCD includes themes of obsessions, types of rituals, presence or absence of tics, etiology, genetics,

124 and response to pharmacotherapy. Complications of OCD include interpersonal difficulties, physical injuries, unemployment, criminal justice issues, substance abuse, and suicide. In adults, both SSRIs and CBT (ERP) are first-line treatments. Children with mild to moderate OCD are best treated with CBT. The SSRIs are generally the preferred pharmacotherapy in both adults and pediatric patients. Higher doses and a longer duration trial of 12 weeks may be needed with SSRIs when treating OCD compared to other psychiatric disorders. No clear choice exists for augmentation pharmacotherapy. More data exist with atypical antipsychotics than other drugs. In extreme cases, surgery may be warranted as a treatment for OCD. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Anderson owns stock in Abbott Laboratories.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References 1. International OCD Foundation. What is OCD or ObsessiveCompulsive Disorder? http://www.ocfoundation.org/whatisocd. aspx?gclid¼CPvXtML3yLoCFQyZ4Aod_gEAOQ. Accessed November 3, 2013. 2. American Psychiatric Association. Obsessive-Compulsive and Related Disorders. Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Washington, DC: American Psychiatric Association; 2013; 235-264. 3. National Institute of Mental Health. Obsessive Compulsive Disorder Among Adults. http://www.nimh.nih.gov/statistics/1ocd_ adult.shtml. Accessed November 13, 2013. 4. American Psychiatric Association. Anxiety Disorders. Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC: American Psychiatric Association; 1994; 393-444. 5. American Psychiatric Association. Highlights of Changes from DSM-IV-TR to DSMS-5. http://www.dsm5.org/Documents/cha nges%20from%20dsm-iv-tr%20to%20dsm-5.pdf. Accessed November 3, 2013. 6. Kouris S. Methylphenidate-induced obsessive-compulsiveness. J Am Acad Child Adolesc Psychiatry. 1998;37(2):135. 7. Serby M. Methylphenidate-induced obsessive-compulsive symptoms in an elderly man. CNS Spectr. 2003;8(8):612-613. 8. Lemke NT, Bustillo JR. Clozapine-induced obsessive-compulsive symptoms in bipolar disorder. Am J Psychiatry. 2013;170(8):930. 9. Kulkarni G, Narayanaswamy JC, Math SB. Olanzapine induced de-novo obsessive compulsive disorder in a patient with schizophrenia. Indian J Pharmacol. 2012;44(5):649-650. 10. Desarkar P, Das A, Nizamie SH. Aripiprazole-induced obsessivecompulsive disorder: a report of 2 cases. J Clin Psychopharmacol. 2007;27(3):305-306. 11. Kelley BJ, Duker AP, Chiu P. Dopamine agonists and pathologic behaviors. Parkinson Dis. 2012;2012:603631. doi:10:1155/2012/ 603631

Journal of Pharmacy Practice 27(2) 12. American Psychiatric Association. Personality Disorders. Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Washington, DC: American Psychiatric Association; 2013; 645-684. 13. American Psychiatric Association. Neurodevelopmental disorders. Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Washington, DC: American Psychiatric Association; 2013;31-86. 14. Jankovic J. Tourette’s syndrome. N Engl J Med. 2001;345(16): 1184-1192. 15. Comings DE.Vocal Tics. Tourette Syndrome and Human Behavior. Duarte, CA: Hope Press; 1990;17-18. 16. Lombroso PJ, Seahill L. Tourette Syndrome and obsessivecompulsive disorder. Brain Dev. 2008;30(4):231-237. 17. Pallanti S, Grassi G, Sarrechia ED. Obsessive-compulsive disorder comorbidity: clinical assessment and therapeutic implications. Front Psychiatry. 2011;70(2):1-11. 18. Berman I. Is there a subtype of obsessive-compulsive schizophrenia. Psychiatric Annals. 1999;29(9):506. 19. Anonymous. Paraphilias. http://www.psychologytoday.com/conditions/paraphilias. Accessed November 20, 2013. 20. American Psychiatric Association. Paraphilic Disorders. Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Washington, DC: American Psychiatric Association; 2013: 685-705. 21. Huppert JD, Simpson HB, Nissenson KJ, Liebowitz MR, Foa EB. Quality of life and functional impairment in obsessivecompulsive disorder: a comparison of patients with and without comorbidity, patients in remission, and healthy controls. Depress Anxiety. 2009;26(1):39-45. 22. Rodriguez Salgado B, Dolengevich Segal H, Arrojo Romero M, et al. Perceived quality of life in obsessive-compulsive disorder: related factors. BMC Psychiatry. 2006;6:20. 23. Kestenbaum T. Obsessive-compulsive disorder in dermatology. Semin Cutan Med Surg. 2013;32(2):83-87. 24. Griffiths J. OCD Taiwanese man arrested for cleaning his neighbors’ cars. http://shanghaiist.com/2013/09/09/ocd_taiwanese_ man_ arrested_for_cleaning_his_neighbours_cars.php. Accessed November 5, 2013. 25. Brady KT, Haynes LF, Hartwell KJ, Killeen TK. Substance use disorders and anxiety: a treatment challenge for social workers. Soc Work Public Health. 2013;28(3-4):407-423. 26. Torres AR, Ramos-Cerqueira AT, Ferrao YA, Fontenelle LF, do Rosa´rio MC, Miguel EC. Suicidality in obsessive-compulsive disorder: prevalence and relation to symptom dimensions and comorbid conditions. J Clin Psychiatry. 2011;72(1):17-26. 27. Kamath P, Reddy YC, Kandavel T. Suicidal behavior in obsessive-compulsive disorder. J Clin Psychiatry. 2007;68(11): 1741-1750. 28. Laven DL, Bednardczyk EM. CNS assessment using functional neuro-PET imaging. J Pharm Pract. 2001;14(4): 308-331. 29. Graybriel AM, Rauch SL. Toward a neurobiology of obsessivecompulsive disorder. Neuron. 2000;28(2):343-347. 30. Maia TV, Cooney RE, Peterson BS. The neural bases of obsessive-compulsive disorder in children and adults. Dev Psychopath. 2008;20(4):1251-1283.

