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Improving Treatment Response in Panic Disorder

Mark Vanelli, MD, MHS

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 Primary Psychiatry. 2005;12(11):68-73

Faculty Affiliations and Disclosures

Dr. Vanelli is chief medical officer at Adheris Inc. in Burlington, and a lecturer in the Department of Psychiatry at Harvard Medical School in Boston, Massachusetts.

Disclosure: Dr. Vanelli has served as a consultant to and on the speaker’s bureaus of Eli Lilly, Janssen, Novartis, Pfizer, and Schwarz Pharma; and has received research support from Abbott.

Please direct all correspondence to: Mark Vanelli MD, MHS, Chief Medical Officer, Adheris Inc., 1 Van De Graaff Dr, Burlington, MA 01803; Tel: 781-425-6636; Fax: 718-229-8878; E-mail: mark.vanelli@adheris.com.
 

Focus Points

• Longitudinal studies of patients with panic and anxiety disorders under routine care suggest that the vast majority of patients will experience ongoing or breakthrough symptoms despite treatment.

• More effective medication strategies, in addition to psychosocial interventions, may help patients self-manage reoccurring symptoms.

• As-needed use of benzodiazepines can help individuals maintain function and quality of life when situational anxiety, avoidance, and panic threaten daily work and social situations.

• Co-therapy of a benzodiazepine and an antidepressant may help improve treatment outcomes by speeding the onset of anti-panic action. Careful follow-up and education at the initiation of therapy may help improve medication compliance.

 

Abstract 

Although antidepressants and benzodiazepines are effective in reducing the frequency of panic attacks during short-term clinical trials, follow-up studies suggest that under routine care, panic disorder is typically a chronic condition characterized by ongoing or breakthrough symptoms. As a result, panic disorder patients are likely to experience levels of work and role impairment similar to that experienced by patients with arthritis, asthma, and major depression. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often considered first-line drug therapy in treating panic disorder, but their effectiveness may be undermined by rates of premature medication discontinuation that may reach 30% to 55% within 3 months of initiating therapy. Strategies to improve treatment response in panic disorder, and anxiety disorders in general, include careful patient follow-up and education during the first 30 days after therapy is initiated, when the risk of medication discontinuation is greatest. Use of benzodiazepines, particularly on an as-needed or “rescue” basis, may be useful in helping patients better manage breakthrough episodes of anticipatory or situational anxiety, phobic avoidance, or panic that often returns and threatens daily function or quality of life. Recent studies suggest that the risk of significant dose escalation with chronic benzodiazepine use occurs in <2% of patients and that benzodiazepines generally provide a favorable risk-benefit profile.

 

Introduction

Panic disorder is common, costly, and often underdiagnosed in primary care settings. Although pharmacotherapy reduces the frequency of panic attacks in panic disorder, particularly in clinical trial settings, studies of patients with panic disorder under routine care suggest that ongoing symptoms and functional impairment are common.

Treatment for patients with panic disorder in primary care may be improved in two ways. First, rates of recognition and diagnosis can be increased; estimates of the prevalence of panic disorder in primary care range from 5% to 8%, but studies suggest that only 34% to 50% of patients with panic disorder are diagnosed and treated.1-3 Second, clinicians can focus on treatment strategies that are likely to help patients with panic disorder improve functioning and quality of life. At 6–10 years after diagnosis, an estimated 70% of patients remain symptomatic with ongoing or breakthrough symptoms.4 The degree of occupational impairment for panic disorder is estimated to be comparable to that associated with other chronic medical conditions, such as arthritis and heart disease.5

With the aim of aiding panic disorder diagnosis and improving the function and quality of life of panic disorder patients, this article will review symptoms of the disorder, diagnostic difficulties, treatment outcomes in clinical trials versus routine care, work and social impairment associated with the disorder, pharmacologic treatment strategies, and recommendations to improve treatment response in clinical practice.

Presenting Symptoms and Diagnostic Difficulties

Panic attacks are characterized by sudden onset of fear or discomfort accompanied by a combination of cardiac, pulmonary, gastrointestinal, neurological, and psychiatric symptoms, which typically peak in 10 minutes. Individuals with unexplained, recurrent panic attacks followed by at least 1 month of ongoing worry about having another attack, are diagnosed with panic disorder, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria.6 Although attacks are frightening and disabling in their own right, they are often accompanied by fear of having another attack (anticipatory anxiety) and avoidance of situations in which attacks have previously occurred or in situations from which escape may be difficult should they reoccur (panic disorder with agoraphobia). These avoidance patterns often lead to impaired role and work performance, and, in patients with agoraphobia, may leave individuals housebound.

Panic disorder symptoms mimic potentially life-threatening medical disorders. Therefore, patients often seek medical assistance soon after symptom onset, and present to medical rather than psychiatric providers. In one study that identified the site of care after a self-defined worst panic attack, patients reported seeking care from medical providers 52% of the time and from mental health professionals 17% of the time.7 Underdiagnosis and misdiagnosis may be common; the presentation of symptoms, which include numerous somatic manifestations, often result in referrals to cardiologists, gastroenterologists, or neurologists.3,8 Panic disorder may account for 40% to 60% of patients with atypical chest pain and normal cardiac catheterization findings; 20% to 40% of patients with irritable bowel symptoms; and 15% to 20% of the patients referred for evaluation of dizziness.9 Once patients present with “medical” symptoms, or attribute symptoms to a plausible psychosocial stressor, psychiatric diagnoses become less likely.10 Comorbid conditions can also complicate treatment.

Clinical Course of Panic Disorder During Routine Care

During clinical trials conducted under highly supervised conditions, 30% to 80% of patients with panic disorder achieve complete suppression of panic attacks. However, the trials typically occur over a period of weeks, which cannot determine how well patients fare under conditions of routine care over a period of years.11,12 To determine the degree of symptom relief achieved under conditions of routine care, investigators in the Harvard/Brown Anxiety Research Project (HARP) designed a prospective, longitudinal, observational study in which 711 subjects were evaluated with respect to the degree of symptom remission they experienced. Patients with diagnoses of panic disorder, panic disorder with agoraphobia, generalized anxiety disorder (GAD), or social phobia were enrolled and followed for an 8-year period. Exclusion criteria was kept to a minimum to reflect characteristics of patients in community medical practices.13-20 Recovery was defined as a 2-month period with minimal or no symptoms. Relapse was defined by a full return of symptoms meeting DSM-IV21 criteria for a 2-week period. Patients with ongoing symptoms were those reporting a continuation of moderate symptoms and functional impairment.  

