Cynthia K. Kirkwood, Sarah T. Melton, and Barbara G. Wells
KEY CONCEPTS
The short-term goal in posttraumatic stress disorder (PTSD) is reduction in core symptoms, while the long-term goal is remission.
Cognitive behavioral therapy and eye movement desensitization and reprocessing are the most effective nonpharmacologic methods to reduce symptoms of PTSD.
The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are considered first-line treatments for PTSD.
An adequate trial of SSRIs in PTSD requires appropriate dosing and duration of treatment.
Patients with PTSD who respond to pharmacotherapy should continue treatment for at least 12 months.
SSRIs are the drugs of choice for the treatment of obsessive-compulsive disorder (OCD).
Augmentation of SSRI treatment with low doses of antipsychotics may be helpful.
If an inadequate response to an SSRI for OCD occurs after 4 to 6 weeks at the maximum dose, switch to another SSRI.
Medication taper can be considered after 1 to 2 years of treatment in patients with OCD.
Traumatic world or local events (e.g., wars, terrorist attacks, natural disasters, kidnappings, interpersonal violence) can lead to development of posttraumatic stress disorder (PTSD). Initially diagnosed in veterans of war, PTSD is now acknowledged as a significant psychiatric illness in the civilian population and more recently among deployed service personnel of the Afghanistan and Iraq campaigns in whom the suicide rate has escalated.1–3 PTSD continues to be poorly recognized and diagnosed in clinical practice.4 Because of its co-occurrence with other anxiety disorders, depression, substance abuse, and traumatic brain injury, the overlapping symptoms can lead to diagnostic uncertainty. Advances in the science and treatment of PTSD can assist clinicians in all fields of healthcare to screen patients for a history of trauma and effectively manage PTSD if it is present.
Intrusive obsessive thoughts and compulsive ritualistic behaviors characterize obsessive-compulsive disorder (OCD). OCD can be severely debilitating and impair functioning in social, family, and work settings, with an overall decrease in quality of life (QOL). OCD is associated with an increased risk of suicide, with 15% of patients reporting a previous history of suicide attempt.5 Increased understanding of symptom dimensions and treatment response can improve QOL in patients suffering from OCD.
EPIDEMIOLOGY
The estimated lifetime prevalence of PTSD is 6.8% in the U.S. population.6 Lifetime prevalence of OCD has been estimated at 2.3% in the general population and 2% to 4% in the pediatric population.7,8
PTSD is associated with the incidence of trauma. It is estimated that approximately 60% of men and 50% of women are exposed to a life-threatening traumatic event.6 Of these individuals 8.2% of men and 20% of women will develop PTSD. Previous exposure to a trauma and the intensity of response to the event increase the risk of PTSD. Men tend to be assaulted more frequently, but women have a higher rate of PTSD after assaults being more likely to experience rape and sexual abuse.6 Genetic factors can increase vulnerability to PTSD if an individual is exposed to a traumatic event. Offspring of Holocaust survivors had a higher lifetime prevalence rate of PTSD compared with a control group.6
The epidemiology of OCD is influenced by age and gender. OCD typically begins early in life, with 20% of cases occurring in childhood, 29% in adolescence, and 49% of cases occurring by age 20.1 Age of onset has a bimodal distribution with peaks around 10 and 21 years.7 The onset of illness is earlier in men than in women.8 Higher rates of other anxiety disorders are reported in first-degree relatives of patients with OCD.9 Early age of onset has been associated with higher probabilities of comorbid impulse control, somatoform, eating, and tic disorders.10 Heredity is stronger when there is an early age of onset or comorbidity with tic disorder.11
ETIOLOGY
The exact etiologies of PTSD and OCD are not known. It is likely that abnormalities in several areas of brain functioning interact to cause these chronic anxiety disorders. Genetics may play a role in expression of PTSD and OCD, but environmental factors likely are also involved. A genome-wide association study did not detect any single nucleotide polymorphisms (SNPs) associated with OCD but there was a significant enrichment of methylation quantitative trait loci (mQTLs) and frontal lobe expression of quantitative trait loci (eQTLs) in the highest ranked autosomal SNPs, suggesting that these signals may influence gene expression and perhaps the etiology of OCD.11Genetic etiologies of both PTSD and OCD are current research areas.
Controversy exists over the existence of a subtype of OCD characterized as a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). A relationship between the sudden onset of OCD and chronic tic disorder with an age of onset between 3 years and puberty with possible exacerbations and remissions, and a temporal association with streptococcal infection associated with symptoms of OCD or neurologic abnormalities has been proposed.12 Although most patients with OCD do not have a streptococcal etiology, an accurate medical history regarding onset of illness is imperative because specific treatment strategies are indicated.