Bokor and Anderson 31. Sbordone RJ, Saul RE. Neuroanatomy. Neuropsychology for Healthcare Professionals and Attorneys 2nd edition. New York: CRC Press; 2000:35-54. 32. Chacko RC, Corbin MA, Harper RG. Acquired obsessivecompulsive disorder associated with basal ganglia lesions. J Neuropsychiatry Clin Neurosci. 2000;12(2):269-272. 33. Billett EA, Richter MA, King N, Heils A, Lesch KP, Kennedy JL. Obsessive-compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Mole Psychiatry. 1997;2(5):403-406. 34. Hesse S, Muller U, Lincke T, et al. Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder. Psychiatry Res. 2005;140(1):63-72. 35. Nemoda Z, Szekely A, Sasvari-Szekely M. Psychopathological aspects of dopaminergic gene polymorphisms in adolescence and young adulthood. Neurosci Biobehav Rev. 2011;35(8): 1665-1686. 36. Olijglagers JE, Werkman TR, Wadman WJ. Modulation of midbrain dopamine neurotransmission by serotonin, a versatile interaction between neurotransmitters and significant for antipsychotic drug action. Curr Neuropharmacol. 2006;4(1):59-68. 37. Pittenger C, Bloch MH, Williams K. Glutamate abnormalities in obsessive compulsive disorder,: neurobiology, pathophysiology, and treatment. Pharmacol Ther. 2011;132(3):314-332. 38. Marsh R, Maia TV, Peterson BS. Functional disturbances within frontostriatal circuits across multiple childhood psychopathologies. Am J Psychiatry. 2009;166(6):664-674. 39. Ahmari SE, Spellman T, Douglass NL, et al. Repeated corticostriatal stimulation generates persistent OCD-like behavior. Science. 2013;340(6137):1234-1239. 40. Welch JM, Lu J, Rodriguiz RM, et al. Cortico-striatal synaptic defects and OCD-like behaviors in SAPAP3 mutant mice. Nature. 2007;448(7156):894-900. 41. Mataix-Cols D, Boman M, Monzani B, et al. Population-based, multigenerational family clustering study of obsessive-compulsive disorder. JAMA Psychiatry. 2013;70(7):709-717. 42. Nestadt G, Grados M, Samuels JF. Genetics of OCD. Psychiatr Clin North Am. 2010;33(1):141-158. 43. Ozomaro U, Cai G, Kajiwara Y, et al. Characterization of SLITRK1 variation in obsessive-compulsive disorder. PLoS One. 2013;8(8):e70376. 44. National Institutes of Health. PANDAS: Frequently Asked Questions about Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. http://www.nimh.nih. gov/health/publications/pandas/index.shtml. Accessed November 29, 2013. 45. Macerollo A, Martino D. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an evolving concept. Tremor Other Hyperkinet Mov (NY). 2013; 3. http://tremorjournal.org/article/167. Accessed November 29, 2013. 46. Bernstein GA, Victor AM, Pipal AJ, Williams KA. Comparison of clinical characteristics of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and childhood obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2010;20(4):333-340.