This study found that low rates of recovery and high rates of relapse were the norm.15 The rates for women only are featured in Figure 1. Two-year remission rates for panic disorder were initially good for women (61%) as well as men (58%).16 In contrast, remission for women or men with panic disorder with agoraphobia (23% and 22%, respectively), women and men with GAD (23% and 22%, respectively), and women and men with social phobia (18% and 15%, respectively), were much worse. At 8 years, men with panic disorder had a remission rate of 69% and a relapse rate of 21%. For women, however, the remission rate was 76%, but the relapse rate was 64%, a 3-fold rate of symptom return relative to men (Figure 2).15 Notably, a high percentage of patients who initially experienced remission subsequently relapsed. Although >80% of subjects with panic disorder and GAD received medication management, the dose, duration, and degree of medication adherence achieved at each point in the study were not reported; self reports, not pharmacy records, were used to document medication use. Given the high rates of medication discontinuation observed among outpatients, it is likely that poor medication adherence contributed to the high rates of relapse.

Other studies also document ongoing impairment and disability among patients with panic disorder who are followed over time under routine care. For example, one follow-up study showed that 60% of patients suffered panic attacks and 20% remained agoraphobic 4 years after participating in a clinical trial.22 According to the American Psychiatric Association (APA) guidelines for panic disorder,4 40% to 50% of panic disorder patients in tertiary care settings are likely to be symptomatic but improved, 20% to 30% the same or worse, and only 30% are well at approximately 4–6 years posttreatment.12,22

Role and Work Impairment

Patients with panic disorder are likely to experience better physical functioning but worse role functioning than those with other serious medical or emotional disorders. For example, the Health-Related Quality of Life survey compared the role function and physical and emotional health of 443 patients with panic disorder to that of 9,839 patients with diabetes, hypertension, depression, arthritis, or heart disease. Patients with panic disorder reported good physical functioning, but greater role limitations due to emotional distress.23 The MacArthur Foundation Midlife Development study surveyed 2,074 individuals in the United States on the number of work-loss days (days home due to illness) and partial work days (physically present, but less productive) experienced in the previous month due to any chronic condition.5 On average, individuals with panic disorder reported 5.1 work impairment days, compared to 4.0 for patients with arthritis, 4.3 for major depression, 6.6 for heart disease, and 10.9 for cancer. Moreover, work loss due to poor productivity was as common as sick days, although largely undetectable from an employer perspective.

Clinical Trials Versus Clinical Reality

The low percentage of patients with panic disorder and related anxiety disorders achieving even a brief period of symptom relief is both surprising and sobering given the increasing number of agents available to treat anxiety disorders. This gap, between the outcomes achieved in clinical trials and those achieved during routine care, helps underscore the need for studies that document the clinical effectiveness and cost of routine care. While major funding mandates exist to support basic research (National Institutes of Health) and the development of new medicines (pharmaceutical manufacturers), the same is not true for routine healthcare delivery. Although biomedical research composes 5.6% of US health expenditures, only 1.7% of this is spent on evaluating the effectiveness and cost of care that patients actually receive. More studies like those conducted by HARP investigators are clearly needed.24,25

Poor Medication Adherence

Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are considered first-line treatments for panic disorder, with ongoing maintenance treatment generally recommended for 12–18 months after improvement.4 Therefore, adherence to antidepressant therapy is especially important. Based on their side-effect profiles, SSRIs and SNRIs were anticipated to replace tricyclic antidepressants and improve adherence to antidepressant therapy. However, this may not have occurred. Recent studies suggest that 30% to 55% of patients starting antidepressants may discontinue therapy within 3 months of starting.26 Health system factors that might predict  higher rates of adherence have eluded investigators; for example, rates of antidepressant discontinuation have been found to be similar for patients under psychiatric and generalist care, and for managed care and fee-for-service systems.27 Factors causing patients to discontinue antidepressants are numerous and may include insufficient education regarding the required extended duration of use; impatience with the delayed onset of action; side effects that emerge on antidepressant initiation, such as anxiety and insomnia, or after extended use, such as sexual dysfunction and weight gain; and perception of clinical improvement.28 The cost of medications may increasingly contribute to antidepressant discontinuation. Studies suggest that a doubling of antidepressant copayments may prompt declines in use that range from 8% to 26%.29 

Knowing the point in therapy and the kinds of patients at greatest risk for discontinuation may help clinicians to practically focus their efforts to improve medication compliance. A study of 20,296 patients who initiated therapy on paroxetine (controlled-release formulation), and were followed over a 12-month period after filling an initial outpatient prescription, found that individuals who were new to the medication were at the greatest risk of discontinuation and that this risk was greatest during the first month of therapy (Figure 3).26 In this study, patients were divided into two groups based on the hypothesis that individuals initiating therapy for the first time would be at greatest risk of discontinuing therapy. Patients new to therapy (rookies) were identified as those who had not received antidepressant prescriptions for 180 days prior to the index antidepressant fill; veterans were those continuing therapy. Patients who switched from one antidepressant to another were considered to have continued therapy. Patients were considered to have discontinued therapy when they were 30 days late for a scheduled refill. Notably, only 58% of  9,295 rookies and 80% of 11,071 veterans remained in therapy 60 days after filling their initial prescription. Four months after initiating therapy, only 37% of rookies and 66% of veterans continued with therapy. Similar results were observed with other SSRIs/SNRIs.26

Current Pharmacologic Treatment Strategies in Panic Disorders

High-potency benzodiazepines (eg, alprazolam and clonazepam) can block panic attacks that suddenly emerge and can provide rapid relief of situational and anticipatory anxiety. Drawbacks include sedation, potential disinhibition, and physiologic dependence.9 Initiation at low doses is recommended with increases every 3–4 days until a therapeutic dose is reached.9 Typical dose ranges for alprazolam are 1.5–8.0 mg/day for panic disorder and 0.75–4.0 mg/day for anxiety. Typical dose range for clonazepam are 0.5–4.0 mg/day for panic disorder.30  

The Table provided presents a comparison of selected benzodiazepines and SSRI/SNRIs.31 One advantage of SSRI/SNRIs is their ability to treat both depression and comorbid anxiety disorders. SSRI/SNRIs are also less likely to be associated with physiological dependence or with major impairments of memory or motor coordination.9 A disadvantage of SSRI/SNRIs is latency to onset of effect; it can take up to 4 weeks before a response occurs and from 8–12 weeks for a complete response.4 Recommended daily starting doses for SSRIs and SNRIs are generally half those used for treating depression, to avoid potential antidepressant-induced anxiety.