PATHOPHYSIOLOGY
Research findings in the areas of neuroendocrinology, neurobiology, and neuroimaging have advanced a number of theories on the pathophysiology of anxiety disorders. Neuroendocrine changes in the hypothalamic–pituitary–adrenal (HPA) axis are implicated in the pathophysiology of PTSD.13 As reviewed in Chapter 53, data from neurochemical and neuroimaging studies indicate that the modulation of normal and pathologic anxiety states is associated with multiple regions of the brain (e.g., amygdala, hippocampus, thalamus, and prefrontal cortex).13,14 Abnormal function in several neurotransmitter systems, including norepinephrine (NE), γ-aminobutyric acid (GABA), glutamate, dopamine (DA), and serotonin (5-HT), may affect the manifestations of anxiety disorders.13,15
Neuroendocrine Theories
Neuroendocrine studies provide data that abnormalities occurring pretrauma, during trauma, and posttrauma contribute to PTSD. Normally the immediate reaction to stress occurs as an automatic response from the amygdala to the sympathetic and parasympathetic systems and the HPA axis.13 The release of corticotropin-releasing factor (CRF) stimulates cortisol secretion from the adrenal gland. Both catecholamines and cortisol levels rise in tandem. Cortisol reduces the stress response by tempering the sympathetic reaction through negative feedback on the pituitary and hypothalamus.13 These systems return to normal after a few hours.
Recent data implicate a role for the neuropeptides CRF and neuropeptide Y (NPY) in PTSD. Patients with PTSD have a hypersecretion of CRF but demonstrate subnormal levels of cortisol at the time of trauma and chronically.13Lower plasma cortisol concentrations were associated with greater severity of PTSD symptoms in nonmilitary patients.15 Dysregulation of the HPA axis is postulated to be a risk factor for eventual development of PTSD.13 Higher plasma concentrations of NPY were found in combat-exposed men who did not develop PTSD and could play a role in resiliency.15
Neurochemical Theories
Several neurotransmitters may be involved in the pathophysiology of PTSD. 5-HT, NE, and glutamate are associated with the processing of emotional and somatic contents of memories in the amygdala. The cortex and hippocampus are involved in storing the facts and related cues of memory.15 The noradrenergic theory posits that the autonomic nervous system of anxious patients is hypersensitive and overreacts to stimuli. The alarm center, the locus ceruleus, releases NE to stimulate the sympathetic and parasympathetic nervous systems. Hyperactive noradrenergic signaling in patients with PTSD is a consistent research finding and includes increased 24-hour catecholamine excretion.15Glutamate signaling abnormalities may result in distortion of amygdala-dependent emotional processing under stress.13,15Dysregulation of the processing of sensory input and memories may contribute to the dissociative and hypervigilant symptoms in PTSD. Abnormalities of GABA inhibition may lead to increased awareness or response to stress, as seen in PTSD.15
Both 5-HT and DA are implicated in the pathogenesis of OCD. Selective and potent serotonergic reuptake inhibitors have consistently been shown effective for symptoms of the illness.16–19 A recent meta-analysis concluded that higher doses of selective serotonin reuptake inhibitors (SSRIs) were associated with improved efficacy in the treatment of OCD.19 A Cochrane systematic review of 17 studies found that SSRIs were more effective than placebo in treating symptoms of OCD, and that SSRIs were similar to each other in efficacy.18 DA dysregulation may contribute to some forms of OCD. Neurologic symptoms (e.g., tics) are part of the clinical presentation in some patients with OCD. Tourette’s disorder, a disorder of DA function, is often a concurrent disease.1 Augmentation with antipsychotic drugs may improve symptoms in patients with OCD who are partially responsive to SSRIs.20
Neuroimaging Studies
Neuroimaging studies suggest that certain areas of the brain are altered by psychological trauma. In PTSD most functional neuroimaging studies have involved the amygdala, ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), and hippocampus. Findings of increased activation of the amygdala after trauma-related imagery, sounds, or smells indicate that this structure plays a role in the persistence of traumatic memory.14Decreased amygdala activation is correlated with resilience to PTSD and response to cognitive behavioral therapy (CBT).14 Hypofunctioning of the vmPFC is theorized to prevent extinction in patients with PTSD and is inversely correlated with severity of symptoms.14 Hyperresponsivity of the dACC and the insular cortex may correlate with impaired response to emotional stimuli or those that predict threat. The most consistent findings are decreased hippocampus volumes and N-acetylaspartate levels in patients with PTSD.13,14 In twin studies, the unaffected twin of patients with PTSD also demonstrated smaller hippocampi compared with twins without PTSD. These findings suggest that lower hippocampal volumes in patients with PTSD are likely a precursor associated with vulnerability for subsequent development of PTSD.13
Neuroimaging studies suggest that dysfunction in the cortical–striatal–thalamic circuits is responsible for impulsive behavior and inability to regulate socially acceptable behaviors.21 Drugs that decrease hyperactivity in the cortical–striatal–thalamic circuits decrease symptoms of OCD.11,22 Glutamate may play a role in OCD symptomatology.23
CLINICAL PRESENTATION
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision classifies anxiety disorders into several categories: generalized anxiety disorder, panic disorder (with or without agoraphobia), social anxiety disorder, specific phobia, OCD, PTSD, and acute stress disorder (ASD).1 The characteristic features of these illnesses are anxiety and avoidance behavior. Generalized anxiety disorder, panic disorder, and social anxiety disorder are discussed in Chapter 53.