125 47. Snider LA, Swedo SE. PANDAS: current status and directions for research. Mol Psychiatry. 2004;9(10):900-907. 48. National Institute of Neurological Disorders and Stroke. NINDS Sydenham Chorea Information Page. http://www.ninds.nih.gov/ disorders/sydenham/sydenham.htm. Accessed November 29, 2013. 49. Lafleur DL, Petty C, Mancuso E, et al. Traumatic events and obsessive compulsive disorder in children and adolescents: is there a link? J Anxiety Disord. 2011;25(4):513-519. 50. Sasson Y, Dekel S, Nacasch N, et al. Posttraumatic obsessivecompulsive disorder: a case series. Psychiatry Res. 2005;135(2): 145-152. 51. Fontenelle LF, Cocchi L, Harrison BJ, et al. Towards a posttraumatic subtype of obsessive-compulsive disorder. J Anxiety Disord. 2012;26(2):377-383. 52. International OCD Foundation. Cognitive Behavior Therapy (CBT) http://www.ocfoundation.org/cbt.aspx. Accessed November 29, 2013. 53. Marazziti D, Picchetti M, Baroni S, Ceresoli D, Consoli G, Catena Dell’Osso M. Current pharmacological and non pharmacological treatments for obsessive-compulsive disorder. J Psychopathology. 2012;18(1):5-18. 54. Greenberg BD, George MS, Martin JD, et al. Effect of prefrontal repetitive transcranial magnetic stimulation in obsessivecompulsive disorder: a preliminary study. Am J Psychiatry. 1997;154(6):867-669. 55. Jaafari N, Rachid F, Rotge JY, et al. Safety and efficacy of repetitive transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder: a review. World J Biol Psychiatry. 2012;13(3):164-177. 56. Aleman A. Use of repetitive transcranial magnetic stimulation for treatment in psychiatry. Clin Psychopharmacol Neurosci. 2013; 11(2):53-59. 57. Bulbu F, Copoglu US, Alpak G, Unal A, Tastan MF, Savas HA. Maintenance therapy with electroconvulsive therapy in a patient with a codiagnosis of bipolar disorder and obsessivecompulsive disorder. J ECT. 2013;29(2):e21-e22. 58. Hanisch F, Friedemann J, Piro J, Gutmann P. Maintenance electroconvulsive therapy for comorbid pharmacotherapyrefractory obsessive-compulsive and schizoaffective disorder. Eur J Med Res. 2009;14(8):367-368. 59. Strassnig M, Riedel M, Muller N. Electroconvulsive therapy in patient with Tourette’s syndrome and co-morbid obsessive compulsive disorder. World J Biol Psychiatry. 2004;5(3):164-166. 60. Casey DA, Davis MH. Obsessive-compulsive disorder responsive to electroconvulsive therapy in an elderly woman. South Med J. 1994;87(8):862-864. 61. Heeramun-Aubeeluck A, Lu Z. Neurosurgery for mental disorders: a review. Afr J Psychiatry. 2013;16(3):177-181. 62. Food and Drug Administration. FDA Approves Humanitarian Device Exemption for Deep Brain Stimulator for Severe Obsessive-Compulsive Disorder. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149529.htm. Accessed November 29, 2013. 63. Stein DJ. Obsessive-compulsive disorder. Lancet. 2002:360(9330): 397-405.