Current APA practice guidelines recommend 12–18 months of maintenance therapy for panic disorder, with discontinuation attempted if the patient has experienced significant or full improvement. Discontinuation with either antidepressants or benzodiazepines is associated with discontinuation-related symptoms and relapse. Patients who relapse may be offered a new trial on medication along with cognitive-behavioral therapy (CBT).4

Current Trends in the Pharmacotherapy of Panic Disorder

Combination Use of SSRI/SNRIs and Benzodiazepines

In principle, combinations of an SSRI/SNRI and a benzodiazepine could be advantageous because of their different, but potentially complementary, mechanisms of action on serotonin and γ-aminobutyric acid systems.32 Advantages of combination use of antidepressant and benzodiazepines include rapid anxiolysis, improved efficacy in combination, and reduced SSRI/SNRI-related anxiety and agitation upon treatment initiation. Combination medication use may also improve medication compliance and reduce medication dosages, perhaps as a result of improved medication effectiveness, reduced side effects, or some combination of the two. The advantages of such augmentation strategies need to be balanced against the risk of drug-drug interactions.

Reduced Time to Symptom Control

A 12-week randomized, double-blind study in patients with panic disorder suggests that the combination of benzodiazepines and SSRI/SNRIs results in more rapid symptom control than either agent alone (Figure 4).32,33 In this study, patients received sertraline on an open-label basis and then were randomly assigned to receive clonazepam 3 times/day or placebo for 4 weeks, after which the clonazepam or placebo dose was tapered over the course of 3 weeks. At the end of the first week of combination treatment, the proportion of responders was significantly higher (P=.003) among those receiving clonazepam/sertraline (41%) than those receiving placebo/sertraline (4%). The between-group difference was also statistically significant at week 3 in favor of the active combination (63% versus 32%; P=05). Adverse events did not differ between groups. These results suggest that the combination of a benzodiazepine and SSRI/SNRI can provide more rapid anxiolysis of panic symptoms in patients with panic disorder than sertraline alone. In line with these results, the APA treatment recommendations suggest use of benzodiazepines for early control of panic and anticipatory anxiety as the effects of nonbenzodiazepine maintenance medications and psychosocial treatment modalities take effect.4

 

Reduced SSRI/SNRI-Related Anxiety  

Not uncommonly, patients with anxiety disorder may experience anxiety or agitation when an SSRI/SNRI is first started.34 Use of a benzodiazepine, either on a regular or as-needed basis (PRN), may alleviate such side effects and reduce the risk of medication discontinuation at the start of treatment.

PRN Benzodiazepine Use

PRN use of benzodiazepines appears to be substantial. As part of the longitudinal HARP study, Bruce and colleagues35 found that among patients with panic disorder and panic disorder with agoraphobia, 40% of those on lorazepam and 51% of those on alprazolam used these agents on a PRN basis. PRN use, which stand for the Latin term pro re nata (according to circumstance), allows patients to manage symptoms as they arise; it is best directed by specifying both a frequency and maximal number of daily doses (eg, alprazolam 0.5 mg PRN every 4 hours; maximum of 4 doses in a 24-hour period). Studies of outpatient PRN benzodiazepine use are lacking.  

To better understand the role of PRN benzodiazepine use in managing anxiety and panic symptoms, Fitzgerald36 analyzed self-reported patterns of alprazolam use among 100 patients with anxiety disorders. Overall, patients used PRNs to reduce situational anxiety, anticipatory anxiety, or phobic avoidance when symptoms threatened function in a work or social role. Activities of daily living in which PRN benzodiazepine use proved beneficial for people with panic disorder and panic disorder with agoraphobia, included leaving the house to shop, keeping doctors’ appointments, attending important social and work-related events, participating in community events, traveling by car or plane, or carrying out job obligations. PRN benzodiazepine use often augmented maintenance medications, such as SSRI/SNRIs or long-acting benzodiazepines, to provide “rescue” treatment for breakthrough symptoms. This is illustrated schematically in Figure 5. APA treatment guidelines for panic disorder recommend the preferential use of benzodiazepines in situations in which rapid symptom control is necessary to preserve function or quality of life.4

Although SSRI/SNRIs demonstrate efficacy in decreasing the frequency of panic attacks, they may be less effective than benzodiazepines in treating the anticipatory anxiety and avoidance, which are frequent behavioral responses to panic attacks. It is in this context that PRN benzodiazepine use may be both more beneficial and more common than generally recognized. In clinical practice, physicians may not learn about PRN use from their patients because such usage occurs outside of the office visit. Furthermore, some data suggest that long-term users of benzodiazepines may not discuss their drug usage with their physicians.37 Moreover, many patients may switch to PRN use or supplement regular schedules with PRN use over time.37 Additional study in the outpatient setting is needed to assess the impact of PRN benzodiazepine use in panic disorder, alone and in combination, and its impact on quality of life and functioning.

Benzodiazepines: Low Risk of Dose Escalation

Ongoing concerns about benzodiazepine dependence, abuse, and dose escalation may limit appropriate use of these agents. The APA Task Force on Benzodiazepine Dependence, Toxicity, and Abuse clearly notes that there are no data to suggest that long-term use of benzodiazepines commonly leads to dose escalation or recreational abuse.4

From a clinical perspective, underuse because of unjustified fears of addiction may be a more critical issue. Several recent studies document that dose escalation of alprazolam is not characteristic of long-term use and that the risk of significant dose escalation may be <2%. One study examined changes in dose among 2,440 Medicaid recipients with a history of ≥2 years of continuous benzodiazepine use, converting all doses into diazepam milligram equivalents (DMEs) for comparison.38 The median daily dose was 10 DMEs over 2 years of continuous use (eg, equivalent to 1 mg alprazolam or .5 mg clonazepam). No clinically or statistically significant increases in daily dosages occurred over time. The incidence of dose escalation to a high dose, defined as 20 DMEs for older patients and 40 DMEs for younger patients, was 1.6%. Statistically significant predictors of dose escalation were the use of lorazepam, use of an antidepressant, and filling prescriptions at two different pharmacies in a 7-day period (“pharmacy hopping”). Patients >65 years of age or with disability were significantly less likely to escalate their doses than younger patients. A naturalistic study of patients with panic disorder found that when benzodiazepines were used PRN, patients used far lower average daily doses than typically prescribed.34

Although some evidence suggests that benzodiazepine abuse is more likely to occur among those with known substance abuse disorder, the data are equivocal and do not support an absolute contraindication in such patients.39,40 Benzodiazepines are not primary drugs of abuse, but may be used to enhance or modulate effects of the primary abused substances, such as cocaine, methadone, and alcohol.39  

