Obsessive-Compulsive Disorder (OCD)

Obsessive-Compulsive Disorder (OCD)

1 Overview

Summary and Quick Facts

  • Obsessive-compulsive disorder, or OCD causes uncontrollable recurring thoughts, called obsessions. These obsessions may make one feel like they must repeat certain behaviors, called compulsions.
  • This protocol will help you understand the signs and symptoms of OCD. You’ll also learn about factors that contribute to the condition and what treatments are available.
  • Exercising and learning to deal with stress in a healthy way may reduce some of the symptoms of OCD. Supplementation with N-acetylcysteine (NAC) reduced OCD symptoms, in a clinical trial.

Obsessive-compulsive disorder (OCD) is a type of anxiety disorder in which people suffer from repeated, unwanted thoughts or ideas (obsessions); engage in irrational repetitive behaviors or mental acts (compulsions); or both. Carrying out the compulsive behaviors tends to ease feelings of anxiety, while repressing compulsive behavior causes stress.

Several integrative interventions, such as N-acetylcysteine, glycine, and inositol have been shown to reduce OCD symptoms in clinical trials.

Signs and Symptoms

  • Mental obsessions and behavioral compulsions, with four subtypes:
    • Symmetry or order, things need to be “just so”
    • Forbidden thoughts or images: an affected person will seek reassurance that they are a good person, ask forgiveness and pray
    • Cleaning and fear of contamination
    • Hoarding (listed as a separate mental illness in the latest Diagnostic and Statistical Manual of Mental Disorders [DSM-5])
  • Tics (sudden, brief movements or sounds) or evidence of excessive handwashing may be signs in some cases

Causes and Risk Factors

The causes of OCD are not yet fully understood, but several factors seem to be involved:

  • There may be abnormal structure and activity of certain parts of the brain and of the neurotransmitters serotonin and dopamine in patients with OCD
  • Lower estrogen levels in both men and women are associated with OCD symptoms
  • Life events such as stress or trauma can modify the gene expression of serotonin and dopamine, which may lead to OCD

Conventional and Emerging Therapies

Conventional treatment for OCD includes both pharmacological and non-pharmacological therapy:

  • Cognitive-behavioral therapy, which seems to be more effective than selective serotonin reuptake inhibitors (SSRIs) in patients with OCD
  • SSRIs and the tricyclic antidepressant clomipramine (Anafranil) (a non-selective serotonin reuptake inhibitor, or SRI) are both considered first-line pharmacotherapy for OCD.
  • Deep-brain stimulation involves the surgical implantation of electrodes and is FDA approved to treat chronic and severe cases of OCD.
  • Amisulpride, a second-generation antipsychotic drug that is widely available outside the United States, modulates the action of dopamine in the brain.
  • Repetitive transcranial magnetic stimulation (rTMS) is being investigated for OCD; it involves stimulating specific brain regions through the use of magnetic current.

Dietary and Lifestyle Changes

  • Exercise may reduce anxiety and depression, symptoms that often accompany OCD, and may increase the ability to tolerate normal stress.
  • Stress reduction, as stress may exacerbate OCD because it can reinforce compulsive behavior.

Integrative Interventions

  • Inositol: In a double-blind controlled trial of patients with OCD, oral inositol resulted in a significant reduction in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score, while placebo treatment resulted in average Y-BOCS score reductions of less than one point.
  • N-Acetyl L-Cysteine (NAC): In a randomized controlled trial, 48 patients with OCD who had not responded to a 12-week course of high-dose SRI medication received either additive NAC or placebo for an additional 12 weeks. In the NAC group, almost 53% had a full clinical response (defined as a decrease in Y-BOCS score of more than 35%), while only 15% in the placebo group achieved a full clinical response.
  • Glycine: In a randomized controlled trial in OCD patients, very high-dose glycine or placebo was added to ongoing pharmaceutical or behavioral therapy. Patients in the glycine group experienced a mean decrease of over six points in Y-BOCS score compared with a mean one point decrease for those receiving placebo.
  • Milk thistle: A double-blind randomized trial in participants with OCD compared milk thistle extract to fluoxetine (Prozac). Judged on the basis of change in Y-BOCS scores, milk thistle extract and fluoxetine were similarly effective.
  • Valerian: In a placebo-controlled trial of valerian root extract in patients with OCD, those taking valerian showed statistically significant reductions in Y-BOCS scores at four, six, and eight weeks compared with those taking placebo.

2 Introduction

Obsessive-compulsive disorder (OCD) is a type of anxiety disorder in which people suffer from recurrent, unwanted thoughts or ideas (obsessions); engage in repetitive, irrational behaviors or mental acts (compulsions); or both. Among people with OCD, carrying out compulsive behavior tends to ease feelings of anxiety while repressing compulsive behavior causes stress (Sudak 2012; Veale 2014; Yip 2014; Nicholas 2009; Mayo Clinic 2013).

Because the distressing thoughts may be embarrassing or shameful, OCD patients often do not reveal them to healthcare professionals or family members (Yip 2014; Sudak 2012; Veale 2014). This is unfortunate, because not disclosing OCD symptoms to a healthcare provider can delay diagnosis and treatment. In fact, one survey of 701 patients with OCD symptoms found that an average of 10.2 years elapsed between the onset of OCD symptoms and the first attempt to obtain professional help, and an average of 7 additional years elapsed before the patients received effective treatment (Hollander 1997).

Conventional treatment for OCD relies primarily on specific forms of psychotherapy such as cognitive-behavioral therapy (CBT) and exposure-response prevention therapy, as well as serotonin reuptake inhibitor (SRI) medications (Sudak 2012; Yip 2014). Up to 70% of patients experience significant improvement with treatment, though up to 25% of patients receive minimal benefit and many patients never become completely symptom free (Sudak 2012; Pittenger 2011; Yip 2014).

Only about one-third of OCD patients receive evidence-based drug treatment, and less than 10% receive evidence-based psychotherapy (Grant 2014). Many of the psychotropic drugs used in OCD have significant side effect profiles (Soomro 2012), and the outcome of long-term treatment with these medications in OCD has not been firmly established (Soomro 2008).

Novel treatments for OCD have been the subject of recent scientific inquiry. These include transcranial magnetic stimulation, neurofeedback, and remote cognitive-behavioral therapy. Moreover, several integrative interventions, such as N-acetylcysteine, glycine, and inositol have been shown to reduce OCD symptoms in clinical trials.

In this protocol you will learn about some of the suspected causes of OCD, and how to recognize the symptoms and signs of this insidious condition. Conventional diagnosis and treatment of OCD will be outlined, and a number of promising emerging therapies and natural agents that may benefit those with OCD will be described.

3 Signs and Symptoms

The symptoms of OCD are primarily mental obsessions and behavioral compulsions (Seibell 2013; BPS 2006a). The condition has few outward signs: tics (sudden, brief, intermittent movements or sounds) or dermatological evidence of excessive hand washing may be apparent in some cases (Sudak 2012; Veale 2014). Several other psychiatric disorders can cause signs and symptoms similar to those caused by OCD, which can make identification and correct diagnosis of OCD difficult (Glazier 2013).

OCD symptoms have been categorized into four “symptom dimensions,” which can be thought of as subtypes of the condition. These are contamination/cleaning, symmetry, forbidden thoughts, and hoarding, as presented in Table 1 (Gentil 2014; Bloch 2008). The subtypes of OCD have different clinical presentations and responses to treatment (Landeros-Weisenberger 2010; Mataix-Cols 2002; Kichuk 2013).

There are some gender associations with obsession subtypes: men are more likely than women to have forbidden thought obsessions, particularly sexual thoughts (Landeros-Weisenberger 2010), while women are more likely than men to have cleaning obsessions and contamination compulsions (Alonso 2011).

Table 1: The Four Symptom Dimensions of OCD (from Bloch 2008; Leckman 2009; Williams 2013; Torres 2012; Veale 2014; Bratiotis 2009)

Subtype

Obsession

Compulsion

Symmetry

Excessive concern with symmetry or order; things need to be “just so”

Ordering, repeating, counting

Forbidden thoughts

Forbidden thoughts or images (aggressive, religious, sexual)

Suppression of unwanted mental images, compulsive avoidance of triggers

Cleaning

Fear of contamination (eg, dirt, germs, bodily fluids, feces, chemicals, dangerous material)

Cleaning or washing compulsion, compulsive avoidance of triggers

Hoarding*

Hoarding (ie, collecting or failing to discard useless items to an extent that causes distress or impairs daily activity)

Hoarding

*Hoarding has been categorized as a separate mental illness in the American Psychiatric Association’s most recent Diagnostic and Statistical Manual of Mental Disorders (DSM-5)


Recognizing OCD

OCD can be difficult to recognize because affected individuals often conceal their distress and behaviors from others. However, OCD is characterized by certain cognitive and behavioral patterns. Some of the most common obsessions and their associated compulsions are listed in Table 2.