Posttraumatic Stress Disorder
Exposure to a traumatic event is required for a diagnosis of PTSD.1 The person must have witnessed, experienced, or been confronted with a situation that involved definite or threatened death or serious injury, or possible harm to himself or herself or others. The patient’s response to the trauma must include intense fear, helplessness, or horror.1 Some examples of traumatic events include physical attacks by an intimate partner, traffic accidents, military combat, earthquakes, being held hostage, child sexual abuse, and witnessing a murder or injury of another.
The resulting PTSD symptoms include persistent reexperiencing of the traumatic event, avoidance of stimuli associated with the trauma, numbing of general responsiveness, and persistent symptoms of hyperarousal. Patients must have at least one reexperiencing symptom, at least three signs or symptoms of persistent avoidance of stimuli associated with the trauma, and at least two symptoms of increased arousal.1 Symptoms from each category need to be present for longer than 1 month and cause significant distress or impairment in functioning. Most persons diagnosed with PTSD also meet criteria for another mental disorder.1
CLINICAL PRESENTATION Posttraumatic Stress Disorder
Reexperiencing Symptoms
• Recurrent, intrusive distressing memories of the trauma
• Recurrent, disturbing dreams of the event
• Feeling that the traumatic event is recurring (e.g., dissociative flashbacks)
• Physiologic reaction to reminders of the trauma
Avoidance Symptoms
• Avoidance of conversations about the trauma
• Avoidance of thoughts or feelings about the trauma
• Avoidance of activities that are reminders of the event
• Avoidance of people or places that arouse recollections of the trauma
• Inability to recall an important aspect of the trauma
• Anhedonia
• Estrangement from others
• Restricted affect
• Sense of a foreshortened future (e.g., does not expect to have a career, marriage)
Hyperarousal Symptoms
• Decreased concentration
• Easily startled
• Hypervigilance
• Insomnia
• Irritability or anger outbursts
Subtypes
• Acute: duration of symptoms is less than 3 months
• Chronic: symptoms last for longer than 3 months
• With delayed onset: onset of symptoms is at least 6 months posttrauma
Data from references 1 and 25.
Anxiety and dissociative symptoms (e.g., absence of emotional responsiveness, derealization, inability to recall important features of the trauma) emerging within 1 month after exposure to a traumatic stressor are classified as ASD. Symptoms of ASD are experienced during or immediately after the trauma, last for at least 2 days, and resolve within 4 weeks.1
The age of onset and course of PTSD are variable. PTSD can occur at any age. The presentation is not predictable because symptoms are related to the duration and intensity of the trauma, the presence of other psychiatric disorders, and how the patient deals with the trauma. Symptoms emerge soon after a traumatic event and either dissipate or chronically persist in survivors.24 About 95% of patients who recover do so within a year, and 40% have persistent symptoms 6 years later. PTSD co-occurs with mood, anxiety, and substance use disorders. The course of illness is fluctuating, worsening with life stressors.24
CLINICAL PRESENTATION Obsessive-Compulsive Disorder
Obsessions
• Repetitive thoughts (e.g., feeling contaminated after touching an object, doubting whether the stove was turned off)
• Repetitive images (e.g., recurrent sexually explicit pictures)
• Repetitive impulses (e.g., need for symmetry or putting things in specific order, impulse to shout out obscenities in a church)
Compulsions
• Repetitive activities (e.g., hand washing, checking, ordering, need to ask, need to confess)
• Repetitive mental acts (e.g., counting, repeating words silently, praying)
Data from references 1 and 5.
Obsessive-Compulsive Disorder
Patients with OCD exhibit a great variety of symptoms on presentation to clinicians. The diversity and oddity of symptoms that manifest can obscure accurate diagnosis and delay appropriate treatment of the disorder. Patients can be secretive about symptoms and purposefully refuse to report symptoms.5 Patients can present in a seemingly incongruous manner to nonpsychiatrists for other complaints—dermatologists for eczema or chapped skin, pediatricians for parental concerns over a child’s compulsive hand washing, neurologists for tics, or dentists for gum lesions from compulsive teeth brushing.