Together, these data indicate that the likelihood of benzodiazepine dose escalation and abuse is minimal in patients who are using benzodiazepines for appropriate medical uses. Nevertheless, clinical experience suggests that patient concerns about dependence on benzodiazepines are common and may contribute to treatment failure, as patients independently reduce the dose or duration or frequency of use of prescribed benzodiazepines. In panic disorder, patients who completed both a short-term treatment plus a maintenance treatment of 6 months with either alprazolam or imipramine were significantly more likely to be panic free than those who did not complete treatment (85% versus 55%; P<.01) and long-term treatment.31 The maintenance period was not associated with tolerance to either agent, and completion of maintenance was predictive of remission. In summary, inadequate dosing or premature discontinuation of  benzodiazepines may contribute to ongoing symptoms and distress, which in turn may exacerbate medication noncompliance and consequent treatment failure.9

Treatment Recommendations

The natural history and high relapse rate of panic disorder underscores the importance of a well thought out long-term treatment plan. Several steps can increase the probability of successful outcomes:

•    Set appropriate expectations and realistic goals for treatment by discussing the chronic nature of panic disorder and the possibility of ongoing or breakthrough symptoms. An appropriate goal is symptom control, as well as the preservation of function and quality of life rather than cure.

•    Engage the patient in the development of a comprehensive treatment plan involving both pharmacologic and non-pharmacologic options. Consider referral to providers who can help patients learn breathing or relaxation techniques, or begin CBT.

•    Initiate drug therapy with a low dose, titrate slowly, and set appropriate expectations for drug therapy. Inform patients about the slow onset of action of SSRI/SNRIs so they will not discontinue the medication out of frustration or belief that it is not working. Provide a clear review of potential side effects and the transient nature of some of the most common ones. When rapid anxiolysis or coverage for SSRI/SNRIs-related activation is a concern, consider prescribing an SSRI/SNRI plus a benzodiazepine.

•    Provide timely follow-up visits during the first 30 days after a new medication is initiated. This is the period of greatest risk for discontinuing pharmacotherapy, especially for newly diagnosed and treated patients. Ask if prescribed refills have been picked up. Re-emphasize the duration of treatment and the importance of adhering to the recommended dosage schedule. Encourage compliance by connecting medication use to problems patients have identified and are motivated to solve and by teaching patients to link medication use to daily activities (eg, with coffee in morning, at bedtime). Try to uncover barriers to adherence (eg, cost, unexpected side effects, perceived lack of need).   

•    Probe for evidence of symptom breakthrough. Develop a written patient “action plan” for breakthrough symptoms, whether it involves recommendations for PRN medication use, relaxation/cognitive strategies, or a combination of the two.

Ongoing or breakthrough symptoms are likely for the majority of patients with panic disorder, and with anxiety disorders more generally. As a result, clinicians need to provide patients with strategies to maintain function and quality of life in work and social situations when symptoms reoccur.  As high rates of medication discontinuation are common soon after the start of treatment, combination use of a benzodiazepine and SSRIs/SNRIs may improve treatment success by speeding the onset of antipanic action.  PRN benzodiazepine use may help patients cope with recurring anxiety or panic in daily work or social situations. PP

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18. Yonkers KA, Zlotnick C, Allsworth J, Warshaw M, Shea T, Keller MB. Is the course of panic disorder the same in women and men? Am J Psychiatry. 1998;155(5):596-602.

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33. Goddard AW, Brouette T, Almai A, Jetty P, Woods SW, Charney D. Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry. 2001;58(7):681-686.

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35. Bruce SE, Vasile RG, Goisman RM, et al. Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Am J Psychiatry. 2003;160(8):1432-1438.

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40. Posternak MA, Mueller TI. Assessing the risks and benefits of benzodiazepines for anxiety disorders in patients with a history of substance abuse or dependence. Am J Addict. 2001;10(1):48-68.

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Patients and Their Family Members Endure Psychological Distress Post-ICU Care

Approximately 4 million Americans are admitted to the Intensive Care Unit (ICU) each year. While there have been numerous advances in ICU treatment, life for patients and their family members post-ICU care is seldom addressed. Two studies, one led by Dimitry S. Davydow, MD, of the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle and the other led by Wendy G. Anderson, MD, MS, of the University of California in San Francisco, reviewed data on posttraumatic stress disorder (PTSD) in surviving ICU patients and examined family members’ risk of mental health morbidity, respectively.

Davydow and colleagues found 15 eligible studies for a systematic literature review using Medline, EMBASE, Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and a hand-search of 13 journals. The selected studies took place in multiple European countries as well as the United Kingdom and the United States. They collectively comprised a sample size of 1,745 ICU survivors. They found that questionnaire-discovered “clinically significant” PTSD symptoms had a median point prevalence of 22% (n=1,104) while clinician-diagnosed PTSD had a median point prevalence of 19% (n=93). Consistent predictors of post-ICU PTSD (ie, prior psychopathology, greater ICU benzodiazepine administration, and post-ICU memories of in-ICU traumatic experiences) were revealed. In contrast, less consistent predictors included gender, younger age, and severity of critical illness. Significantly lower health-related quality of life was related to post-ICU PTSD.

Though Davydow and colleagues’ review is based on studies using screening tools for PTSD assessment, results still indicate in-ICU trauma as a trigger for PTSD symptoms in survivors that is detrimental to a patient’s quality of life post-ICU care. The researchers suggested that future studies should note how patient-specific factors (eg, pre-ICU psychopathology), ICU management factors (eg, sedative administration), and ICU clinical factors (eg, in-ICU hallucinations) are associated with one another and with post-ICU PTSD. Further, monitoring of both PTSD risk factors in ICU survivors and their needs for early intervention is necessary.

Anderson and colleagues conducted a prospective, longitudinal cohort study on 50 family members of ICU patients. Participants were interviewed at time of enrollment (n=50), 1 month (n=39), and 6 months (n=34). Prevalence of and factors related to anxiety, depression, PTSD, and complicated grief were measured by the Hospital Anxiety and Depression scale, Impact of Event scale, and Inventory of Complicated Grief scale. Anxiety and depression presented at all time points but diminished over time. However, PTSD presented in 35% of all participants (95% Confidence Interval [CI] 21% to 52%) and complicated grief presented in 46% of 19 bereaved participants (95% CI 22% to 71%). Anderson and colleagues concluded that it is important to assess PTSD and complicated grief in family members after a loved one’s stay in the ICU, as both conditions remained over time.

Funding for Davydow and colleagues’ study was provided by the National Institutes of Health and Canadian Institutes of Health Research. Funding for Anderson and colleagues’ study was provided by the University of Pittsburgh’s Institute for Doctor-Patient Communication and the Greenwall Foundation. (Davydow DS. Gen Hosp Psychiatry. 2008;30(5):421-434; Anderson WG. J Gen Intern Med. 2008. Epub ahead of print.) –ML

Long-term Cancer Survivors at Increased Risk for Severe Psychosocial Distress Following Treatment

According to the Centers for Disease Control, improved screening methods and earlier and more frequent screening as well as more effective treatment modalities have caused a significant decline in death rates among patients with cancer, among other interventions. It is estimated that there are 12 million cancer survivors living in the United States, with approximately 66% of those survivors living for >5 years following treatment.