Table 2: Common obsessions and examples of compulsive responses (Mayo Clinic 2013; Grant 2014)

Example Obsession

Associated Compulsions

Fear of contamination from shaking hands or by touching objects others have touched

Excessive hand washing

Doubts that one has locked the door or turned off the stove

Checking doors repeatedly to make sure they are locked; checking the stove repeatedly to be certain it has been turned off

Severe stress when objects are not orderly or facing a certain way

Arranging items so they all face the same direction

Fear of harming others; recurrent violent images

Seeking reassurance that one is a good person; monitoring news for reports of violent crime

Thoughts about eternal damnation, or that one is immoral

Asking forgiveness or praying

Recurrent anxiety about doing things incorrectly or incompletely

Excessive checking; performing actions in a particular order

Fear of making inappropriate comments in public

Avoidance of social situations

4 Causes and Risk Factors

While the causes of OCD are not fully understood, several genetic, neurobiological, and environmental factors appear to be at least partially involved.

Brain Structure and Function

Multiple neuroimaging and neurophysiology studies have identified abnormal activity in specific regions of the brain in patients with OCD; researchers are also investigating the possibility that structural abnormalities exist in specific parts of the brain in OCD patients. A report of a patient whose severe OCD disappeared after a small stroke destroyed a small, specific part of the brain supports the theory that disturbances in localized brain regions are involved in OCD (Nakao 2014; Pallanti 2011).

Additional support for the central role of the brain in OCD comes from a significant body of evidence that OCD is associated with abnormal activity of the neurotransmitters dopamine and serotonin (Koo 2010; Hesse 2005; Denys 2004). More recent evidence suggests that dysregulation of the excitatory neurotransmitter glutamate may also contribute to OCD (Kellner 2010; Pittenger 2011).

Variants of genes involved in serotonin, glutamate, and dopamine metabolism have been implicated in OCD (Pauls 2014; Delorme 2009; Nicolini 2010). More studies are needed to establish the specific role of particular genes in OCD, and to develop therapies on the basis of these discoveries (Stewart 2013; Mattheisen 2015).

Sex Hormones

In women and men, estrogen and progesterone levels, as well as individual differences in an estrogen receptor gene, have been associated with obsessive-compulsive symptoms (Alonso 2011; Hill 2007; Boon 2011; Avgoustinaki 2012). Estrogens are known to influence neurotransmitter pathways implicated in OCD, including serotonin, dopamine, and glutamate (Alonso 2011).

In one study, women on hormonal contraception consisting of both a progestin (a synthetic, progesterone-like compound) and estrogen exhibited less depression and OCD symptoms than those on progestin-only or no hormone therapy (Young 2007). In a rodent model, progesterone administration reduced OCD-like behavior (Umathe 2009). While there is evidence to suggest that sex hormones may be related to OCD symptoms, further studies are needed to clarify these relationships, and to establish whether manipulating hormone levels will be of therapeutic value for people with OCD.

Other Risk Factors

Stress. Studies have demonstrated that environmental and genetic factors contribute approximately equally to OCD risk. Life events such as stress or trauma may serve as “epigenetic modifiers” (meaning they modify gene expression and function without altering the sequence of specific genes) that impact serotonin, dopamine, and glutaminergic pathways (Pauls 2014; Mataix-Cols 2013; Cath 2008).

Gender. Men and women are equally affected by OCD, though the symptom subtype does differ between genders. Women are more likely than men to exhibit contamination obsessions and cleaning compulsions, and less likely to have sexual or religious obsessions (Labad 2008; Veale 2014; Landeros-Weisenberger 2010).

Age. The average age of OCD onset is early 20s in women and late adolescence in men (Veale 2014). Earlier age at onset is associated with greater incidence of the symmetry subtype, sexual or religious obsessions, and a greater likelihood of tic disorders (Janowitz 2009; Labad 2008).

Family history. OCD risk is markedly higher for first-degree relatives of patients with OCD or Tourette’s syndrome (Yip 2014).

Pregnancy. In a rigorous review of studies on OCD prevalence in women, pregnancy increased the risk of OCD 1.45-fold, and post-partum women were 2.38 times as likely to experience OCD (Russell 2013).

Infection. Rarely, OCD in children appears to be caused by a group A β­hemolytic streptococcal infection that results in a rapid onset of symptoms. This is an autoimmune condition known as “pediatric autoimmune neuropsychiatric disorder associated with Streptococcus infection,” known by the acronym PANDAS. Encephalitis and bacterial or viral infections have also been associated with the onset of OCD (Ercan 2008; Murphy 2010; Yip 2014; Sudak 2012).

Central nervous system trauma or disease. OCD symptoms can sometimes be associated with other neurological conditions, such as stroke, brain tumor, trauma to the frontal lobe, Huntington’s disease, Tourette’s syndrome, frontotemporal dementia, or hypoxia (Pallanti 2011; Veale 2014; Yip 2014).

5 Diagnosis

As is the case for many psychiatric disorders, there is no laboratory test for OCD. There are, however, specific clinical interview and assessment tools designed to aid in diagnosis. Even with the correct clinical diagnostic tools, it can be difficult to distinguish OCD from other psychiatric conditions (Seibell 2013; Sudak 2012).

The difficulty in correctly diagnosing OCD may stem in part from the frequency with which OCD is associated with other psychiatric disorders (Seibell 2013; Sudak 2012). In one study, 92% of patients with a primary diagnosis of OCD had at least one additional psychiatric diagnosis (de Mathis 2013). Nevertheless, in order to make an OCD diagnosis, a clinician must rule out other psychiatric conditions such as depression, anxiety disorder, psychosis, and ADHD (Masi 2006; Yip 2014; Sudak 2012).

Once an OCD diagnosis has been made, severity can be graded using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Clinical Global Impressions (CGI) scale, or both:

  • The Y-BOCS is a clinician-administered 10-item questionnaire that rates the frequency, severity, and types of symptoms in an OCD patient, and can be used to monitor disease progression or treatment. Y-BOCS scores range from 0 to 40, with 40 being the most severe (Rosario-Campos 2006; Goodman 1989; Farris 2013).
  • The CGI scale can be used to assess the clinical severity of any mental disorder. It scores symptoms on two 7-point scales: severity of symptoms and response to treatment. The CGI usually rates the patient’s symptoms, behavior, and function over the previous seven days (Busner 2007; Seibell 2013).

Diagnostic Criteria for OCD

Both the World Health Organization (International Statistical Classification of Diseases and Related Health Problems; ICD-10) and the American Psychiatric Association (Diagnostic and Statistical Manual of Mental Disorders; DSM-5) have developed diagnostic criteria for OCD.

ICD-10 criteria (National Collaborating Centre for Mental Health 2006):

Obsessional symptoms or compulsive acts or both must be present on most days for at least two successive weeks and be a source of distress or interference with activities. Obsessional symptoms should have the following characteristics:

  1. must be recognized as the individual's own thoughts or impulses;
  2. must be at least one thought or act that is still resisted unsuccessfully, even though others, which the sufferer no longer resists, may be present;
  3. thought of carrying out the act must not in itself be pleasurable (simple relief of tension or anxiety is not regarded as pleasure in this sense);
  4. thoughts, images, or impulses must be unpleasant and repetitive.

DSM-V criteria (APA 2013):

A. Presence of obsessions, compulsions, or both:

Obsessions are defined by (1) and (2):

  1. Recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted, and in most individuals cause marked anxiety or distress.
  2. The individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (by performing a compulsion).

Compulsions are defined by (1) and (2):

  1. Repetitive behaviors (eg, hand washing, ordering, checking) or mental acts (eg, praying, counting, repeating words silently) that the individual feels driven to perform in response to an obsession or according to rules that must be applied rigidly.
  2. The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts are not connected in a realistic way with what they are designed to neutralize or prevent, or are clearly excessive. Note: young children may not be able to articulate the aims of these behaviors or mental acts.

B. The obsessions or compulsions are time-consuming, taking more than one hour per day, or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C. The obsessive-compulsive symptoms are not attributable to the physiological effects of a substance (eg, a drug of abuse or a medication) or another medical condition.

D. The disturbance is not better explained by the symptoms of another mental disorder.

6 Conventional Treatment

Conventional treatment for OCD includes both pharmacological and non-pharmacological therapy. These therapies, alone or in combination, can be successful in managing OCD symptoms. However, complete remission of symptoms is rare, and approximately 25% of patients with OCD will receive little if any benefit from conventional OCD therapies (Pittenger 2011).

Cognitive-Behavioral Therapy

Cognitive behavioral therapy (CBT), a specific type of psychotherapy, appears to be roughly as effective for OCD as medication. A rigorous analysis of many studies on behavioral and pharmacotherapy did not find evidence for superiority of pharmacotherapy over behavioral treatment. Importantly, this analysis also did not find that addition of medication to behavioral treatment was associated with an improvement in outcomes, compared with behavioral treatment alone (Romanelli 2014).

Some important limitations to CBT are difficulty accessing treatment (BPS 2006b), patient aversion to the indicated methods, and a high dropout rate. Additionally, the methods are not equally applicable to all symptom dimensions (subtypes). CBT for OCD encompasses two approaches: exposure with response prevention and cognitive therapy (Hebbar 2013; Bonchek 2009; McKay 2015; Ponniah 2013; Grant 2014; Romanelli 2014).