The diagnostic criteria for OCD require the presence of obsessions and/or compulsions (although most patients have both) that are severe enough to cause marked distress, to be time-consuming (occupy more than 1 hour/day), and to cause significant impairment in social or occupational functioning.1 An obsession is a recurrent, persistent idea, thought, impulse, or image that is experienced as intrusive and inappropriate and produces marked anxiety. Common obsessions involve thoughts about contamination (e.g., concern with germs or dirt) and repeated doubts.1
Individuals must recognize that their obsessions or compulsions are excessive or unreasonable. Obsessions must be acknowledged as products of the individual’s own mind, and attempts must be made to ignore or suppress them. The obsessions produce marked feelings of anxiety and are not simply excessive worry about a real-life situation.1
A compulsion is defined as a repetitive behavior or mental act generally performed in response to an obsession. Diagnostically, compulsive behavior is not pleasurable and is designed to prevent discomfort or the occurrence of a dreaded event that is often unknown. For example, many patients are obsessed with feelings of doubt (e.g., whether a door was left unlocked), causing them marked distress and leading to repetitive checking (or compulsive behaviors). These behaviors are usually performed according to certain rules or in a stereotyped fashion. Because patients recognize their compulsive behavior as silly or senseless, they become extremely adept at denying symptoms, disguising their rituals, and concealing their illness from friends and family.1
Patients with OCD often have concurrent depression, other anxiety disorders, and substance abuse. It is a chronic illness in most patients, with severity of symptoms varying in intensity over time. Many patients with OCD have significantly impaired QOL and ability to function.5
TREATMENT
Posttraumatic Stress Disorder
Desired Outcome
The short-term goal of therapy in the management of PTSD is reduction in core symptoms (i.e., intrusive reexperiencing, avoidance, and hyperarousal). Patients should also have improvements in disability, concurrent psychiatric conditions, and QOL. The long-term goal in PTSD is remission.
General Approach to Treatment
In general, patients who seek treatment acutely after a trauma and are in intense distress should receive therapy based on their presenting symptoms (e.g., a nonbenzodiazepine hypnotic for difficulty sleeping). Short courses of exposure-based, trauma-focused cognitive behavioral therapy (TFCBT) can be helpful to prevent chronic PTSD in patients who present during the first 3 months of the event.26 If symptoms (e.g., hyperarousal, avoidance, dissociation, sleep difficulties, or depressed mood) persist for 3 to 4 weeks and the patient experiences marked social, occupational, and/or interpersonal impairment, they can be treated with pharmacotherapy, psychotherapy, or both. Many patients with PTSD will improve substantially with pharmacotherapy but retain some symptoms. Treatment regimens usually combine psychoeducation, psychosocial support and/or treatment, and pharmacotherapy.24,25
Nonpharmacologic Therapy
Psychotherapy can be used when a patient suffers from mild symptoms, in patients who prefer not to use medications, or in conjunction with drugs in patients with severe symptoms to improve response. Patients who have experienced trauma should be educated that they can experience anxiety, depression, nightmares, and even flashbacks as a reaction to the event. Brief courses of prolonged exposure, a form of CBT, in close proximity to the traumatic event resulted in lower rates of PTSD 3 and 6 months later.4,26 Single-session critical incident stress debriefing was not shown to be effective in preventing development of PTSD and actually can cause harm.26,27
Psychotherapies for treating PTSD include stress management, TFCBT, eye movement desensitization and reprocessing (EMDR), and psychoeducation.28 Short-term reductions in symptoms can be achieved with stress management, group therapy, hypnosis, or psychodynamic therapy.27,28 The cognitive and behavioral approaches of TFCBT and EMDR are more effective than stress management or group therapy to reduce symptoms of PTSD.28Psychoeducation includes information about the disease state, treatment options, and avoidance of excessive use of alcohol and other substances of abuse. Novel nonpharmacologic approaches (e.g., interpersonal psychotherapy, narrative exposure therapy, imagery modification) and delivery methods (e.g., telemedicine, computer-delivered CBT) are under study.29
Pharmacologic Therapy
Antidepressants are the major pharmacotherapeutic treatment for PTSD. In addition to their efficacy in PTSD, these agents are also effective for concurrent depression and anxiety disorders. SSRIs and venlafaxine are the first-line pharmacotherapy of PTSD.27,30–32 The tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) can also be effective, but they have less favorable side effect profiles (Table 54-1). Both sertraline and paroxetine are approved for the acute treatment of PTSD,33,34 and sertraline is approved for the long-term (i.e., 52 weeks) management of PTSD.34 A number of drugs can be used as augmentation agents (e.g., antiadrenergic drugs and atypical antipsychotics).31,32 Benzodiazepines are not effective for PTSD.31,32 A number of treatment guidelines are published.35 Table 54-2provides a summary of key points from the treatment guidelines for PTSD. An algorithm for the treatment of PTSD appears in Figure 54-1.
TABLE 54-1 Dosing of Antidepressants in the Treatment of Posttraumatic Stress Disorder
TABLE 54-2 Summary of Key Points in Treatment Guidelines for the Pharmacologic Treatment of Posttraumatic Stress Disorder
FIGURE 54-1 Algorithm for the pharmacotherapy of posttraumatic stress disorder (PTSD). (Data from references 27 and 31.)