126 64. Johnson C, Blair-West S. Obsessive-compulsive disorder: the role of the GP. Aust Fam Physician. 2013:42(9):606-609. 65. Decloedt EH, Stein DJ. Current trends in drug treatment of obsessive-compulsive disorder. Neuropsychiatr Dis Treat. 2010;6: 233-242. 66. Forest Laboratories. Package Insert Celexa. http://www.frx.com/ pi/celexa_pi.pdf. Accessed November 30, 2013. 67. Forest Laboratories. Package Insert Lexapro. http://www.frx. com/pi/lexapro_pi.pdf. Accessed November 30, 2013. 68. Soomro GM, Altman D, Rajagopal S, Oakley-Browne M. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive-compulsive disorder (OCD). Cochrane Database Syst Rev. 2008;23(1):CD001765. Doi: 10.1002/14651858.pub3. 69. Kellner M. Drug treatment f obsessive-compulsive disorder. Dialogues Clin Neurosci. 2010;12(2):187-197. 70. Bloch MH, McGuire J, Landeros-Weisenberger A, Leckman JF, Pittenger C. Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder. Mol Psychiatry. 2010; 15(8):850-855. 71. Pittenger C, Kelmendi B, Bloch M, Krystal JH, Coric V. Clinical treatment of obsessive compulsive disorder. Psychiatry. 2005; 2(11):34-43. 72. Williams Js, Moore T, Collins CL, Thomas KA. Selective serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder in children and adolescents. J Pediatr Pharmacol Ther. 2003;8(3):177-186. 73. Perse TL, Greist JH, Jefferson JW, Rosenfeld R, Dar R. Fluvoxamine treatment of obsessive-compulsive disorder. Am J Psychiatry. 1987;144(12):1543-1548. 74. Goodman WK, Price LH, Rasmussen SA, Delgado PL, Heninger GR, Charney DS. Efficacy of fluvoxamine in obsessive-compulsive disorder: a double-blind comparison with placebo. Arch Gen Psychiatry. 1989;46(1):36-44. 75. Koran LM, Bromberg D, Hornfeldt CS, Shepski JC, Wang S, Hollander E. Extended-release fluvoxamine and improvements in quality of life in patients with obsessive-compulsive disorder. Compr Psychiatry. 2010:51(4):373-379. 76. Nakatani E, Nakagawa A, Nakao T, et al. A randomized controlled trial of Japanese patients with obsessive-compulsive disorder—effectiveness of behavior therapy and fluvoxamine. Psychother Psychosom. 2005;74(5):269-276. 77. Mundo E, Rouillon F, Figuera ML, Stigler M. Fluvoxamine in obsessive-compulsive disorder: similar efficacy but superior tolerability in comparison with clomipramine. Hum Psychopharmacol. 2001;16(6):461-468. 78. Mundo E, Maina G, Uslengi C. Multicentre, double-blind, comparison of fluvoxamine and clomipramine in the treatment of obsessive-compulsive disorder. Int Clin Psychopharmacol. 2000;15(2):69-76. 79. Riddle MA, Reeve EA, Yaryura-Tobias JA, et al. Fluvoxamine for children and adolescents with obsessive-compulsive disorder: a randomized, controlled, multicenter trial. J Am Acad Child Adolesc Psychiatry. 2001;40(2):222-229. 80. Jenike MA, Buttolph L, Baer L, Ricciardi J, Holland A. Open trial of fluoxetine in obsessive-compulsive disorder. Am J Psychiatry. 1989;146(7):909-911.

Journal of Pharmacy Practice 27(2) 81. Jenike MA, Baer L, Minichiello WE, Rauch SL, Buttolph ML. Placebo-controlled trial of fluoxetine and phenelzine for obsessivecompulsive disorder. Am J Psychiatry. 1997;154(9):1261-1264. 82. Alaghband-Rad J, Hakimshooshtary M. A randomized controlled clinical trial of citalopram versus fluoxetine in children and adolescents with obsessive-compulsive disorder (OCD). Eur Child Adolesc Psychiatry. 2009;18(3):131-135. 83. Geller DA, Biederman J, Reed ED, Spencer T, Wilens TE. Similarities of response to fluoxetine in the treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 1995;34(1):36-44. 84. Lopez-Ilbor JJ, Saiz J, Cottraux J, et al. Double-blind comparison of fluoxetine versus clomipramine in the treatment of obsessivecompulsive disorder. Eur Neuropsychopharmacol. 1996;6(2): 111-118. 85. Mandrioli, Forti GC, Raggi MA. Fluoxetine metabolism and pharmacological interactions: the role of cytochrome p450. Curr Drug Metab. 2006;7(2):127-133. 86. Chouinard G, Goodman W, Greist J, et al. Results of a doubleblind placebo controlled trial of a new serotonin uptake inhibitor, sertraline, in the treatment of obsessive-compulsive disorder. Psychopharmacol Bull. 1990;26(3):279-284. 87. Hoeh-Saric R, Ninan P, Black DW, et al. Multicenter doubleblind comparison of sertraline and desipramine for concurrent obsessive-compulsive and major depressive disorders. Arch Gen Psychiatry. 2000;57(1):76-82. 88. Kronig MH, Apter J, Asnis G, et al. Placebo-controlled, multicenter study of sertraline treatment for obsessive-compulsive disorder. J Clin Psychopharm. 1999;19(2):171-176. 89. Cook EH, Wagner KD, March JS, et al. Long-term sertraline treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2001;40(10):1175-1181. 90. March JS, Biederman J, Wolkow R, et al. Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA. 1998;280(20):1752-1756. 91. Zohar J, Judge R. Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. Br J Psychiatry. 1996; 169(4):468-474. 92. Hollander E, Allen A, Steiner M, et al. Acute and long-term treatment and prevention of relapse of obsessive-compulsive disorder with paroxetine. J Clin Psychiatry. 2003;64(9):1113-1121. 93. Budenholzer B. Paroxetine use should be avoided during pregnancy. Am Fam Physician. 2012;85(8):747. 94. Renoir T. Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. Front Pharmcol. 2013;4:1-10. 95. Montgomery SA, Kasper S, Stein DJ, Bang Hedegaard K, Lemming OM. Citalopram 20mg, 40mg and 60mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2001;16(2):75-86. 96. Marrazziti D, Golia F, Consoli G, et al. Effectiveness of long-term augmentation with citalopram to clomipramine in treatmentresistant OCD patients. CNS Spectr. 2008;13(11):971-976. 97. Vulink NC, Denys D, Fluitman SB, Meinardi JC, Westenberg HG. Quetiapine augments the effect of citalopram in non-refractory