Exposure with response prevention. In this therapy, the patient is guided through exposure to fear- and anxiety-producing situations and stimuli, progressing from least to most distressing. At the same time, the patient refrains from the compulsive behaviors that temporarily relieve anxiety and distress. An important part of this treatment is for the patient to learn that the anxiety and fear pass on their own, and to develop tolerance for this distress (Grant 2014; McKay 2015). Sixty to eighty-five percent of patients improve with exposure-response prevention treatment, although for up to 30% of patients this treatment is not effective, or patients refuse or discontinue treatment due to the anxiety associated with the exposure (Grant 2014; Veale 2014; Yip 2014). Contamination and washing obsessions are the most responsive to this therapy, while hoarding obsession responds poorly (Veale 2014; Yip 2014).

Cognitive therapy. Cognitive therapy helps patients correct their obsessions and compulsions by identifying unrealistic thoughts and beliefs. Unlike exposure-response prevention, cognitive therapy is not aimed at reducing the anxiety associated with a specific situation (eg, handling a dirty object without washing), but rather at challenging the belief that not washing will lead to negative consequences (Grant 2014). Cognitive therapy may be used independently as a therapy for OCD, or as an adjunct to exposure-response prevention. As an adjunct, cognitive therapy may help increase the patient’s ability to tolerate distress, help address dysfunctional beliefs, and help the patient adhere to and remain in treatment (McKay 2015; Whittal 2005; Ponniah 2013).

Pharmacological Therapy

Serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRIs) and the tricyclic antidepressant clomipramine (Anafranil) (a non-selective serotonin reuptake inhibitor, or SRI) are both considered first-line pharmacotherapy for OCD. However, SSRIs have a more favorable side effect profile than clomipramine, so they are usually the preferred primary medications (Seibell 2013; Kellner 2010; Grant 2014).

The SSRI medications fluvoxamine (Luvox), paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) are approved by the Food and Drug Administration (FDA) for use in OCD patients (Sudak 2012), though they have comparable efficacy (Soomro 2012). Although drug treatment of OCD is not proven more effective than behavioral therapy, it is sometimes used as the sole treatment, including in patients who find the idea of behavioral therapy intimidating (Grant 2014).

Roughly 40–65% of OCD patients respond to treatment with clomipramine or an SSRI, with an average improvement in symptom severity of 20–40%. Relatively few patients experience complete remission with drug treatment alone. Also, OCD patients usually need to undergo drug treatment for longer duration and at a higher dose to achieve benefit, compared with patients using these drugs to treat depression. Symptoms of OCD tend to relapse when medication is discontinued, particularly in those on medication for less than two years (Grant 2014). Most studies of pharmacotherapy for OCD have only lasted 8‒12 weeks, though some studies lasting longer than 12 months demonstrated efficacy. Uncertainty remains, however, about adverse effects and the long-term efficacy of SSRIs for OCD, as well as the ideal duration of treatment (NLM 2014; Soomro 2008).

The side effect profile of SSRIs, while better than the tricyclic antidepressant clomipramine, is significant. Almost a quarter of patients taking SSRIs report adverse effects on sexual function, and other commonly reported side effects include sleep problems, tiredness and fatigue, restlessness, dry mouth, nausea, constipation, dizziness, and weight gain (Bet 2013).

Augmentation therapy. Augmentation is the use of additional medications in patients who do not respond to initial therapy with an SRI. This might include the addition of the tricyclic antidepressant clomipramine to treatment with fluoxetine; or the use of second-generation antipsychotic agents such as risperidone (Risperdal) or haloperidol (Haldol), stimulants, and glutamate receptor modulators such as memantine (Namenda) (Pittenger 2011; Walsh 2011; Seibell 2013). Though there are conflicting data on the efficacy of augmentation therapy, and there are no FDA-approved drugs for this purpose, this medication strategy is often part of clinical practice for OCD (Pittenger 2005; Grant 2014; Soomro 2012; Seibell 2013).

Deep-Brain Stimulation

Deep-brain stimulation involves the surgical implantation of electrodes within specific areas of the brain, and electrical stimulation to produce changes in these regions (Hammond 2008; Lapidus 2014; Malaty 2014; Denys 2009). Deep-brain stimulation is FDA approved to treat chronic and severe cases of OCD (Grant 2014), with reports of successful treatment from case reports and small trials (de Koning 2011; Kisely 2014). Deep-brain stimulation is an invasive procedure in which probes are inserted directly into brain tissue, and carries a risk of adverse effects including infection, intracerebral hemorrhage, acute mood changes, and seizures (de Koning 2011).

7 Novel and Emerging Therapies

Amisulpride

Amisulpride is a second-generation antipsychotic drug that is widely available outside the United States (Svestka 2007; Szarfman 2006). It blocks the action of dopamine in the brain (Komossa 2010; Schoemaker 1997). In an open-label trial, 10 patients received 200 mg amisulpride as augmentation therapy for six weeks. Average Y-BOCS scores decreased from 25.3 at study entry to 12.2 by the end of the study (Miodownik 2015). An earlier, similarly designed trial in 20 patients used 200‒600 mg per day of amisulpride, in addition to an SSRI, for 12 weeks. Y-BOCS scores decreased from 26.7 at baseline to 12.5 at the end of the study (Metin 2003).

Repetitive Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a method of stimulating specific brain regions through the use of magnetic current similar to that used in magnetic resonance imaging (MRI). It is an FDA-approved treatment for major depression in patients who have not responded to at least one antidepressant drug. This procedure does not require anesthesia, and the magnetic pulse penetrates no more than two inches into the brain from a magnetic coil placed over the forehead on the scalp. The mechanism of action of rTMS is not completely understood, but it is thought that because OCD has been associated with increased neural activity in the prefrontal cortex of the brain, the inhibitory effects of magnetic therapy may be beneficial (Blom 2011; NIH 2015; Mayo Clinic 2015).

rTMS is a lower-risk procedure than deep brain stimulation; seizures and hearing damage are the most serious side effects. Selection of the best brain regions for rTMS treatment is an evolving area of investigation, with newer studies finding more effective treatment regimens (Saba 2015; Jaafari 2012; Lapidus 2014). A rigorous analysis of published studies concluded that rTMS is an effective augmentation to SSRI medication, though many authors call for large, randomized trials to fully clarify the value of rTMS in treating OCD (Ma 2014; Jaafari 2012).

Surgical Treatment

Surgical treatments may be considered in extreme, debilitating OCD cases that do not respond to exposure therapy and medication (Yip 2014; Grant 2014).

Ablative neurosurgery. Ablative neurosurgery techniques destroy or “ablate” specific regions or connections in the brain using precisely placed radiofrequency probes (Hariz 2013). Some studies have found ablative neurosurgery an effective treatment for severe, treatment-resistant OCD (Pepper 2015).

Ablative neurosurgery is available only at specialty centers, is not FDA-approved for treatment of OCD, and carries a substantial risk of adverse effects, including postoperative seizures and memory problems (BPS 2006c; Grant 2014; Soomro 2012; Sudak 2012; Rück 2008).

Non-invasive ablative neurosurgery . A newer, non-invasive ablative neurosurgery technique uses an MRI-guided, focused ultrasound device called ExAblate 4000. In one study of four patients, ultrasound ablation resulted in a gradual, 33% average reduction in Y-BOCS scores over the six months following the procedure, along with rapid and substantial improvements in depression and anxiety (61.1% and 69.4% average reductions, respectively) (Jung 2014).

Chronotherapy

The term “chronotherapy” refers to treatment that interacts with or modulates the body’s sleep-wake cycles (ie, the circadian rhythm). Chronotherapy has been applied to a range of conditions including major depression, high blood pressure, and even cancer (Martiny 2012; Eriguchi 2003; Watanabe 2013). Hormone dysregulation and disordered sleep patterns have been observed in people with OCD symptoms. Also, some evidence suggests OCD may respond to the drug agomelatine, which is chemically related to melatonin, and is considered a melatonergic antidepressant (Dubovsky 2009; Tzavellas 2014; Coles 2011; Lange 2012). In a rigorous review of 12 studies, patients with OCD were found to have shorter duration of sleep and more disordered sleep than healthy controls (Nota 2015). The hormone melatonin and bright light are powerful chronotherapeutic agents (Dodson 2010; Martiny 2015; Portaluppi 2010; Innominato 2010).

A case report of a 54-year old woman who had severe OCD and was treated with chronotherapy shows the promise of this modality. This patient had not responded to medication and psychotherapy. After adjusting her sleep schedule from 6 AM to 1 PM, to 12 AM to 10 AM, she experienced a 43% (15-point) reduction in her Y-BOCS (Coles 2011). Controlled studies on chronotherapy for OCD are still needed.