Antidepressant Therapy
Selective Serotonin Reuptake Inhibitors SSRIs act pharmacologically to enhance serotonergic functioning. Large prospective studies documented the efficacy of sertraline and paroxetine in the acute management of PTSD. Approximately 60% of the patients show improvement.30 In general, SSRIs reduced the numbing symptoms of PTSD, whereas other drugs did not. Adverse reactions reported in patients with PTSD treated with SSRIs include GI symptoms, sexual dysfunction, insomnia, and agitation. Long-term use of SSRIs (durations of 9 to 12 months) was effective in preventing relapse.30–32
Other Antidepressants The serotonin–norepinephrine reuptake inhibitor (SNRI) venlafaxine has shown efficacy in PTSD. In a 12-week, placebo-controlled trial comparing venlafaxine extended-release and sertraline, venlafaxine was effective in reducing the avoidance/numbing and hyperarousal clusters of PTSD, whereas sertraline improved all PTSD symptom clusters.36 The remission rates for venlafaxine extended-release were 30.2% after 12 weeks36 and 50.1% after 6 months.37
Other antidepressants have been studied in controlled trials. Mirtazapine was effective on global ratings of symptoms in 64% of patients with PTSD in doses up to 45 mg/day and is considered a second-line agent.27,31 Bupropion sustained-release was not effective in patients with chronic PTSD.38
The TCAs amitriptyline and imipramine are also considered second-line agents, and the MAOI phenelzine is considered a third-line antidepressant if therapeutic trials of SSRIs or venlafaxine have failed. TCAs are associated with a higher burden of adverse effects compared with SSRIs (e.g., daytime drowsiness, toxicity in overdose, and poor compliance).27,31
Alternative Drug Treatments
Atypical antipsychotics, α1-adrenergic antagonists, antidepressants, mood stabilizers, and anticonvulsants can be used as augmenting agents for persistent symptoms, in cases of partial response to SSRI therapy after 4 to 6 weeks, or for comorbidities.39 Risperidone reduced PTSD symptoms in combat veterans on antidepressants with and without psychosis.40 Olanzapine added adjunctively to SSRIs decreased PTSD symptoms and significantly improved sleep compared with placebo. Patients gained an average of 13.2 lb (6 kg) over the course of the 8-week trial.40 Quetiapine reduced core PTSD symptoms over an 8-week period when added to concurrent therapy.41 Overall there is a modest positive effect of risperidone and quetiapine in double-blind trials with intrusive and hypervigilance symptoms showing the most improvement.42
Prazosin can be useful in some patients with PTSD. It decreased nightmares and sleep disturbances and improved the core PTSD symptoms in daily doses of 1 to 4 mg. Its presumed mechanism of action is reduction of noradrenergic transmission.43,44 Other options for persistent sleep disturbances with less evidence include trazodone, mirtazapine, and atypical antipsychotics.44
Anticonvulsants can assist in reducing impulsive anger and can also be used in patients with comorbid bipolar disorder. Some data support efficacy of lamotrigine as an augmenting agent. Data with other anticonvulsants are inconsistent.39 The use of an anticonvulsant is not recommended as monotherapy.27
Special Populations
Children who experience stress and trauma (e.g., sexual or physical abuse or loss of a parent) are predisposed to develop mood and anxiety disorders. SSRIs are the initial pharmacologic agents of choice in this patient population. Psychotherapy is also a treatment option (e.g., play therapy).45
Dosage and Administration
Acute Phase PTSD symptoms respond slowly to pharmacotherapy, and some patients never experience full resolution. SSRIs should be started 3 to 4 weeks after exposure to a trauma in patients with no improvement in their acute stress response. The initiation of an SSRI should be at a low dose with gradual titration upward toward antidepressant doses. 
Eight to 12 weeks is an appropriate duration of antidepressant therapy to determine response.27,46
Continuation Phase Many patients are undergoing psychotherapy during the continuation phase of therapy, and dosages can vary as patients deal with past traumatic experiences. During this phase symptoms continue to improve, and the maximal drug benefit (i.e., improvement of disability) accrues.46 Six-month relapse prevention trials in patients responsive to fluoxetine or sertraline indicate low rates of relapse with SSRI therapy compared with placebo.46
Maintenance and Discontinuation Patients with PTSD who respond to pharmacotherapy should continue treatment for at least 12 months.31 If residual symptoms persist, drug therapy should be continued. The decision about when to discontinue therapy is based on response to therapy, presence of ongoing stresses, and adverse effects. The patient must be confident in the discontinuation plan and can require extra support throughout the process. Drug therapy should be withdrawn and tapered slowly over a period of at least 1 month to reduce the potential for relapse.
Personalized Pharmacotherapy
The choice of pharmacotherapy should be individualized to the patient’s presenting symptoms. Selection of an SSRI or venlafaxine monotherapy is based on the patient’s history of prior response, safety, and side effect tolerability. When selecting an agent, the clinician should consider the potential for adverse consequences in patients with comorbid conditions (e.g., anticholinergic effects and weight gain with paroxetine in patients with diabetes, obesity, or benign prostatic hypertrophy) or adverse effects (e.g., insomnia with fluoxetine in patients with sleep difficulties). Increased risk of suicidality should be considered in patients taking antidepressants who are less than 25 years of age. If symptoms of insomnia or nightmares continue, prazosin can be added to provide relief. Risperidone or quetiapine can be added for patients who fail to respond or have a partial response to antidepressant therapy.
Clinical Controversy
It is unknown how long a patient with PTSD should be treated with an SSRI or venlafaxine to achieve a maximal response. The initial SSRI trial duration most clinicians use is 4 to 6 weeks, although sometimes up to 12 weeks is required.