Bokor and Anderson

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110. 111. 112. 113.

obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled study of 76 patients. J Clin Psychiatry. 2009; 70(7):1001-1008. Khan MN, Hotiana UA, Ahmad S. Escitalopram in the treatment of obsessive-compulsive disorder: a double blind placebo control trial. J Avub Med Coll Abbottabad. 2007;19(4):58-63. Stein DJ, Carey PD, Lochner C, Seedat S, Fineberg N, Andersen EW. Escitalopram in obsessive-compulsive disorder: response of symptom dimensions to pharmacotherapy. CNS Spectr. 2008;13(6):492-498. Stein DJ, Andersen EW, Tonnoir B, Fineberg N. Escitalopram in obsessive-compulsive disorder: a randomized, placebocontrolled, paroxetine-referenced, fixed-dose, 24 week study. Curr Med Res Opin. 2007;23(4):701-711. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3(1):13-37. Sheeler RD, Ackerman, Richelson E, et al. Considerations on safety concerns about citalopram prescribing. Mayo Clin Proc. 2012;87(11):1042-1045. Food and Drug Administration. Abnormal Heart rhythms associated with high doses of Celaxa (citalopram hydrobromide). http://www.fda.gov/drugs/drugsafety/ucm269086.htm. Accessed December 1, 2013. Mohammed R, Norton J, Geraci SA, Newman DB, Koch CA. Prolonged QTc interval due to escitalopram overdose. J Miss State Med Assoc. 2010;51(12):350-353. Schreffler SM, Marraffa JM, Stork CM, Mackey J. Sodium channel blockade with QRS widening after an escitalopram overdose. Pediatr Emerg Care. 2013;29(9):998-1001. Tseng PT, Lee Y, Lin YE, Lin PY. Low-dose escitalopram for 2 days associated with corrected QT interval prolongation in a middle-aged woman: a case report and literature review. Gen Hosp Psychiatry. 2012;34(2):210.e13-e15. Medicines and Health Care Products Regulatory Agency. Citalopram and Escitalopram: QT Interval Prolongation- new maximum dose restrictions (including elderly patients) contraindications, and warnings. http://www.mhra.gov.uk/Safetyinfor mation/DrugSafetyUpdate/CON137769. Accessed December 1, 2013. Hayes BD, Klein-Schwartz W, Clark RF, Muller AA, Miloradovich JE. Comparison of toxicity of acute overdoses with citalopram and escitalopram. J Emerg Med. 2010;39(1):44-48. Chen J, Fang Y, Kemp DE, Calabrese JR, Gao K. Switching to hypomania and mania: differential neurochemical, neuropsychological, and pharmacologic triggers and their mechanisms. Curr Psychiatry Rep. 2010;12(6):512-521. Anderson PD. Forensic aspects of drug interactions, part II. Forensic Examiner. 1999;8(11-12);13-16. Ables AZ, Nagubilli R. Prevention, diagnosis, and management of serotonin syndrome. Am Fam Physician. 2010;81(9):1139-1142. Martin TG. Serotonin Syndrome. Ann Emerg Med. 1996;28(5): 520-526. The database and ontology of chemical entities of biological interest. http://www.ebi.ac.uk/chebi/searchId.do?chebiId¼CHEBI: 47780. Accessed December 1, 2013.