Remote Cognitive-Behavioral Therapy

Cognitive-behavioral therapy (CBT) is typically delivered face-to-face by a trained psychotherapist. However, technology-based delivery (through the internet, remote communication technologies, or deliverables like DVDs) may improve access to the treatment and may benefit patients reluctant to engage in face-to-face therapy, or unable to conveniently meet with a trained therapist. In a rigorous review of 8 randomized controlled trials, remote technology-based CBT was superior to controls for OCD, with a non-significant difference between therapist- and technology-administered CBT (Dèttore 2015).

Neurofeedback

Neurofeedback is a form of biofeedback that allows a patient to influence their own brain activity through interaction with an electroencephalogram (EEG) display. This is a non-invasive technique in which, through concentration, a patient can learn to modify dysfunctional brain activity associated with neuropsychological disorders such as OCD (Deng 2014). Three case reports of individuals with moderate-to-severe OCD (Y-BOCS scores 16–26) demonstrated a marked reduction in Y-BOCS scores (Hammond 2005). In a separate review of clinical reports on 36 individuals whose OCD did not respond to pharmacotherapy, neurofeedback treatment (from 9 to 84 sessions, each lasting 60 minutes per day) resulted in clinical improvements in 33 of 36 patients. Nineteen of these patients maintained their improvements for two years after cessation of neurofeedback treatment (Sürmeli 2011).

Mindfulness-Based Cognitive Therapy

Mindfulness is attention to moment-by-moment experience in a non-judgmental way (Chiesa 2011). Mindfulness-based interventions use mindfulness meditation to teach OCD patients to recognize and refocus or “let go” of obsessive intrusions into their thoughts and feelings (Hanstede 2008). Mindfulness exercises can also incorporate yoga, breathing exercises, as well as body-scanning, a technique in which each external body part is mentally “scanned” for sensations like pain or warmth. Mindfulness-based cognitive therapies have been successful in reducing OCD symptoms (as measured by Y-BOCS scores) in multiple case reports and one small study (Hale 2012). In the study, OCD patients were trained to refocus obsessive attention through the use of mindfulness exercises. They were also trained to identify individual OCD triggers and perform mindfulness and attention exercises whenever they noticed obsessive thoughts; two-thirds of patients in the study reported reductions in OCD symptoms (Hertenstein 2012).

8 Lifestyle Considerations

Aerobic Exercise

Exercise may reduce anxiety and depression, symptoms that often accompany OCD, and may increase resiliency to normal stress. Moderate aerobic exercise combined with regular cognitive-behavioral training and incentives (rewards for adhering to the exercise and behavior training programs) produced reductions in OCD symptoms in a study of 15 OCD patients. The symptom reductions persisted through the 6-month follow-up in patients that adhered to the exercise regimen (Brown 2007). A preliminary trial that added a 12-week structured exercise program to cognitive-behavioral therapy for OCD found a robust benefit, which surpassed the effects of CBT alone observed in other studies (Rector 2015). A larger trial of aerobic exercise in 102 OCD patients is currently underway (Abrantes 2012).

Stress Management

Stress may precipitate OCD (Albert 2000; Grisham 2011; Pace 2011; Visser 2014) because it can reinforce compulsive behavior (Pauls 2014). There are many methods that have been used for stress reduction, such as supplementation with the hormone DHEA and maintaining sex hormone balance. For more information, refer to Life Extension’s Stress Management protocol.

9 Integrative Interventions

Inositol

Inositol is a natural chemical compound common in many foods, and it is also present in relatively high concentrations in the brain, where it plays an important role in cellular communication (Levine 1997; Camfield 2011). Inositol’s therapeutic mechanism of action is not firmly established, but is believed to involve modulation of serotonin activity in the brain (Harvey 2002; Camfield 2011).

In a six-week, double-blind, controlled, crossover trial of 13 patients with OCD, administration of 18 g per day of oral inositol resulted in an average 4-point reduction in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, while placebo treatment resulted in average Y-BOCS score reductions of less than 1 point (Fux 1996). In an unblinded study of 14 untreated OCD patients, a 12-week treatment with 18 g daily inositol resulted in an average reduction in Y-BOCS score of 10.7 points—a nearly 50% reduction from baseline values—and a clinical response, defined as a reduction of baseline Y-BOCS score by half, was achieved in 57% of study participants (Carey 2004).

N-Acetylcysteine

N-acetylcysteine (NAC), an amino acid derivative, can inhibit glutamate release from brain cells, aid in cellular and metabolic detoxification, lower homocysteine levels, and boost levels of glutathione, an important neutralizer of potentially damaging cellular metabolic byproducts (De Flora 1995; van Zandwijk 1995; Kasperczyk 2015; Sarris 2012). In a randomized controlled trial, 48 patients with OCD (Y-BOCS score greater than 16) who had not responded to a 12-week course of high-dose SRI medication received either additive NAC or placebo while continuing SRI medication for an additional 12 weeks. Twenty-four patients received NAC (starting at 600 mg per day and increasing to 2400 mg per day by week 3) and twenty-four control subjects received a placebo. In the NAC group, 53% had a full clinical response (defined as a decrease in Y-BOCS score of more than 35%), while only 15% in the placebo group achieved a full clinical response. Total average reductions in Y-BOCS score were 10.9 points for the NAC group and 5.7 points for the control group (Afshar 2012).

A case study of a 58-year old woman with OCD who did not respond to SRI therapy reported that the addition of NAC (beginning with 600 mg daily, and increasing to 3000 mg per day over six weeks, and then continuing at that dose for an additional seven weeks) to fluvoxamine treatment resulted in a clinically significant improvement in OCD symptoms (Lafleur 2005). In this case, a reduction of 8 points on the Y-BOCS scale was noticed after only one week of treatment, which is indicative of a much more rapid treatment response compared with SSRI treatment alone (Camfield 2011).

Glycine

Glycine is an amino acid capable of modifying the activity of some neurotransmitter systems in the brain. Along with glutamate, glycine binds and activates N-methyl-D-aspartate receptors in the brain; activation of these receptors has an anti-compulsive effect in animal models of OCD (Camfield 2011). In a randomized controlled trial in 24 OCD patients with a Y-BOCS score greater than or equal to 18, very high-dose glycine (60 g/day) or placebo was added to ongoing pharmaceutical or behavioral therapy. Patients in the glycine group experienced an average decrease of over six points in Y-BOCS score compared with an average one point decrease for those receiving placebo. Eight of twelve participants in the glycine group dropped out of the study due to side effects from the large dose of glycine, though two patients who responded to glycine treatment continued to take glycine for over a year (Greenberg 2009).

In a case report of a 22-year old male patient with severe, debilitating OCD and no satisfactory response to SSRIs, five years of glycine treatment led to a large reduction in OCD symptoms, and resumption of education and social life (Cleveland 2009).

Milk Thistle

Milk thistle has been shown in experimental studies to inhibit monoamine oxidase enzymes, and may increase serotonin levels in the cerebral cortex; both of these properties are similar to mechanisms occurring in prescription antidepressants. A double-blind randomized trial in 35 participants with OCD and Y-BOCS scores greater than 20 compared 600 mg of milk thistle extract to 30 mg daily of fluoxetine. Judged on the basis of change in Y-BOCS scores, milk thistle extract and fluoxetine were similarly effective (Camfield 2011; Sayyah 2010; Mazzio 1998).

Valerian

Valerian root (Valeriana officinalis L.) has historically been used as a sedative, pain reliever, anxiolytic, and migraine treatment; it is thought to act on the GABA neurotransmitter system in the brain. In a placebo-controlled trial of valerian root extract in 31 patients with OCD and Y-BOCS scores greater than 21, those taking 750 mg/day of valerian showed statistically significant reductions in Y-BOCS scores at four, six, and eight weeks compared with those taking placebo (Pakseresht 2011).

St. John’s wort

St. John’s wort (Hypericum perforatum) has been shown to inhibit monoamine reuptake, increase serotonin binding to its cellular receptors, and modulate activity of the hypothalamic-pituitary axis. St. John’s wort has been extensively studied for depression (Sarris 2012). In an open-label uncontrolled trial, 12 OCD patients were given 450 mg of St. John’s wort extract standardized to 0.3% hypericin twice daily for 12 weeks, which produced a significant 7.4 point average reduction in Y-BOCS score (Taylor 2000).

Vitamin B12 and Folate

Vitamin B12 and folate are cofactors in the synthesis of the neurotransmitters serotonin and dopamine (Valizadeh 2011; Atmaca 2005), and vitamin B12 deficiency may be associated with psychiatric disorders (Valizadeh 2011; Upadhyaya 2012; Sahoo 2011). One study found a significantly higher incidence of serum B12 deficiency in OCD patients compared with healthy controls, with 20% of OCD patients showing low B12 levels (Hermesh 1988). Case reports have also described vitamin B12 deficiency in OCD patients (Valizadeh 2011; Sharma 2012).

Two studies identified low levels of folate and significantly higher levels of the amino acid homocysteine in OCD patients compared with healthy controls. One of these studies found that lower folate levels and higher homocysteine levels were associated with higher Y-BOCS scores. The other study found that vitamin B12 levels were lower and homocysteine levels higher in 35 OCD patients compared with healthy controls (Atmaca 2005; Türksoy 2014). Folate and vitamin B12, along with vitamin B6, are able to lower homocysteine levels (Smith 2010).