Evaluation of Therapeutic Outcomes
During the acute phase of therapy, patients should be seen frequently. During months 3 to 6 of therapy, the patient can be seen monthly, and in months 6 to 12, visits can be extended to every 2 months. On each visit the patient should be asked about previously identified target symptoms of PTSD as well as other symptoms including insomnia, suicidal ideation, anger outbursts, irritability, psychosis, ongoing trauma, and disability. The Clinician-Administered PTSD Scale (CAPS) can be used by the clinician to assess symptom severity at visits.27 A remission in patients with PTSD is defined as a 70% or greater reduction in symptoms. Patients who have a 50% response or greater reduction in symptoms are considered to have an adequate response, while those with a 25% to 50% reduction in symptoms are considered partial responders. Before deciding that a patient is not responsive to pharmacotherapy, the clinician should ensure that the medication trial has been adequate in both dose and duration.
Many patients with PTSD are sensitive to the adverse effects of drugs. They should be monitored carefully for adverse reactions that can delay the escalation of drug dosages or cause the patient distress. See Chapter 51 for details on monitoring antidepressants. Routine assessment of the metabolic profile is necessary if an atypical antipsychotic is used concurrently.31 When pharmacotherapy is discontinued, patients should be seen more frequently and monitored carefully for signs of relapse or withdrawal.
TREATMENT
Obsessive-Compulsive Disorder
Desired Outcomes
Major goals of therapy for OCD include reduction in the frequency and severity of obsessive thoughts and time spent performing compulsive acts. Treatment for OCD generally does not completely eliminate obsessions or compulsions, but patients can feel remarkably improved with partial resolution of symptoms. Patients typically experience waxing and waning symptoms with only 20% achieving full remission.47 Optimal treatment increases psychosocial and occupational functioning and improves overall QOL. Efforts should be made to minimize adverse drug events and prevent drug interactions.
General Approach to Treatment
It is important at the outset of therapy to identify and document the specific target symptoms for pharmacotherapy. Rating scales can be used to measure symptom severity at baseline and during treatment to ascertain the degree of improvement. The Yale-Brown Obsessive-Compulsive Scale (YBOCS) is the most widely used clinician-administered scale. A QOL scale can assist the clinician in identifying other areas to target for treatment (e.g., depression and reduced physical well-being).48
The FDA has approved five antidepressants for the management of OCD: clomipramine, fluoxetine, fluvoxamine, paroxetine, and sertraline. CBT and SSRIs are considered effective first-line treatment modalities.49 Initial therapy may include CBT alone, SSRI monotherapy, or the combination of CBT and an SSRI, and is based on clinical judgment of symptom severity and patient preferences.49 CBT alone can be used in cooperative patients who do not desire drug therapy, or those with mild anxiety or depressive symptoms. Patients unable to participate in CBT or with a prior history of medication therapy response should be treated with SSRI monotherapy. Combined CBT and SSRIs is recommended in patients with failure on an SSRI alone or in those with severe OCD. If a combination of CBT and an SSRI is unsuccessful, another SSRI should be tried before augmentation therapy. If there is no response or partial response to combined CBT and three adequate antidepressant trials (one of which is clomipramine), augmentation with another drug and more intensive CBT can be tried.49 Augmentation with antipsychotics has proven efficacious in some patients with partial response.20,49
Table 54-3 provides a summary of key points from the treatment guidelines for OCD. Although some OCD symptoms can improve over the first 4 to 6 weeks of therapy, an adequate trial of any medication is considered to be 8 to 12 weeks.