Studies have shown that patients who survive cancer are at an increased risk for receiving inadequate health care, which may be necessary due to possible recurrence and lingering effects of prior cancer treatment. In addition, cancer survivors are at an increased risk for experiencing severe psychosocial distress, potentially due to changes in social support, difficulty maintaining employment, or fear of cancer recurrence. However, few prior studies have investigated the prevalence of psychosocial distress and depression among this patient population.

Karen E. Hoffman, MD, of the Harvard Radiation Oncology Program at Harvard Medical School in Boston, and colleagues, studied prevalence rates of distress and depression among 4,712 long-term cancer survivors and 126,841 adults who had never been diagnosed with cancer. They sought to determine if long-term cancer survivors experience distress and depression at rates higher than the general population as well as what clinical factors may impact the development of distress and depression.

Data were utilized from the National Health Interview Survey, a continuous health survey of 40,000 households conducted by the National Center for Health Statistics of the CDC. In the survey, participants were asked if they were  ever informed of having cancer or a malignant disease by a health professional. Participants who had received a cancer diagnosis ≥5 years prior to the study beginning and who were ≥18 years of age were included in the study. Distress was measured using a K6 scale, which asked participants to evaluate aspects of their mood and affect in the past 30 days, including presence and frequency of sadness, anxiety, restlessness, and worthlessness.

Hoffman and colleagues found that psychosocial distress was identified in 5.6% of cancer survivors as opposed to 3% of participants without cancer, and this finding persisted after controlling for demographic factors. In addition, survivors who experience comorbid conditions related to cancer and/or treatment were more likely to experience severe distress as were younger survivors (45–65 years of age), when compared to older survivors (≥65 years of age). Being unmarried and having difficulty completing daily activities without assistance were also factors that contributed to increased psychosocial distress.
They concluded that distress often occurs for patients who survive cancer for >5 years, with symptoms being unrelated to initial diagnosis and treatment. Thus, primary care physicians and other health professionals should remain aware of risk factors for distress and focus on screening and patient education for affected patients. Study limitations included use of self-report data and lack of additional diagnostic information. (50th Annual Meeting of the American Society for Therapeutic Radiology and Oncology; September 24, 2008; Boston, Massachusetts) –CP

Telephone-administered versus Traditional Psychotherapy for Depression

Telephone-administered psychotherapy, although slow to catch on, has received far more attention within the past decade than ever before. As the need for mental health care grows, along with the concurring recognition of access issues and boundaries to treatment, clinical trials are beginning to recognize the utility of telepsychiatry in certain cases. David C. Mohr, PhD, at Northwestern University, and colleagues,  examined the literature on using telepsychiatry to treat depression, and compared the effectiveness of face-to-face psychotherapy to telephone-administered methods.

“In a survey of primary care physicians, we found that 75% of depressed patients identified one or more barriers that would make it impossible or extremely difficult to attend face to face psychotherapy,” Dr. Mohr said. “While cost was a common one, structural problems, such as time constraints (job, childcare, etc), transportation problems, physical symptoms, and availability of services were also common.”

Mohr and colleagues reviewed 51 studies for inclusion into their meta-analysis, of which only 12 met inclusion criteria. Ten of the accepted studies had control conditions, with a mean effect size of d=0.26 (CI, 0.14-0.39). All therapist-patient interaction in the accepted studies was conducted over the telephone with adult patients; ≥4 sessions per patient with a clear treatment plan were required; and reduction of depressive symptoms was a treatment outcome.

A significant reduction in depressive symptoms was associated with telephone-administered psychotherapy. In the studies with a control condition, telepsychiatry had a mean effect size of d=0.26, although a 1997 meta-analysis of face-to-face psychotherapy with no control condition had a mean effect size of d=0.42. However, the pretreatment to posttreatment effect size for telepsychiatry was d=0.82, comparable to the pre-post treatment effects of face-to-face therapy in the range of d=0.71–0.73.

Although Mohr and colleagues’ analysis demonstrated a reduction of depressive symptoms with telepsychiatry, its low attrition rate, compared to face-to-face therapies, is an important aspect of this analysis. The telepsychiatry attrition rate of 7.56% (CI, 4.23-10.90) compared favorably to the 46.9% attrition rate of a 1993 meta-analysis of face-to-face psychotherapy, although such rates can range from 13.9% to 64.4% in the literature.

Despite the favorable attrition rates in telepsychiatry, Dr. Mohr said it is not clear whether there are types of problems or patients who benefit more or less from it.

“My sense is that it is most beneficial for those people who have barriers that would make it difficult for them to attend face-to-face treatments,” he said. “It is also probably less appropriate for more severe disorders, such as psychotic disorders.”

Funding for this study was provided by the National Institute of Mental Health. (Clinical Psychology: Science and Practice. 2008;15(3):243–253.) –LS

Personality May Affect PCPs’ Assessment of Patients’ MDD

For the majority of patients experiencing symptoms of major depressive disorder (MDD) and related disorders, the first healthcare professional visited for diagnosis and treatment is the primary care physician (PCP). However, there are often obstacles to completing a thorough mental health assessment by PCPs, such as limited time to gather patient information. In addition, there may be possible hesitation on the part of the PCP to inquire into a patient’s history of MDD or suicidal ideation and behavior due to the PCP’s own discomfort. Recently, researchers at the University of Rochester Medical Center in New York studied the effect of PCP personality and temperament on the consistency of complete patient MDD assessments.

Paul R. Duberstein, PhD, and colleagues studied data from 86 standardized patient visits with 46 PCPs who specialized in internal and family medicine. Six female actors portrayed patients with MDD or an adjustment disorder with depressed mood, and each physician was evaluated after one unannounced visit by an actor portraying a patient with MDD and another visit by an actor portraying a patient with an adjustment disorder.

Visits were taped without the physician’s knowledge, and recordings along with reports from the actors on doctoring behaviors and medical records were assessed to determine rates of MDD or related diagnosis. PCP personality was then divided into three categories: dutifulness, vulnerability, and openness to feelings. Dutifulness was defined as conscientiousness and ability to follow through with plans; vulnerability was defined as the presence of anxiety, unease, and stress; and openness was defined as empathy.