Minerals

Some evidence suggests that, compared with healthy individuals, people with OCD may have lower blood levels of zinc, iron, magnesium, and selenium (Shohag 2012; Ozdemir 2009). Studies investigating the role of mineral supplementation in individuals with OCD are needed as available evidence is currently limited. Nevertheless, one small randomized controlled trial did show that supplementation with very high doses of zinc (440 mg/day) plus fluoxetine led to greater reductions in Y-BOCS scores compared to fluoxetine plus placebo in OCD patients (Sayyah 2012). The dosage of zinc used in this study was extremely high, and should not be attempted without close physician supervision.

Additional Support

Several additional natural agents have shown promise in modulating OCD-like behavior in preclinical research, but studies in humans with OCD are needed before the role of these interventions can be clarified.

Probiotics. A rodent model found that the probiotic strain Lactobacillus rhamnosus GG was able to alleviate chemically induced OCD-like behavior, with an effect similar to the SSRI medication fluoxetine (Kantak 2014). The mechanisms by which the gastrointestinal microbiota may influence the central nervous system are not completely understood, but rodent models have shown that an absence of intestinal bacteria can affect the expression of N-methyl-D-aspartate receptors and the production of stress hormones. Additionally, some bacteria and yeast synthesize neurotransmitters and neuromodulators, including dopamine and serotonin; and in mice, a reduction in anxiety-like behavior in response to probiotic administration was demonstrated to be mediated by activity of the vagus nerve, which communicates directly between the gastrointestinal tract and the brain (Bravo 2012; Cryan 2012; Bercik 2011). More studies are needed to clarify the potential of probiotic microorganisms in individuals with OCD.

Ashwagandha (Withania somnifera). Ashwagandha is an Ayurvedic herb with historical usage as an adaptogen that increases resiliency to physical and mental stress (Singh 2011). It has been investigated for its anxiolytic and antidepressant activities in human and animal models (Pratte 2014; Bhattacharya 2000). In a mouse model of OCD-like behavior induced by a neurotoxin, injection of 50 mg/kg of ashwagandha extract reduced this behavior with an efficacy similar to the SSRI fluoxetine (Kaurav 2012).

Saffron. Saffron, a spice derived from the dried stigmas of Crocus sativus L., contains neuroactive compounds that have demonstrated anxiolytic and antidepressant activities in animal models. In multiple randomized controlled trials, saffron extract has shown superior antidepressant effects compared to placebo and efficacy similar to antidepressant medication (Ghasemi 2014; Lopresti 2014; Pitsikas 2008; Hosseinzadeh 2009; Hausenblas 2013; Shahmansouri 2014). In a rodent model of chemically induced OCD, unique water-soluble carotenoids from saffron, called crocins, prevented OCD-like behavior when given as an injection into the abdominal cavity at daily doses ranging from 30‒50 mg/kg (Georgiadou 2012).

Abrantes AM, McLaughlin N, Greenberg BD, et al. Design and Rationale for a Randomized Controlled Trial Testing the Efficacy of Aerobic Exercise for Patients with Obsessive-Compulsive Disorder. Ment Health Phys Act. 2012;5(2):155-165.

Afshar H, Roohafza H, Mohammad-Beigi H. N-Acetylcysteine Add-On Treatment in Refractory Obsessive-Compulsive Disorder. Journal of Clinical Psychopharmacology. 2012;32(6):797–803.

Albert U, Maina G, Bogetto F, and Ravizza L. The role of recent life events in the onset of obsessive-compulsive disorder. CNS Spectr. 2000;5(12):44–50.

Alonso P, Gratacòs M, Segalàs C, et al. Variants in estrogen receptor alpha gene are associated with phenotypical expression of obsessive-compulsive disorder. Psychoneuroendocrinology. 2011;36(4):473–83.

APA. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5®). American Psychiatric Pub. 2013.

Atmaca M, Tezcan E, Kuloglu M, Kirtas O, and Ustundag B. Serum folate and homocysteine levels in patients with obsessive-compulsive disorder. Psychiatry Clin. Neurosci. 2005;59(5):616–20.

Avgoustinaki PD, Mitsopoulou E, Chlouverakis G. Sex steroids and personality traits in the middle luteal phase of healthy normally menstruating young professional women. Hormones (Athens). 2012;11(3):333–43.

Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, . . . Verdu EF. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterology and motility: the official journal of the European Gastrointestinal Motility Society. Dec 2011;23(12):1132-1139.

Bet PM, Hugtenburg JG, Penninx BWJH, and Hoogendijk WJG. Side effects of antidepressants during long-term use in a naturalistic setting. Eur Neuropsychopharmacol. 2013;23(11):1443–51.

Bhattacharya SK, Bhattacharya A, Sairam K, Ghosal S. Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study. Phytomedicine: international journal of phytotherapy and phytopharmacology. Dec 2000;7(6):463-469.

Bloch MH, Landeros-Weisenberger A, Rosario MC, Pittenger C, and Leckman JF. Meta-analysis of the symptom structure of obsessive-compulsive disorder. Am J Psychiatry. 2008;165(12):1532–42.

Blom RM, Figee M, Vulink N, and Denys D. Update on Repetitive Transcranial Magnetic Stimulation in Obsessive-Compulsive Disorder: Different Targets. Curr Psychiatry Rep. 2011;13(4):289–94.

Bonchek A. What's broken with cognitive behavior therapy treatment of obsessive-compulsive disorder and how to fix it. American journal of psychotherapy. 2009;63(1):69-86.

Boon WC and Horne MK. Aromatase and its inhibition in behaviour, obsessive compulsive disorder and parkinsonism. Steroids. 2011;76(8):816–9.

BPS. British Psychological Society. Chapter 2: Obsessive-Compulsive Disorder and Body Dysmorphic Disorder. In: Obsessive-Compulsive Disorder: Core Interventions in the Treatment of Obsessive-Compulsive Disorder and Body Dysmorphic Disorder. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0015824/. Copyright 2006a. Accessed 4/14/2015.

BPS. British Psychological Society. Chapter 5: Psychological Interventions. In: Obsessive-Compulsive Disorder: Core Interventions in the Treatment of Obsessive-Compulsive Disorder and Body Dysmorphic Disorder. Available at: http://www.ncbi.nlm.nih.gov/books/NBK56465/. Copyright 2006b. Accessed 4/14/2015.

BPS. British Psychological Society. Chapter 8: Other Medical Interventions. In: Obsessive-Compulsive Disorder: Core Interventions in the Treatment of Obsessive-Compulsive Disorder and Body Dysmorphic Disorder. Available at: http://www.ncbi.nlm.nih.gov/books/NBK56463/. Copyright 2006c. Accessed 4/14/2015.

Bratiotis C, Otte S, Skeketee G, et al. Hoarding-Fact-Sheet. Copyright 2009 International OCD Foundation (IOCDF). Available at: http://iocdf.org/wp-content/uploads/2014/10/Hoarding-Fact-Sheet.pdf.

Bravo JA, Julio-Pieper M, Forsythe P, et al. Communication between gastrointestinal bacteria and the nervous system. Current Opinion in Pharmacology. 2012;12(6):667–72.

Brown RA, Abrantes AM, Strong DR. A Pilot Study of Moderate-Intensity Aerobic Exercise for Obsessive Compulsive Disorder. The Journal of Nervous and Mental Disease. 2007;195(6):514–20.

Busner J and Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28–37.

Camfield DA, Sarris J, and Berk M. Progress in Neuro-Psychopharmacology & Biological Psychiatry. Progress in Neuropsychopharmacology & Biological Psychiatry. 2011;35(4):887–95.

Carey PD, Warwick J, Harvey BH, Stein DJ, and Seedat S. Single photon emission computed tomography (SPECT) in obsessive-compulsive disorder before and after treatment with inositol. Metab Brain Dis. 2004;19(1-2):125–34.

Cath DC, van Grootheest DS, Willemsen G, van Oppen P, Boomsma DI. Environmental factors in obsessive-compulsive behavior: evidence from discordant and concordant monozygotic twins. Behavior genetics. Mar 2008;38(2):108-120.

Chiesa A and Serretti A. Mindfulness based cognitive therapy for psychiatric disorders: a systematic review and meta-analysis. Psychiatry Research. 2011;187(3):441–53.

Cleveland WL, DeLaPaz RL, Fawwaz RA, and Challop RS. High-Dose Glycine Treatment of Refractory Obsessive-Compulsive Disorder and Body Dysmorphic Disorder in a 5-Year Period. Neural Plasticity. 2009;2009(6):1–25.

Coles ME and Sharkey KM. Compulsion or chronobiology? A case of severe obsessive-compulsive disorder treated with cognitive-behavioral therapy augmented with chronotherapy. J Clin Sleep Med. 2011;7(3):307–9.

Cryan JF and Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat. Rev. Neurosci. 2012;13(10):701–12.