127 114. Thase ME. Are SNRIs more effective than SSRIs? a review of the current state of the controversy. Psychopharmacol Bull. 2008;41(2):58-85. 115. Austin LS, Lydiard RB, Ballenger, et al. Dopamine blocking activity of clomipramine in patients with obsessive-compulsive disorder. Biol Psychiatry. 1991;30(3):225-232. 116. Takano A, Nag S, Gulyas B, Halldin C, Farde L. NET occupancy by clomipramine and its active metabolite desmethylclomipramine, in non-human primates in vivo. Psychopharmacology(Berl). 2011;216(2):279-286. 117. Philpott R. The assessment of drugs in obsessional states. Br J Clin Pharmaco. 1976;3(1 suppl 1):91-95. 118. Ackerman DL, Greenland S. Multivariate meta-analysis of controlled drug studies for obsessive-compulsive disorder. J Clin Psychopharmacol. 2002;22(3):309-317. 119. Greist JH, Jefferson JW, Kobak KA, Katzelnick DJ, Serlin RC. Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder: a meta-analysis. Arch Gen Psychiatry. 1995;52(1):53-60. 120. Leonard HL, Meyer MC, Swedo SE, et al. Electrcardiographic changes during desipramine and clomipramine treatment in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1995;34(11):1460-1468. 121. Singh G. Cardiac arrest with clomipramine. Br Med J. 1972; 3(5828):698. 122. Jo SH, Hong HK, Chong SH, et al. Clomipramine block of the hERG Kþ channel: accessibility to F656 and Y652. Eur J Pharmacol. 2008;592(1-3):19-25. 123. Kristensen E, Jakobsen J, Bartels U, Vestergaard P. Cholinergic dysfunction of the heart, pupil, salivary glands, and urinary bladder in healthy volunteers during long-term treatment with clomipramine. Psychopharmacology. 1989;98(3):398-402. 124. Dick P, Ferroro E. A double-blind comparative study of the clinical efficacy of fluvoxamine and chlorimipramine. Br J Clin Pharmacol. 1983;15 supp 3:419S-425S. 125. Ottevanger EA. Fluvoxamine and clomipramine in depressed hospitalised patients: results from a randomised, double-blind study. Encephale. 1995;21(4):317-321. 126. Isbister GK, Buckley NA. Clomipramine and neuroleptic malignant syndrome. BMJ. 2005;330(7494):790-791. 127. Spigset O, Mjorndal T, Lovheim O. Serotonin syndrome caused by a moclobemide-clomipramine interaction. BMJ. 1993; 306(6872):248. 128. Sathyanarayana V, Khanna S, Channabasvanna SM. Clomipramine induced mania. Indian J Psychiatry. 1991;33(3):206-211. 129. Maina G, Albert U, Salvi V, Bogetto F. Weight gain during longterm treatment of obsessive-compulsive disorder: a prospective comparison between serotonin reuptake inhibitors. J Clin Psychiatry. 2004;65(10):1365-1371. 130. Hicks JK, Swen JJ, Thorn CF, et al. Clinical pharmacogenetics implementation consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013;93(5):402-408. 131. Koran LM, Sallee FR, Pallanti S. Rapid benefit of intravenous pulse loading of clomipramine in obsessive-compulsive disorder. Am J Psychiatry. 1997;154(3):396-401.

128 132. Sansone RA, Sansone LA. SNRIs pharmacological alternatives for the treatment of obsessive-compulsive disorder? Innov Clin Neurosci. 2011;8(6):10-14. 133. 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(11):1004-1009. 134. Sabljiv, Ruzic K, Rakun R. Venlafaxine withdrawal syndrome. Psychiatr Danub. 2011;23(1):117-119. 135. Johnson EM, Whyte E, Mulsant BH, et al. Cardiovascular changes associated with venlafaxine in the treatment of latelife depression. Am J Geriatr Psychiatry. 2006;14(9):796-802. 136. Mbaya P, Alam F, Ashim S, Bennett D. Cardiovascular effects of high dose venlafaxine XL in patients with major depressive disorder. Hum Psychopharmacol. 2007;22(3):129-133. 137. Dell’osso B, Mundo E, Marazziti D, Altamura AC. Switching from serotonin reuptake inhibitors to duloxetine in patients with resistant obsessive-compulsive disorder. J Psychopharmacol. 2008;22(2):210-213. 138. Yeh YW, Chen CH, Kuo SC, Wang SC, Chen CK, Feng HM. High-dose duloxetine for treatment-resistant obsessive-compulsive disorder: a case report with sustained full remission. Clin Neuropharmacol. 2009;32(3):174-176. 139. Luis Blay S, Black DW. A case of obsessive-compulsive disorder responding to duloxetine. Prim Care Companion J Clin Psychiatry. 2007;9(3):234-235. 140. Auclair AL, Martel JC, Assie MB, et al. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety. Neuropharmacology. 2013;70:338-347. 141. Linder H. Treatment of refractory obsessive compulsive disorder: what can we recommend? a systematic review of the literature. http://www.northshorelij.com/ccurl/810/560/winning_ paper_linder_09,0.pdf. Accessed December 15, 2013. 142. McDougle CJ, Goodman WK, Price LH, et al. Neuroleptic addition to fluvoxamine-refractory obsessive-compulsive disorder. Am J Psychiatry. 1990;147(5):652-654. 143. Simpson HB, Foa EB, Liebowitz MR, et al. Cognitivebehavioral therapy vs risperidone for augmenting serotonin reuptake inhibitors in obsessive-compulsive disorder: a randomized clinical trial. JAMA Psychiatry. 2013;70(11):1190-1199. 144. Selvi Y, Alti A, Aydin A, Besiroglu L, Ozdemir P, Ozdemir O. The comparison of aripiprazole and risperidone augmentation in selective serotonin reuptake inhibitor-refractory obsessivecompulsive disorder: a single-blind, randomised study. Hum Psychopharmacol. 2011;26(1):51-57. 145. Maina G, Pessina E, Albert U, Bogetto F. 8-week, single-blind, randomized trial comparing risperidone versus olanzapine augmentation of serotonin reuptake inhibitors in treatmentresistant obsessive-compulsive disorder. Eur Neurpsychopharmacol. 2008;18(5):364-372. 146. Buchsbaum MS, Hollander E, Pallanti S, et al. Positron emission tomography imaging of risperidone augmentation in serotonin reuptake inhibitor-refractory patients. Neuropsychobiology. 2006;53(3):157-168. 147. Hollander E, Baldini Rossi N, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessive-compulsive