Duberstein and colleagues found that PCPs who were more dutiful and vulnerable had higher rates of reporting depression, but they asked fewer questions concerning MDD symptoms. Personality style did not affect the likelihood of PCPs inquiring about suicide.

The authors concluded that a PCP’s personality can affect the likelihood of MDD diagnosis and alter how often patients are asked about mood symptoms. While the area of interest requires further study, interventions for PCPs could include use of a screening questionnaire or mental health specialist who can further assess for the presence of MDD and other mood disorders. Nevertheless, the authors added, there is no “correct” method of inquiring about mood symptoms but that PCPs should select a method that fits best with their personal preference.

Study limitations included use of a single geographic location, that the majority of PCPs in the study were white men, and that roles portrayed by actors may not reflect the experience of a typical patient. (J Gen Intern Med. 2008. In press.) –CP

Long-term Antidepressant Treatment is Non-beneficial in Bipolar Disorder

Long-term antidepressant therapy for depression in patients with bipolar disorder is common. However, its benefits and risks remain ambiguous. Meta-analyses of relevant research in the subject conducted by S. Nassir Ghaemi, MD, of the Tufts Medical Center in Boston, Massachusetts, and colleagues, further investigated this issue.

Ghaemi and colleagues searched databases such as Medline, EMBASE, and the Cochrane Library for randomized controlled trials of bipolar disorder patients who underwent ≥6 months of antidepressant therapy plus mood stabilizer versus placebo with or without mood stabilizer. Seven trials with 12 contrasts, collectively comprising of 350 bipolar disorder patients, qualified for further investigation. Meta-analyses were used to compare reported risks of new depression with those reported of mania. Results revealed that long-term treatments with antidepressants led to 27% lower risk of new depression compared to both mood stabilizer-only and no treatment (pooled relative risk [RR]=.73; 95% confidence interval [CI] .55–.97; number-needed-to-treat [NNT)=11). However, there was a 72% greater risk for new mania (RR=1.72; 95% CI 1.23–2.41; number-needed-to-harm [NNH]=7). In studies comparing mood stabilizer-alone to mood stabilizer plus antidepressant, the addition of an antidepressant yielded no major protection from depression (RR=.84; 95% CI .56–1.27; NNT=16) or significant increase in risk of mania (RR=1.37; 95% CI .81–2.33; NNH=16).

The data indicated that long-term adjunctive antidepressant treatment was not superior to mood stabilizer monotreatment in patients with bipolar disorder, suggesting that reliance on mood stabilizers lays the foundation for prophylaxis in type-I bipolar disorder. Clinicians should be cautious in long-term use of antidepressants aimed at mitigating recurrences of bipolar disorder. (Acta Psychiatr Scand. 2008;118(5):347-356.) –ML


Psychiatric dispatches is written by Michelisa Lanche, Carlos Perkins, Jr, and Lonnie Stoltzfoos.

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Needs Assessment: There has been an exponential rise in direct-to-consumer (DTC) advertising of pharmaceuticals in recent years. Studies suggest the average patient spends much more time each year viewing DTC ads than discussing medicines with their doctor. Psychotropic agents are some of the most heavily advertised classes of medications. Little is known of the impact this has had on the field of psychiatry and clinical practice. 

Learning Objectives:
• Understand the historic context of direct-to-consumer (DTC) advertising including the recent, dramatic growth in DTC advertisements. 
• Review survey data of psychiatrists concerning various aspects of DTC advertisements, including personal experience, impact on clinical practice, and educational value.
• Appreciate potential benefits and drawbacks of DTC advertisements as they relate to psychiatric practice.


Target Audience:
Primary care physicians and psychiatrists.


CME Accreditation Statement:
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: October 6, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Pfizer.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by November 1, 2010 to be eligible for credit.

Release date: November 1, 2008. Termination date: November 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

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Primary Psychiatry. 2008;15(11):67-71

 

Dr. Bhanji is clinical associate professor at the University of Calgary in Alberta, Canada. Dr. Baron is professor and chair in the Department of Psychiatry at Temple University School of Medicine in Philadelphia, Pennsylvania. Dr. Lacy is Chief of the Behavioral Health Clinic in Ft. Stewart, Georgia. Drs. Gross and Goin are professors of clinical psychiatry at the University of Southern California Keck School of Medicine in Los Angeles. Dr. Sumner is senior vice president and chief medical officer at the BioBehavioral Diagnostics Company in Cambridge, Massachusetts and clinical associate professor of Behavioral Medicine and Psychiatry at West Virginia University School of Medicine in Morgantown. Dr. Fischer is Schizophrenia Research Fellow at the Maryland Psychiatric Research Center at the University of Maryland School of Medicine in Baltimore. Dr. Slaby is clinical professor of psychiatry at New York University in New York City.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Benjamin Lacy, MD, Chief, Behavioral Health Clinic, 1061 Harmon Ave Ste 1d03, Ft. Stewart, GA 31314-5611; Tel: 912-767-1641; Fax: 912-767-3507.


Abstract

Direct-to-consumer (DTC) advertising of pharmaceuticals has historically been a controversial subject. DTC marketing involves stakeholders from the pharmaceutical industry, medical and healthcare sectors, public groups, and others. Concerns regarding DTC marketing, including its influence on prescribing practices, and drug expenditures, are the subject of continuing debate. Little is known about how mental health providers perceive the role of DTC marketing in their practices. The authors surveyed 114 psychiatric physicians to assess their perspectives on the merits and risks of DTC marketing. The results of the survey provide a perspective on the views of psychiatrists concerning DTC marketing.

Introduction

Direct-to-consumer (DTC) advertising of pharmaceuticals is a topic sparking considerable debate among drug manufacturers, federal agencies, consumer groups, managed care organizations, and physicians.1-3 Since 1995, this issue has become more intense following the United States Food and Drug Administration’s decision allowing greater freedom of advertising requirements.4

Of all groups involved in the debate, physicians are often caught in the middle.1,5,6 While they are perceived by a majority of stakeholders as knowledgeable experts in diseases and treatment, they are also perceived as “drug pushers” by some consumers groups.7,8 DTC advertising not only reinforces this misperception, but it also leads to internal conflicts among doctors when their patients demand specific medications. Many third party payers have restricted drug formularies, and conflicts may occur when patients request specific advertised medications not covered by their insurance.1