De Flora S, Cesarone CF, Balansky RM, Albini A, D'Agostini F, Bennicelli C, . . . et al. Chemopreventive properties and mechanisms of N-Acetylcysteine. The experimental background. Journal of cellular biochemistry. Supplement. 1995;22:33-41.

de Koning PP, Figee M, van den Munckhof P, Schuurman PR, Denys D. Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets. Curr Psychiatry Rep. 2011;13(4):274–82.

de Mathis MA, Diniz JB, Hounie AG, Shavitt RG. Trajectory in obsessive-compulsive disorder comorbidities. European Neuropsychopharmacol. 2013;23(7):594-601.

Delorme R, Betancur C, Chaste P. Reduced 3- O-methyl-dopa levels in OCD patients and their unaffected parents is associated with the low activity M158 COMT allele. Am. J. Med. Genet. 2009;153B:542-548.

Deng X, Wang G, Zhou L, Zhang X, Yang M, Han G, . . . Liu B. Randomized controlled trial of adjunctive EEG-biofeedback treatment of obsessive-compulsive disorder. Shanghai archives of psychiatry. Oct 2014;26(5):272-279.

Denys D, Mantione M. Deep brain stimulation in obsessive-compulsive disorder. Progress in brain research. 2009;175:419-427.

Denys D, Zohar J, Westenberg HG. The role of dopamine in obsessive-compulsive disorder: preclinical and clinical evidence. The Journal of clinical psychiatry. 2004;65 Suppl 14:11-17.

Dèttore D, Pozza A, Andersson G. Efficacy of Technology-delivered Cognitive Behavioural Therapy for OCD Versus Control Conditions, and in Comparison with Therapist-Administered CBT: Meta-Analysis of Randomized Controlled Trials. Cognitive Behaviour Therapy. 2015;44(3):190–211.

Dodson ER, Zee PC. Therapeutics for Circadian Rhythm Sleep Disorders. Sleep medicine clinics. Dec 2010;5(4):701-715.

Dubovsky SL, Warren C. Agomelatine, a melatonin agonist with antidepressant properties. Expert opinion on investigational drugs. Oct 2009;18(10):1533-1540.

Ercan TE, Ercan G, Severge B, Arpaozu M, Karasu G. Mycoplasma pneumoniae infection and obsessive-compulsive disease: a case report. Journal of child neurology. Mar 2008;23(3):338-340.

Eriguchi M, Levi F, Hisa T, Yanagie H, Nonaka Y, Takeda Y. Chronotherapy for cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. Oct 2003;57 Suppl 1:92s-95s.

Farris SG, McLean CP, Van Meter PE, Simpson HB, Foa EB. Treatment Response, Symptom Remission, and Wellness in Obsessive-Compulsive Disorder. J. Clin. Psychiatry. 2013;74(7):685–90.

Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry. 1996;153(9):1219–21.

Gentil AF, Lopes AC, Dougherty DD, Ruck C, Mataix-Cols D, Lukacs TL, . . . Miguel EC. Hoarding symptoms and prediction of poor response to limbic system surgery for treatment-refractory obsessive-compulsive disorder. Journal of neurosurgery. Jul 2014;121(1):123-130.

Georgiadou G, Tarantilis PA, Pitsikas N. Neuroscience Letters. Neuroscience Letters. 2012;528(1):27–30.

Ghasemi T, Abnous K, Vahdati F, Mehri S, Razavi BM, Hosseinzadeh H. Antidepressant Effect of Crocus sativus Aqueous Extract and its Effect on CREB, BDNF, and VGF Transcript and Protein Levels in Rat Hippocampus. Drug research. Apr 2 2014.

Glazier K, Calixte RM, Rothschild R, Pinto A. High rates of OCD symptom misidentification by mental health professionals. Annals of Clinical. 2013;25(3):201-9.

Goodman WK, Price LH, Rasmussen SA. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989;46(11):1006–11.

Grant JE. Obsessive–Compulsive Disorder. N Engl J Med. 2014;371(7):646–53.

Greenberg WM, Benedict MM, Doerfer J. Adjunctive glycine in the treatment of obsessive-compulsive disorder in adults. Journal of Psychiatric Research. Journal of Psychiatric Research. 2009;43(6):664–70.

Grisham JR, Fullana MA, Mataix-Cols D, Moffitt TE, Caspi A, Poulton R. Risk factors prospectively associated with adult obsessive-compulsive symptom dimensions and obsessive-compulsive disorder. Psychol Med. 2011;41(12):2495–506.

Hale L, Strauss C, Taylor BL. The Effectiveness and Acceptability of Mindfulness-Based Therapy for Obsessive Compulsive Disorder: A Review of the Literature. Mindfulness. 2012;4(4):375–82.

Hammond DC. Neurofeedback with anxiety and affective disorders. Child Adolesc Psychiatr Clin N Am. 2005;14(1):105–23–vii.

Hammond C, Ammari R, Bioulac B, Garcia L. Latest view on the mechanism of action of deep brain stimulation. Mov. Disord. 2008;23(15):2111–21.

Hanstede M, Gidron Y, Nyklíček I. The Effects of a Mindfulness Intervention on Obsessive-Compulsive Symptoms in a Non-Clinical Student Population. The Journal of Nervous and Mental Disease. 2008;196(10):776–9.

Hariz MI and Hariz G-M. Therapeutic stimulation versus ablation. Handb Clin Neurol. 2013;116:63–71.

Harvey BH, Brink CB, Seedat S, Stein DJ. Defining the neuromolecular action of myo-inositol: application to obsessive-compulsive disorder. Progress in Neuropsychopharmacology & Biological Psychiatry. 2002;26(1):21–32.

Hausenblas HA, Saha D, Dubyak PJ, Anton SD. Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. J Integr Med. Nov 2013;11(6):377-383.

Hebbar S. Cognitive therapy of obsessive compulsive disorder with chronic tic disorder. Indian journal of psychological medicine. Jan 2013;35(1):93-95.

Hermesh H, Weizman A, Shahar A, Munitz H. Vitamin B12 and folic acid serum levels in obsessive compulsive disorder. Acta Psychiatr Scand. 1988;78(1):8–10.

Hertenstein E, Rose N, Voderholzer U. Mindfulness-based cognitive therapy in obsessive-compulsive disorder – A qualitativestudy on patients’ experiences. BMC Psychiatry. 2012;12(1):1–1.

Hesse S, Muller U, Lincke T, Barthel H, Villmann T, Angermeyer MC, . . . Stengler-Wenzke K. Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder. Psychiatry research. Oct 30 2005;140(1):63-72.

Hill RA, McInnes KJ, Gong ECH, Jones MEE, Simpson ER, Boon WC. Estrogen Deficient Male Mice Develop Compulsive Behavior. Biol. Psychiatry. 2007;61(3):359–66.

Hollander E, Stein DJ, Kwon JH, et al. Psychosocial Function and Economic Costs of Obsessive Compulsive Disorder. CNS Spectrums. 1997;2(10):16–25.

Hosseinzadeh H, Noraei NB. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytotherapy research: PTR. Jun 2009;23(6):768-774.

Innominato PF, Levi FA, Bjarnason GA. Chronotherapy and the molecular clock: Clinical implications in oncology. Advanced drug delivery reviews. Jul 31 2010;62(9-10):979-1001.

Jaafari N, Rachid F, Rotge JY, Polosan M, El-Hage W, Belin D, . . . Pelissolo A. Safety and efficacy of repetitive transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder: a review. World J Biol Psychiatry. Mar 2012;13(3):164-177.

Janowitz D, Grabe HJ, Ruhrmann S, Ettelt S, Buhtz F, Hochrein A, . . . Wagner M. Early onset of obsessive-compulsive disorder and associated comorbidity. Depression and anxiety. 2009;26(11):1012-1017.

Jung HH, Kim SJ, Roh D, et al. Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: a proof-of-concept study. Mol Psychiatry. 2014 Nov 25. [Epub ahead of print].

Kantak PA, Bobrow DN, Nyby JG. Obsessive–compulsive-like behaviors in house mice are attenuated by a probiotic (Lactobacillus rhamnosus GG). Behav Pharmacol. 2014;25(1):71–9.

Kasperczyk S, Dobrakowski M, Kasperczyk A, Romuk E, Rykaczewska-Czerwinska M, Pawlas N, Birkner E. Effect of N-acetylcysteine administration on homocysteine level, oxidative damage to proteins, and levels of iron (Fe) and Fe-related proteins in lead-exposed workers. Toxicology and industrial health. Mar 2 2015.

Kaurav BP, Wanjari MM, Chandekar A, Chauhan NS, Upmanyu N. Influence of Withania somnifera on obsessive compulsive disorder in mice. Asian Pac J Trop Med. 2012;5(5):380–4.

Kellner M. Drug treatment of obsessive-compulsive disorder. Dialogues in clinical neuroscience. 2010;12(2):187-197.

Kichuk SA, Torres AR, Fontenelle LF. Symptom dimensions are associated with age of onset and clinical course of obsessive-compulsive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2013;44:233–9.