Journal of Pharmacy Practice 27(2)

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158. 159.

160.

disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2003;6(4):397-401. McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebo-controlled study of risperidone addition in serotonin inhibitor-refractory obsessivecompulsive disorder. Arch Gen Psychiatry. 2000;57(8): 794-801. Storch EA, Goddard AW, Grant JE, et al. Double-blind, placebocontrolled, pilot trial of paliperidone augmentation in serotonin reuptake inhibitor-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2013;74(6):e527-532. Bystritsky A, Ackerman DL, Rosen RM, et al. Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry. 2004;65(4):565-568. Shapira NA, Ward HE, Mandoki M, et al. A double-blind, placebo-controlled trial of olanzapine addition to fluoxetinerefractory obsessive-compulsive disorder. Biol Psychiatry. 2004;55(5):553-555. 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(8):524-527. Korton A, Wahl K, Koch N, et al. Quetiapine addition to serotonin reuptake inhibitors in patients with severe obsessivecompulsive disorder: a double-blind, randomized, placebocontrolled study. J Clin Psychopharmacol. 2008;28(5):550-554. Fineberg NA, Sivakumaran T, Roberts A, Gale T. Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: a randomized controlled treatment study. Int Clin Psychopharmacol. 2005;20(4):223-226. Carey FD, Vythilingum B, Seedat S, Muller JE, van Ameringen M, Stein DJ. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebo-controlled study [ISRCTN83050762]. BMC Psychiatry. 2005;5:5. doi: 10.1186/1471-244X-5-5 Denys D, de Geus F, van Megan HJ, Westenberg HG. A doubleblind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry. 2004; 65(8):1040-1048. Diniz JB, Shavitt RG, Pereira CA, et al. Quetiapine versus clomipramine in the augmentation of selective serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder: a randomized, open-label trial. J Psychopharmacol. 2010; 24(3):297-307. Carnahan RM, Lund BC, Perry PJ. Ziprasidone, a new atypical antipsychotic drug. Pharmacotherapy. 2001;21(6):717-730. Savas HA, Yumru M, Ozen ME. Quetiapine and ziprasidone as adjuncts in treatment-resistatant obsessive-compulsive disorder: a retrospective comparative study. Clin Drug Investig. 2008; 28(7):439-442. Sayyah M, Sayyah M, Boostani H, Ghaffari SM, Hoseini A. Effects of aripiprazole augmentation in treatment-resistant obsessive-compulsive disorder (a double blind clinical trial). Depress Anxiety. 2012;29(10):850-854.