Background

Although currently a hot topic, DTC advertising in the US has been around for nearly 300 years.2,4 In 1708, Nicholas Boone placed the first advertisement for a patent medication in a Boston newspaper. For the next 230 years, advertisements for patented medications claiming to treat everything from dandruff to infidelity could be found in magazines, newspapers, and traveling medicine shows. In 1938, Congress passed the Food, Drug, and Cosmetic Act, which gave the FDA authority over the labeling of pharmaceuticals and the Federal Trade Commission control over their advertising. No new legislation was introduced until 1962 when the Kefauver-Harris amendments proposed the concept of consumer protectionism when dealing with pharmaceuticals. Under these amendments, authority for drug promotional advertising review was reassigned to the FDA. The FDA established requirements similar to those in existence today, ie, specifications of contraindications, effectiveness, side-effect profiles, and a cost-benefit discussion. Virtually all of the advertisements were targeted to physicians.
In 1981, the pharmaceutical industry proposed shifting marketing to include the consumer.1 At issue was the requirement to include extensive clinical information on the product, making it problematic to use television media to reach potential customers. That same year the Commissioner of the FDA, Arthur Hayes, requested the pharmaceutical industry put a voluntary moratorium on DTC advertising to allow the FDA to study their request to reduce the required disclaimers. In 1985, the FDA concluded that the existing regulations to safeguard the public interest were adequate. This ruling had the effect of postponing the growth of DTC for the next 12 years. However, 1997 marked the beginning of rapid growth in DTC advertising.9 This change in marketing was attributed to the new FDA guidelines on broadcast DTC marketing. For the first time, drug manufacturers could present the name of the product and the condition it was intended to treat, and not report all of the contraindications. The financial implications of this change in policy were enormous. In 1985, $17 million was spent on DTC marketing. By 2000, that figure rose to $2.5 billion, and $4.2 billion in 2005. In 2008, the estimated DTC marketing budget will be in the sum of $8 billion.4,8,9 Real spending on DTC advertising increased by 330% from 1996–2005.10 As of 2007, only the US and New Zealand permit DTC advertising of prescription medications.11 In countries outside the US, the pharmaceutical industry has applied pressure to relax regulations regarding DTC marketing with little success. Despite DTC advertising being banned in most non-US countries, there is growing international concern that drug companies are circumventing legislation through the use of internet advertising and “spam” E-mail.12 Pharmaceutical companies also provide “awareness campaigns” or infomercials with vague references to prescription treatments in order to improve their sales abroad.13

Impact of DTC Advertising on Prescribing in Mental Health

Research clearly indicates that DTC advertising alters prescribing behaviors and volume leading to greater drug expenditures. A systematic review of the literature by Gilbody and colleagues14 found that DTC advertisements increase both new diagnoses of a condition and the proportion of prescriptions specifically for the advertised drug. This has a compounding effect on the number of overall prescriptions for a particular drug. For example, Zachry and colleagues15 found that for every $1,000 spent on advertising a cholesterol-lowering drug, there were approximately 32 new diagnoses of hyperlipidemia and 41 additional prescriptions of the advertised cholesterol lowering drug. Another study5,16 comparing US and Canadian prescribing practices found that DTC advertisements resulted in significantly more frequent requests for specific advertised drugs. Patients making these requests were 16 times more likely to be prescribed a drug than those not making specific requests.
The topic of DTC advertising is especially pertinent to the field of psychiatry where there is a desire to decrease stigma and properly educate the public on mental illness. Approximately 20% of the 50 most advertised drugs in the US were medications used to treat psychiatric and neurologic disorders.17 Antidepressants, antipsychotics, and anticonvulsants are among the top five most heavily advertised classes of medicine. Whether DTC marketing leads to over-prescribing of more expensive non-generic drugs, as critics contend, or de-stigmatizes mental illness and promotes use of effective medications, as proponents claim, is a matter of ongoing debate.6-8,12,14-16

Method

In keeping with its mandate of examining contemporary issues in mental health, the Group for Advancement of Psychiatry (GAP) Committee on Psychopharmacology (Table 1) conducted a pilot survey study of the attitudes of psychiatric residents and psychiatric physicians on DTC marketing of medications. A questionnaire was developed by the committee to gather information about psychiatrists’ exposure, experience, and opinions regarding DTC marketing of medications.

 

The questionnaire was reviewed and approved by the GAP Executive Committee and distributed to members attending one of the organization’s semi-annual meetings. The sample was broadened to include residents and faculty in selected psychiatric training programs in Philadelphia (Temple University) and Southern California (University of Southern California; Cedars-Sinai Medical Center). The multiple choice survey was distributed at scheduled resident and faculty meetings, with voluntary completion of the questionnaire requested at the end of the meeting. Since the pilot information was obtained from small selected groups, survey return rates were not calculated. The demographics and responses of the 114 completed questionnaires are summarized below. Non-parametric and descriptive statistics were used to analyze the data.

 

Results

Physician Experiences with DTC Advertising

During the month preceding survey completion, respondents were asked how often they had seen a DTC advertisement. Responses varied, with 18 respondents (16%) acknowledging at most a single personal exposure to DTC advertising, 29 respondents (25%) reporting 2–5 exposures, 24 respondents (21%) reporting 6–10 contacts, and 43 respondents (38%) reporting >10 personal DTC exposures (n=114).

Types of DTC advertisements were reviewed. Of the media noted by the respondents, television was the most frequent (96% of responses). This was followed by direct mailings to physicians (76%), newspaper advertisements (57%), radio advertisements (50%), direct mailings to consumers (42%), Internet or E-mail (37%), and newspaper articles (28%). Since multiple responses were allowed, respondents checked off at least four types of DTC advertising on average.

When asked how often they were made aware of DTC advertisements by patients or colleagues in a typical month, 19 (17%) respondents reported at most one contact, 49 (43%) reported 2–5 contacts, 22 (19%) reported 6–10 contacts, and 23 (20%) reported >10 contacts (n=113).

Impact of DTC on Clinical Practice

Physician attitudes when dealing with DTC advertising in their clinical practice was surveyed. When asked how often they prescribed a patient-requested product (ie, a brand-name prescription drug), 13% of respondents replied “not at all”, while 79% indicated “sometimes.” Slightly >5% prescribed the requested medication “fairly often,” but no one reported prescribing requested medications “all the time” (n=114; Figure).

 

The authors of this article asked how respondents perceived the impact of DTC advertising on the physician-patient relationship. Fifty-two out of 114 respondents (46%) felt that DTC had neither positively nor negatively impacted the doctor-patient relationship. Forty-five (39%) reported a negative impact, whereas 12 respondents (11%) felt that DTC had affected the relationship “somewhat positively.” Only 1 respondent indicated an “overwhelmingly positive” effect, and 4 responses were “overwhelmingly negative.”

Respondents were surveyed whether DTC advertising has opened an opportunity for dialogue with patients. Here, respondents were more positive that DTC had increased dialogue. Seventy-three respondents (64%) agreed that DTC had opened up an avenue for more dialogue, whereas twenty-five (22%) disagreed. Sixteen (14%) indicated that DTC had no impact.