TABLE 54-3 Summary of Key Points in Treatment Guidelines for Obsessive-Compulsive Disorder
Nonpharmacologic Therapy
A number of nonpharmacologic treatments are effective for OCD. CBT with behavioral techniques (i.e., exposure and response prevention [ERP]) is the most common initial nonpharmacologic treatment of choice. ERP is preferred for patients with mild symptoms, particularly children and adolescents, and in those without a psychiatric comorbidity or desire to avoid medications.50 Clinicians can use motivational interviewing techniques to assist patients with treatment acceptance.49
Other options are deep brain stimulation (DBS) and ablative neurosurgery.51 DBS is FDA-approved as a humanitarian device for severe, treatment-resistant OCD. It should not be used alone as first-line treatment but may be added to CBT or used in refractory patients. Surgery should be reserved for rare cases.49,51
Pharmacologic Therapy
Practice guidelines for the treatment of patients with OCD were published by the American Psychiatric Association.49
SSRIs are considered to be the drugs of choice for patients with OCD.49 While not FDA-approved, escitalopram has also shown efficacy in reduction of OCD symptoms.52 Clomipramine, a TCA with strong 5-HT reuptake inhibition, has an active metabolite, desmethylclomipramine, which inhibits NE reuptake.49,53 Meta-analytic findings of greater efficacy of clomipramine than SSRIs are not consistent with comparative trial data.49
Alternative Drug Treatments
Recent studies have examined novel augmentation approaches. Augmentation with the drugs that modulate the excitatory neurotransmitter glutamate (e.g., riluzole, memantine, and topiramate) have shown initial promising results.47,50 Ondansetron, dextroamphetamine, and D-cycloserine as possible augmentation agents in refractory OCD patients have had mixed results. These alternative augmenting treatments are reserved for refractory patients.47,49
Special Populations
Children and Adolescents OCD affecting children and adolescents is prevalent. There are symptom and treatment similarities and differences between OCD developing earlier in life and that which develops later. Younger patients exhibit poorer insight regarding obsessions, have more obsessions involving fear of harm and separation, and possess more rituals involving family members.7 CBT weekly or daily and including family members has also been effective.50 ERP is preferred as the first-line treatment for children and adolescents with milder symptom severity and less comorbidity.50 Effects of pediatric ERP have been reported to last up to 2 years.50 CBT and SSRI treatment are considered first-line for pediatric patients.54
Clomipramine, fluvoxamine, sertraline, paroxetine, and fluoxetine are approved by the FDA for treatment of OCD in children and adolescents.49 Childhood and adult OCD appear to respond similarly to drug therapy. SSRIs are effective (50% to 56% respond to the initial agent) and well tolerated in the treatment of OCD and are generally considered first-line agents.49,54 In children, the most commonly described side effects of SSRI therapy include sedation, nausea, diarrhea, insomnia, anorexia, tremor, and hyperstimulation.54 The starting dose of clomipramine in children is 25 mg daily in divided doses. The dose can be increased over the first 2 weeks up to 3 mg/kg or 100 mg, whichever is smaller. Over the next several weeks, the dose can be increased up to 3 mg/kg with a maximum of 200 mg daily.53 The risk of suicidality in youth is discussed in Chapter 51.
Hepatic and Renal Disease Clomipramine and the SSRIs are extensively metabolized in the liver, and patients with significant liver disease should be prescribed these drugs cautiously and in lower doses than those used in healthy subjects. The pharmacokinetics of sertraline is not altered in patients with significant renal dysfunction, and dosage adjustment is not necessary in these patients.34 Increased plasma concentrations of paroxetine occur in subjects with renal impairment.33 The initial dose of paroxetine should be reduced in patients with severe renal impairment, and upward titration should occur more slowly.33 No dosage adjustment is necessary for patients with renal impairment receiving clomipramine.53
Elderly Little information is available on treating OCD in the elderly. Case reports and anecdotal information suggest that the antiobsessional drugs are likely to be equally effective in the elderly and in younger adults.55 Selection of medication for an elderly person with OCD, however, should be based on history of response and adverse side effect profile. Treatment should be initiated with low doses in elderly patients, and doses should be increased slowly, with vigilance for emergence of side effects.49 Because of clomipramine’s sedative and anticholinergic side effects, it is not usually chosen as first-line therapy for elderly OCD patients.49 The use of SSRIs in elderly patients is discussed in Chapter 51.
Pregnancy Risk–benefit analysis should be made by practitioners when deciding to use pharmacotherapy options during pregnancy.49 The use of SSRIs in pregnancy and lactation is discussed in Chapter 51.
Antidepressant Therapy
Serotonergic Antidepressants The only potent 5-HT reuptake inhibitors consistently demonstrating efficacy in controlled trials are the TCA clomipramine and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline.
Current evidence indicates that 5-HT is important for the antiobsessional effects of medication.11,54 SSRIs and clomipramine inhibit 5-HT reuptake into the presynaptic neuron. Inhibiting reuptake of 5-HT makes more 5-HT available to postsynaptic receptors and reduces formation of the 5-HT metabolite 5-hydroxyindoleacetic acid. Although other antidepressants, such as imipramine and amitriptyline, inhibit 5-HT reuptake, they are less potent and selective than SSRIs. Prolonged exposure to increased amounts of 5-HT after chronic antidepressant treatment (2 to 3 weeks) leads to altered responsiveness of postsynaptic 5-HT receptors or presynaptic autoregulatory receptors that govern 5-HT release in specific brain regions. An improvement in obsessional symptoms may correlate with plasma concentrations of clomipramine but not desmethylclomipramine, the metabolite of clomipramine with less selectivity for 5-HT reuptake inhibition.
Most experts agree that SSRIs are better tolerated than clomipramine. SSRIs are less likely to cause cardiovascular, sedative, anticholinergic, and weight-gain side effects, and to reduce the seizure threshold. Clomipramine is less likely than SSRIs to cause insomnia, akathisia, nausea, and diarrhea. Antidepressant side effects can be more severe when larger doses are used and with faster dose escalation. Tolerance to antidepressant adverse effects often develops over 6 to 8 weeks of treatment, and tolerance is more likely to develop to nausea, diarrhea, sedation, diminished libido and/or orgasm, anxiety, restlessness, insomnia, and anticholinergic side effects than to akathisia.55
Pharmacokinetics Clomipramine is rapidly absorbed after oral administration. Maximum plasma concentrations occur within 2 to 6 hours. Clomipramine is highly protein-bound (97%) in the blood and has a half-life of 19 to 37 hours.53 The drug is metabolized to desmethylclomipramine, which is pharmacologically active. The pharmacokinetics of SSRIs is discussed in Chapter 51.