Bokor and Anderson 161. Muscatello MR, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of serotonin reuptake inhibitors or clomipramine in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2011;31(2):174-179. 162. Delle Chiaie R, Scarciglia P, Pasquini M, Caredda M, Biondi M. Aripiprazole augmentation in patients with resistant obsessive compulsive disorder: a pilot study. Clin Pract Epidemiol Ment Health. 2011;7:107-111. 163. McDougle CJ, Barr LC, Goodman WK, et al. Lack of efficacy of clozapine monotherapy in refractory obsessive-compulsive disorder. Am J Psychiatry. 1995;152(12):1812-1814. 164. Schirmbeck F, Zink M. Clozapine-induced obsessive-compulsive symptoms in schizophrenia: a critical review. Curr Neuropharmacol. 2012;10(1):88-95. 165. Paparrigopoulos T, Tzavellas E, Karaiskos D, Liappas I. Paliperidone-induced obsessive symptoms. J Neuropsychiatry Clin Neurosci. 2011;23(2):E46. 166. Stamouli S, Lykouras L. Quetiapine-induced obsessive-compulsive symptoms: a series of five cases. J Clin Psychopharmacol. 2006; 26(4):396-400. 167. Alevizos B, Lykouras L, Zervas IM, Christodoulou GN. Risperidone-induced obsessive-compulsive symptoms: a series of six cases. J Clin Psychopharmacol. 2002;22(5):461-467. 168. Stern TA, Jenike MA. Treatment of obsessive-compulsive disorder with lithium carbonate. Psychosomatics. 1983;24(7): 671-673. 169. McDougle CJ, Price LH, Goodman WK, Charney DS, Heninger GR. A controlled trial of lithium augmentation in fluvoxaminerefractory obsessive-compulsive disorder: lack of efficacy. J Clin Psychopharmacol. 1991;11(3):175-184. 170. Dannon PN, Sasson Y, Hirschmann S, Iancu I, Grunhaus LJ, Zohar J. Pindolol augmentation in treatment-resistant obsessive compulsive disorder: a double –blind placebo controlled trial. Eur Neuropsychopharmacol. 2000;10(3):165-169. 171. Pallanti S, Bernardi S, Antonini S, Singh N, Hollander E. Ondansetron augmentation in treatment-resistant obsessive-compulsive disorder: a preliminary, single-blind, prospective study. CNS Drugs. 2009;23(12):1047-1055. 172. Askari N, Moin M, Sanati M, et al. Granisetron adjunct to fluvoxamine for moderate to severe obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial. CNS Drugs. 2012;26(10):883-892. 173. Hewlett WA, Schmid SP, Salomon RM. Pilot trial of ondansetron in the treatment of 8 patients with obsessive-compulsive disorder. J Clin Psychiatry. 2003;64(9):1025-1030. 174. Grady TA, Pigott TA, L’Heureux F, Hill JL, Bernstein SE, Murphy DL. Double-blind study of adjuvant buspirone for fluoxetine-treated patients with obsessive-compulsive disorder. Am J Psychiatry. 1993;150(5):819-821.

129 175. McDougle CJ, Goodman WK, Leckman JF, et al. Limited therapeutic effect of addition of buspirone in fluvoxamine refractory obsessive-compulsive disorder. Am J Psychiatry. 1993;150(4): 647-649. 176. Pigott TA, L’Heureux F, Hill JL, Bihari K, Bernstein SE, Murphy DL. A double-blind study of adjuvant buspirone hydrochloride in clomipramine-treated patients with obsessivecompulsive disorder. J Clin Psychopharmacol. 1992;12(1): 11-18. 177. Faird BT, Bulto M. Buspirone in obsessional compulsive disorder. a prospective case study. Pharmacopsychiatry. 1994;27(5): 207-209. 178. Pallanti S, Quercioli L, Bruscoli M. Response acceleration with mirtazapine augmentation of citalopram in obsessive-compulsive disorder without comorbid depression: a pilot study. J Clin Psychiatry. 2004;65(10):1394-1395. 179. Koran LM, Gamel NN, Choung HW, Smith EH, Aboujaoude EN. Mirtazapine for obsessive-compulsive disorder: an open trial followed by double-blind discontinuation. J Clin Psychiatry. 2005;66(4):515-520. 180. Grant P, Lougee L, Hirshtritt 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(6):761-767. 181. Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an openlabel trial. Biol Psychiatry. 2005;58(5):424-428. 182. National Institutes of Health. Riluzole Augmentation in Treatment-Refractory Obsessive-Compulsive Disorder. http:// clinicaltrials.gov/show/NCT00523718. Accessed December 15, 2013. 183. Bruno A, Mico U, Pandolfo G, et al. Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessivecompulsive disorder: a double-blind, placebo-controlled study. J Psychopharmacol. 2012;26(11):1456-1462. 184. Rodriguez CI, Kegeles LS, Levinson A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013; 38(12):2475-2483. 185. Bloch MH, Wasylink S, Landeros-Weisenberger A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012;72(11):964-970. 186. American Psychiatric Association. Practice Guidelines for the treatment of patients with obsessive-compulsive disorder. http://www.guideline.gov/content.aspx?id¼11078. Accessed August 13, 2013. 187. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of child and adolescents with obsessive compulsive disorder. http://www.guideline. gov/content.aspx?id¼36079. Accessed August 13, 2013.

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Journal of Pharmacy Practice 27(2)

Continuing Education Credit The New York State Council of Health-system Pharmacists (NYSCHP) is pleased to provide you with the opportunity to obtain continuing education credit for this article online at HealthSystemCE.org (http://www.healthsystemce.org); login using your email address and HSCE password; then click the ‘‘Journal CE’’ tab. There is no charge to NYSCHP members. If you are not a member of NYSCHP, call 1-518-456-8819 to pay the $15 fee to access the quiz and obtain the password necessary to access the Journal’s CE article. In lieu of this fee, a completed membership application with your dues may be submitted. A grade of 70% or above is required to earn the CE credit. Repeat examinations will be permitted once for a grade below 70%. The NYSCHP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.2 contact hours (0.12CEUs) of continuing education. Universal Activity Number is 0134-0000-14-060-H01P. Submission of exam for CE credit expires April 30, 2017.