Kisely S, Hall K, Siskind D, Frater J, Olson S, Crompton D. Deep brain stimulation for obsessive-compulsive disorder: a systematic review and meta-analysis. Psychol Med. 2014;44(16):3533–42.

Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Silveira da Mota Neto JI, . . . Leucht S. Amisulpride versus other atypical antipsychotics for schizophrenia. The Cochrane database of systematic reviews. 2010(1):Cd006624.

Koo MS, Kim EJ, Roh D, Kim CH. Role of dopamine in the pathophysiology and treatment of obsessive-compulsive disorder. Expert review of neurotherapeutics. Feb 2010;10(2):275-290.

Labad J, Menchon JM, Alonso P. Gender differences in obsessive-compulsive symptom dimensions. Depress. Anxiety. 2008;25(10):832–8.

Lafleur DL, Pittenger C, Kelmendi B. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl.). 2005;184(2):254–6.

Landeros-Weisenberger A, Bloch MH, Kelmendi B. Dimensional predictors of response to SRI pharmacotherapy in obsessive-compulsive disorder. J Affect Disord. 2010;121(1-2):175–9.

Lange KW, Lange KM, Hauser J, Tucha L, Tucha O. Circadian rhythms in obsessive–compulsive disorder. J Neural Transm. 2012;119(10):1077–83.

Lapidus KAB, Stern ER, Berlin HA, Goodman WK. Neuromodulation for Obsessive–Compulsive Disorder. Neurotherapeutics. 2014;11(3):485–95.

Leckman JF, Bloch MH, King RA. Symptom dimensions and subtypes of obsessive-compulsive disorder: a developmental perspective. Dialogues in clinical neuroscience. 2009;11(1):21-33.

Levine J. Controlled trials of inositol in psychiatry. European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology. May 1997;7(2):147-155.

Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Human psychopharmacology. Nov 2014;29(6):517-527.

Ma ZR, Shi LJ. Repetitive transcranial magnetic stimulation (rTMS) augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant obsessive-compulsive disorder (OCD): a meta-analysis of randomized controlled trials. International journal of clinical and experimental medicine. 2014;7(12):4897-4905.

Malaty IA and Akbar U. Updates in medical and surgical therapies for Tourette syndrome. Curr Neurol Neurosci Rep. 2014;14(7):458.

Martiny K, Refsgaard E, Lund V, Lunde M, Sorensen L, Thougaard B, . . . Bech P. A 9-week randomized trial comparing a chronotherapeutic intervention (wake and light therapy) to exercise in major depressive disorder patients treated with duloxetine. The Journal of clinical psychiatry. Sep 2012;73(9):1234-1242.

Martiny K, Refsgaard E, Lund V, Lunde M, Thougaard B, Lindberg L, Bech P. Maintained superiority of chronotherapeutics vs. exercise in a 20-week randomized follow-up trial in major depression. Acta psychiatrica Scandinavica. 2015;131(6):446-57.

Masi G, Millepiedi S, Mucci M, Bertini N, Pfanner C, Arcangeli F. Comorbidity of obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in referred children and adolescents. Comprehensive psychiatry. Jan-Feb 2006;47(1):42-47.

Mataix-Cols D, Boman M, Monzani B. Population-Based, Multigenerational Family Clustering Study of Obsessive-compulsive Disorder. JAMA Psychiatry. 2013;70(7):709.

Mataix-Cols D, Marks IM, Greist JH, Kobak KA, Baer L. Obsessive-compulsive symptom dimensions as predictors of compliance with and response to behaviour therapy: results from a controlled trial. Psychother Psychosom. 2002;71(5):255–62.

Mattheisen M, Samuels JF, Wang Y, et al. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry. 2015;20(3):337–44.

Mayo Clinic. Obsessive-compulsive disorder (OCD). Available at: http://www.mayoclinic.org/diseases-conditions/ocd/basics/definition/con-20027827. Last updated 8/9/2013. Accessed 8/14/2014.

Mayo Clinic. Tests and Procedures page. Transcranial magnetic stimulation. Available at: http://www.mayoclinic.org/tests-procedures/transcranial-magnetic-stimulation/basics/definition/prc-20020555. 2/4/2015. Accessed 3/31/2015.

Mazzio EA, Harris N, Soliman KF. Food constituents attenuate monoamine oxidase activity and peroxide levels in C6 astrocyte cells. Planta medica. Oct 1998;64(7):603-606.

McKay D, Sookman D, Neziroglu F, Wilhelm S, Stein DJ, Kyrios M, . . . Veale D. Efficacy of cognitive-behavioral therapy for obsessive–compulsive disorder. Psychiatry research. 2/28/2015;225(3):236-246.

Metin O, Yazici K, Tot S, Yazici AE. Amisulpiride augmentation in treatment resistant obsessive-compulsive disorder: an open trial. Hum Psychopharmacol. 2003;18(6):463–7.

Miodownik C, Bergman J, Lerner PP, Kreinin A, Lerner V. Amisulpride as add-on treatment for resistant obsessive-compulsive disorder: retrospective case series. Clin Neuropharmacol. 2015;38(1):26–9.

Murphy DL, Timpano KR, Wheaton MG, Greenberg BD, Miguel EC. Obsessive-compulsive disorder and its related disorders: a reappraisal of obsessive-compulsive spectrum concepts. Dialogues in clinical neuroscience. 2010;12(2):131-148.

Nakao T, Okada K, Kanba S. Neurobiological model of obsessive-compulsive disorder: evidence from recent neuropsychological and neuroimaging findings. Psychiatry Clin. Neurosci. 2014;68(8):587–605.

National Collaborating Centre for Mental Health. National Institute for Health and Clinical Excellence: Guidance. Obsessive-Compulsive Disorder: Core Interventions in the Treatment of Obsessive-Compulsive Disorder and Body Dysmorphic Disorder. Leicester (UK): British Psychological Society. The British Psychological Society & The Royal College of Psychiatrists. 2006;1-350.

Nicholas LM, Runge MS (ed.). Netter’s Internal Medicine, Second Edition. Chapter 167: Obsessive Compulsive Disorder. Copyright 2009 by Saunders, an Imprint of Elsevier Inc. Available at: www.clinicalkey.com. Accessed 1/29/2015.

Nicolini H. Serotonin transporter gene polymorphisms & obsessive-compulsive disorder. The Indian journal of medical research. Dec 2010;132:663-666.

NIH. National Institute of Mental Health. Health & Education page. What are brain stimulation therapies? Available at: http://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml. Accessed 3/31/2015. 2015.

NLM. U.S. National Library of Medicine. Obsessive-compulsive disorder: Treatment of obsessive-compulsive behavior. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072745/. Last updated 9/10/2014. Accessed 4/14/2015.

Nota JA, Sharkey KM, Coles ME. Sleep, arousal, and circadian rhythms in adults with obsessive-compulsive disorder: A meta-analysis. Neurosci Biobehav Rev. 2015;51C:100–7.

Ozdemir E, Cetinkaya S, Ersan S, Kucukosman S, Ersan EE. Serum selenium and plasma malondialdehyde levels and antioxidant enzyme activities in patients with obsessive-compulsive disorder. Progress in Neuropsychopharmacology & Biological Psychiatry. 2009;33(1):62–5.

Pace SM, Thwaites R, Freeston MH. Exploring the role of external criticism in Obsessive Compulsive Disorder: a narrative review. Clin Psychol Rev. 2011;31(3):361–70.

Pakseresht S, Boostani H, Sayyah M. Extract of valerian root (Valeriana officinalis L.) vs. placebo in treatment of obsessive-compulsive disorder: a randomized double-blind study. J Complement Integr Med. 2011;8(1). DOI: 10.2022/1553-3840.1465.

Pallanti S, Grassi G, Sarrecchia ED, Cantisani A, Pellegrini M. Obsessive-compulsive disorder comorbidity: clinical assessment and therapeutic implications. Frontiers in psychiatry. 2011;2:70.

Pauls DL, Abramovitch A, Rauch SL, Geller DA. Obsessive–compulsive disorder:an integrative genetic and neurobiological perspective. Nat. Rev. Neurosci. 2014;15(6):410–24.

Pepper J, Hariz M, Zrinzo L. Deep brain stimulation versus anterior capsulotomy for obsessive-compulsive disorder: a review of the literature. Journal of neurosurgery. Jan 30 2015:1-10.

Pitsikas N, Boultadakis A, Georgiadou G, Tarantilis PA, Sakellaridis N. Effects of the active constituents of Crocus sativus L., crocins, in an animal model of anxiety. Phytomedicine: international journal of phytotherapy and phytopharmacology. Dec 2008;15(12):1135-1139.

Pittenger C, Bloch MH, Williams K. Glutamate abnormalities in obsessive compulsive disorder: Neurobiology, pathophysiology, and treatment. Pharmacol. Ther. 2011;132(3):314–32.

Pittenger C, Kelmendi B, Bloch M, Krystal JH, Coric V. Clinical treatment of obsessive compulsive disorder. Psychiatry (Edgmont (Pa. : Township)). Nov 2005;2(11):34-43.