Efficacy SSRIs are effective in the treatment of OCD. Well-designed trials comparing these medications with placebo, head-to-head comparative trials, and meta-analyses have established that fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram are equally effective and that clomipramine may be somewhat more effective.16,52 Forty percent to 60% of patients with OCD respond to a serotonergic antidepressant, with remission occurring in 8% to 37% of patients. Most patients continue to have symptoms that limit their functioning.56
Other Antidepressants Venlafaxine, which acts as a 5-HT and NE reuptake inhibitor, may be effective for OCD.50,55
Augmentation with Antipsychotics 
Augmentation of SSRI treatment with low doses of antipsychotics may be helpful. Typical antipsychotics are generally not recommended because of an increased risk for extrapyramidal symptoms.47,55 One-third to one-half of treatment-refractory patients with OCD responded to antipsychotic augmentation.20,47 Evidence supports augmentation with low-dose risperidone or aripiprazole in short-term efficacy trials.20,57 The efficacy for olanzapine and quetiapine is inconclusive.20,58 The long-term use of second-generation antipsychotic augmentation resulted in modest improvement and higher rates of adverse effects (i.e., sedation, weight gain, increased blood glucose).59 The benefits and risks of using second-generation antipsychotic augmentation should be evaluated carefully.
Dosage and Administration Table 54-4 summarizes dosing guidelines for SSRIs and clomipramine. The dose to achieve response in OCD is often higher than doses used in other indications.49,60 If there is inadequate response to an average dose, then it should be incrementally increased to the maximum dose within 5 to 9 weeks from the start of treatment. 
If there is an inadequate response after 4 to 6 weeks at the maximum dose, then another SSRI should be tried.49 Eight to 12 weeks is considered an adequate trial before changing to another agent. Experts recommend waiting for a 3-month trial of an antidepressant before augmenting with a second-generation antipsychotic.20,60
TABLE 54-4 Dosing of Serotonin Reuptake Inhibitors in the Treatment of OCD
Although the appropriate maintenance dose of antidepressants is unknown, gradual dose reduction can occur in some patients without loss of efficacy.47
Personalized Pharmacotherapy
The choice of an SSRI for treatment is based on history of prior response, safety, and side effect tolerability of the patient. All SSRIs are considered to be equally efficacious, but a patient may respond better to one agent over another.49 When selecting pharmacotherapy, the clinician should consider FDA warnings (e.g., QTc prolongation for citalopram), potential for adverse consequences in patients with comorbid conditions (e.g., anticholinergic effects and weight gain with paroxetine in patients with diabetes, obesity, or benign prostatic hypertrophy), or adverse effects (e.g., insomnia with fluoxetine in patients with sleep difficulties). Increased risk of suicidality should be considered in patients taking SSRIs who are less than 25 years of age. Drug interactions should be avoided—citalopram, escitalopram, and sertraline have the least potential for inhibition of CYP450 isoenzymes (see Chap. 51).
Risks to consider with clomipramine include lethality in overdose in patients with suicidal ideation, anticholinergic effects in patients with constipation, narrow-angle glaucoma, or urinary hesitancy, and potential for seizures in patients with epilepsy. Clomipramine use is associated with the risk of QTc prolongation when used alone and in combination with other agents that prolong the QTc interval.53
Clinical Controversy…
When a patient with OCD has a partial response to an SSRI, it is unclear whether a second-generation antipsychotic should be used preferentially to increasing the dose of the SSRI or to augmenting with another agent, such as clomipramine. Many practitioners will increase the SSRI dose if well tolerated before adding in a low dose of an antipsychotic because of the risk of adverse effects.
Evaluation of Therapeutic Outcomes
Target symptoms of OCD should be monitored closely. The degree of response can indicate a need to modify dosage, change drug, or augment therapy. Rating scales can be used to monitor symptom response to therapy for OCD (e.g., YBOCS) and changes in QOL. The clinician should inquire about and address problematic adverse effects (including the emergence of suicidal ideation) reported by the patient and the amount of time the patient spends obsessing and performing compulsions. Changes in social and occupational functioning should be assessed.
Table 54-5 details the monitoring of clomipramine pharmacotherapy in patients with OCD. Monitoring of SSRIs can be found in Chapter 51 and antipsychotics in Chapter 50. After patients have responded to the acute phase of treatment, treatment gains are maintained with maintenance-phase strategies.
TABLE 54-5 Monitoring of Patients Being Treated for Obsessive-Compulsive Disorder
Monthly followup visits are recommended for at least 3 to 6 months, and a medication taper can be considered after 1 to 2 years of treatment. Medication should not be rapidly discontinued, and booster CBT sessions can reduce the risk of relapse when medication is withdrawn. The drug dosage can be decreased by 10% to 25% every 1 to 2 months with careful observation for symptom relapse.49 Some patients require lifelong medication therapy.
ABBREVIATIONS
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