Ponniah K, Magiati I, Hollon SD. An update on the efficacy of psychological therapies in the treatment of obsessive-compulsive disorder in adults. Journal of obsessive-compulsive and related disorders. Apr 1 2013;2(2):207-218.

Portaluppi F, Smolensky MH. Perspectives on the chronotherapy of hypertension based on the results of the MAPEC study. Chronobiology international. Sep 2010;27(8):1652-1667.

Pratte MA, Nanavati KB, Young V, Morley CP. An alternative treatment for anxiety: a systematic review of human trial results reported for the Ayurvedic herb ashwagandha (Withania somnifera). Journal of alternative and complementary medicine. Dec 2014;20(12):901-908.

Rector NA, Richter MA, Lerman B, Regev R. A Pilot Test of the Additive Benefits of Physical Exercise to CBT for OCD. Cognitive behaviour therapy. Mar 4 2015:1-13.

Romanelli RJ, Wu FM, Gamba R, Mojtabai R, Segal JB. Behavioral therapy and serotonin reuptake inhibitor pharmacotherapy in the treatment of obsessive-compulsive disorder: a systematic review and meta-analysis of head-to-head randomized controlled trials. Depression and anxiety. Aug 2014;31(8):641-652.

Rosario-Campos MC, Miguel EC, Quatrano S, Chacon P, Ferrao Y, Findley D, . . . Leckman JF. The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS): an instrument for assessing obsessive-compulsive symptom dimensions. Molecular psychiatry. May 2006;11(5):495-504.

Russell EJ, Fawcett JM, Mazmanian D. Risk of Obsessive-Compulsive Disorder in Pregnant and Postpartum Women. J. Clin. Psychiatry. 2013;74(04):377–85.

Rück C, Karlsson A, Steele JD. Capsulotomy for obsessive-compulsive disorder: long-term follow-up of 25 patients. Arch Gen Psychiatry. 2008;65(8):914–21.

Saba G, Moukheiber A, Pelissolo A. Transcranial cortical stimulation in the treatment of obsessive-compulsive disorders: efficacy studies. Current psychiatry reports. May 2015;17(5):571.

Sahoo MK, Avasthi A, Singh P. Negative symptoms presenting as neuropsychiatric manifestation of vitamin B12 deficiency. Indian journal of psychiatry. Oct 2011;53(4):370-371.

Sarris J, Camfield D, Berk M. Journal of Affective Disorders. J Affect Disord. 2012;138(3):213–21.

Sayyah M, Boostani H, Pakseresht S, Malayeri A. Comparison of Silybum marianum (L.) Gaertn. With fluoxetine in the treatment of Obsessive-Compulsive Disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2010;34(2):362–5.

Sayyah M, Olapour A, Saeedabad YS, Parast RY, Malayeri A. Evaluation of oral zinc sulfate effect on obsessive-compulsive disorder: A randomized placebo-controlled clinical trial. Nutrition. 2012;28(9):892–5.

Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, . . . Scatton B. Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. The Journal of pharmacology and experimental therapeutics. Jan 1997;280(1):83-97.

Seibell PJ, Pallanti S, Bernardi S, Hughes ME, Hollander E. ePocrates. Obsessive-compulsive disorder. Available at: https://online.epocrates.com/u/2911362/Obsessive-compulsive+disorder. Last updated 4/16/2013. Accessed 8/19/2014.

Shahmansouri N, Farokhnia M, Abbasi SH, Kassaian SE, Noorbala Tafti AA, Gougol A, . . . Akhondzadeh S. A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus L. with fluoxetine for improving mild to moderate depression in post percutaneous coronary intervention patients. J Affect Disord. Feb 2014;155:216-222.

Sharma V and Biswas D. Cobalamin deficiency presenting as obsessive compulsive disorder: case report. General Hospital Psychiatry. 2012;34(5):578.e7–578.e8.

Shohag H, Ullah A, Qusar S, Rahman M, Hasnat A. Alterations of Serum Zinc, Copper, Manganese, Iron, Calcium, and Magnesium Concentrations and the Complexity of Interelement Relations in Patients with Obsessive–Compulsive Disorder. Biological Trace Element Research. 2012;148(3):275–80.

Singh N, Bhalla M, de Jager P, Gilca M. An overview on ashwagandha: a Rasayana (rejuvenator) of Ayurveda. African journal of traditional, complementary, and alternative medicines: AJTCAM / African Networks on Ethnomedicines. 2011;8(5 Suppl):208-213.

Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, . . . Refsum H. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PloS one. 2010;5(9):e12244.

Soomro GM, Altman D, Rajagopal S, et al. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD) Cochrane Database System Review. 2008;1:CD001765.

Soomro GM. Obsessive compulsive disorder. Clinical evidence. 2012;2012.

Stewart SE, Yu D, Scharf JM, et al. Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry. 2013;18(7):788-98.

Sudak D. First Consult. Obsessive Compulsive Disorder. Copyright Elsevier BV. Available at www.clinicalkey.com. Last updated 12/6/2012. Accessed 8/14/2014.

Sürmeli T and Ertem A. Obsessive Compulsive Disorder and the Efficacy of qEEG-Guided Neurofeedback Treatment: A Case Series. Clinical EEG and Neuroscience. 2011;42(3):195–201.

Svestka J, Synek O, Tomanova J, Rodakova I, Cejpkova A. Differences in the effect of second-generation antipsychotics on prolactinaemia: six weeks open-label trial in female in-patients. Neuro endocrinology letters. Dec 2007;28(6):881-888.

Szarfman A, Tonning JM, Levine JG, et al. Atypical Antipsychotics and Pituitary Tumors: A Pharmacovigilance Study. Pharmacotherapy. 2006;26(6):748-758.

Taylor LH and Kobak KA. An open-label trial of St. John's Wort (Hypericum perforatum) in obsessive-compulsive disorder. J. Clin. Psychiatry. 2000;61(8):575–8.

Torres AR, Fontenelle LF, Ferrao YA, do Rosario MC, Torresan RC, Miguel EC, Shavitt RG. Clinical features of obsessive-compulsive disorder with hoarding symptoms: a multicenter study. Journal of psychiatric research. Jun 2012;46(6):724-732.

Türksoy N, Bilici R, Yalciner A, et al. Vitamin B12, folate, and homocysteine levels in patients with obsessive compulsive disorder. NDT. 2014;10:1671-5.

Tzavellas E, Karaiskos D, Ilias I, Liappas I, Paparrigopoulos T. Agomelatine augmentation in obsessive compulsive disorder: a preliminary report. Psychiatrike = Psychiatriki. Jul-Sep 2014;25(3):179-184.

Umathe S, Vaghasiya J, Jain N, Dixit P. Neurosteroids modulate compulsive and persistent behavior in rodents: implications for obsessive-compulsive disorder. Progress in neuro-psychopharmacology & biological psychiatry. Oct 1 2009;33(7):1161-1166.

Upadhyaya SK and Sharma A. Obsessive Compulsive Disorder due to B12 Deficiency: Justification Required. Indian J Psychol Med. 2012;34(3):298–9.

Valizadeh M and Valizadeh N. Obsessive compulsive disorder as early manifestation of B12 deficiency. Indian J Psychol Med. 2011;33(2):203–4.

van Zandwijk N. N-acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer. Journal of cellular biochemistry. Supplement. 1995;22:24-32.

Veale D, Roberts A. Obsessive-compulsive disorder. BMJ (Clinical research ed.). 2014;348:g2183.

Visser HA, van Minnen A, van Megen H. The Relationship Between Adverse Childhood Experiences and Symptom Severity, Chronicity, and Comorbidity in Patients With Obsessive-Compulsive Disorder. J. Clin. Psychiatry. 2014;75(10):1034–9.

Walsh KH, McDougle CJ. Psychotherapy and medication management strategies for obsessive-compulsive disorder. Neuropsychiatric disease and treatment. 2011;7:485-494.

Watanabe Y, Halberg F, Otsuka K, Cornelissen G. Toward a personalized chronotherapy of high blood pressure and a circadian overswing. Clinical and experimental hypertension (New York, N.Y.: 1993). 2013;35(4):257-266.

Whittal ML, Thordarson DS, McLean PD. Treatment of obsessive–compulsive disorder: Cognitive behavior therapy vs. exposure and response prevention. Behaviour Research and Therapy. 2005;43(12):1559-1576.

Williams MT, Mugno B, Franklin M, Faber S. Symptom dimensions in obsessive-compulsive disorder: phenomenology and treatment outcomes with exposure and ritual prevention. Psychopathology. 2013;46(6):365-376.

Yip AG, Satterfield JM, Ferri FF (ed.) Ferri’s Clinical Advisor. Obsessive-Compulsive Disorder (OCD). Copyright 2014 by Mosby, and Imprint of Elsevier Inc. Available at: www.clinicalkey.com. Accessed 1/29/2015.

Young EA, Kornstein SG, Harvey AT. Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression. Psychoneuroendocrinology. 2007;32(7):843–53.