With respect to whether DTC advertising had improved patient compliance, most respondents (67%) did not feel that it had any effect on compliance. Twenty-four percent thought it had a positive benefit, whereas 9% indicated it had a negative impact on medication compliance.

Attitudes on DTC Advertising as an Educational Tool

The opinions of respondents on DTC as an educational tool revealed that 19% felt that DTC advertising had improved patient awareness of mental illness “a fair amount” or “overwhelmingly so.” Eighty-one percent reported that DTC improved mental illness awareness only “somewhat” or “not at all.”

Similar opinions were expressed about DTC advertising’s impact on patient awareness of treatment options. Twenty percent indicated that patient awareness of treatment options had improved at least a fair amount, whereas 80% felt it had helped somewhat or not at all. The opinions on patient awareness of treatment options did not differ between male and female respondents.

The impact of DTC advertising in reducing stigma for mental illness was also surveyed. Fifty-seven percent felt that DTC advertising had decreased stigma, with an additional 3% believing that DTC advertising had strongly decreased stigma. In comparison, 36% thought DTC advertising had no impact, and 4% reported that DTC advertising had increased stigma on mental illness.

Opinions Regarding DTC Regulations

Participants were asked for opinions regarding the present regulations covering DTC advertisement. Seventy- eight percent of respondents were not satisfied with current regulations and felt that DTC advertising should be regulated differently. The remainder were either neutral (19%) or disagreed with making any changes (3%).

When asked who should regulate DTC advertising, respondents were invited to choose multiple responses. One hundred thirteen responders gave 166 responses. In descending order, they chose regulation by government associations (49%), medical associations (37%), pharmaceutical industry (9%), third-party payers (1%), and others (4%).

Regarding additional information to be included in DTC advertising, improved side-effect information was the most frequent selection (61%). This was followed by non-pharmacologic treatment options (50%), cost (48%), and information on differential diagnoses (47%).

Discussion

The surveyed psychiatrists had broad views on DTC advertising. Almost all were either directly or indirectly (via colleagues or by their patients) exposed to DTC advertising. Most clinicians (85%) felt that DTC advertising had a minimal or negative influence on the physician-patient relationship. However, in >80% of cases, clinicians prescribed medications “sometimes” or “all the time” when requested by their patients, and many physicians (64%) felt that DTC advertising improved the opportunity for increased dialogue with patients.

From the survey responses, DTC advertising appears to be changing the nature of the physician-patient relationship. Historically, physicians have perceived themselves as uniquely expert in medical therapeutics. DTC advertising appears to be shifting the balance with patients receiving information about medication and illness outside of the clinical encounter. Information is power and the shifting balance brings up tension and ethical dilemmas when patients request specific treatments.

The role of the pharmaceutical industry in educating consumers about specific diseases (eg, major depression or osteoporosis), may be arguably viewed as beneficial in reducing stigma and in enhancing patient compliance with treatment.4,11,12 However, our respondents did not feel that this objective was consistently met. Approximately 60% felt it was effective in decreasing stigma but only 20% thought it increased knowledge of illness and treatment options.

A significant majority of psychiatrists surveyed (78%) felt there should be changes to regulations regarding DTC advertising. This finding is consistent with other survey studies of US physicians. A survey by Robinson and colleagues18 querying American Medical Association members found that 73% of primary care and 65% specialty care physicians felt the need for improved regulations.

The authors of this article would caution generalizing from our survey because it is a small sample. Nevertheless the views expressed by the respondents appear to be consistent with the extant literature addressing this topic.5,12,13,18 The survey examined self-reported attitudes and not necessarily actual behaviors. For example, we did not confirm whether DTC advertising is generating changes in prescribing patterns. The sample size was too small to detect statistical significance, and therefore, the authors were also unable to discern clear patterns among genders or practitioners with different levels of experience. Further longitudinal studies are required to better characterize the dynamic nature of physician-patient relationship in an era of expanding advertising.

Conclusion

DTC marketing is an industry-sponsored initiative that has revolutionized how medical information and treatment options are disseminated to the public. Previously, only physicians and healthcare professionals were the target audience of pharmaceutical company advertising. In recent years, the public has increasingly become the focus of promotional marketing by the industry. The authors’ pilot survey of psychiatrists revealed that DTC advertising has the potential to improve awareness of medical conditions and decrease the stigma of mental illness. Surveyed psychiatrists believed that DTC had little significant effect on their personal prescribing practices. However, >80% of respondents reported they had prescribed medications specifically requested by their patients. Most respondents failed to endorse that DTC had a positive effect on the doctor-patient relationship, or on improved patients’ medication compliance.

Despite the finding of an ambivalent relationship of physicians with DTC advertising, certain matters are clear. The authors’ professional obligation to educate the patient remains and the need for dialogue has not decreased in the era of DTC marketing. Application of good medical practice principles including patient education must continue to guide clinician behavior. PP

References

1.    Lyles A. Direct marketing of pharmaceuticals to consumers. Annu Rev Public Health. 2002;23(1):73-91.
2.    Duke University. Should Direct-to-Consumer Advertisements of Prescription Drugs be Restricted?. Available at: www.duke.edu/~zfg/website/?C=M&O=A. Accessed September 24, 2008.
3.    Hollon MF. Direct to consumer advertising: a haphazard approach to health promotion. JAMA. 2005;293(16):2030-2033.
4.     PhRMA. Principles and Guidelines. Direct to Consumer Advertising. Available at: www.phrma.org/principles_and_guidelines/. Accessed September 24, 2008.
5.    Mintzes B, Barer ML, Kravitz RL, et al. Influence of direct to consumer pharmaceutical advertising and patients’ requests on prescribing decisions: two site cross sectional survey. BMJ. 2002;324(7332):278-279.
6.    Hoffman JR, Wilkes M. Direct to consumer advertising of prescription drugs. BMJ. 1999;318(7194):1301-1302.
7    Mintzes B. For and against: direct to consumer advertising is medicalising normal human experience. BMJ. 2002;324(7342):908-909.
8.    Bonaccorso SN, Sturchio JL. For and against: direct to consumer advertising is medicalising normal human experience: against. BMJ. 2002;324(7342):910-911.
9.    U.S. Government Accountability Office. Prescription Drugs: Improvements Needed in FDA’s Oversight of Direct-to-Consumer Advertising’, GAO report Number GAO-07-54, text rev. December 14, 2006.
10.    Donohue JM, Cevasco M, Rosenthal MB. A decade of direct-to-consumer advertising of prescription drugs. N Engl J Med. 2007;357(7):673-681.
11.    Gellad ZF, Lyles KW. Direct-to-consumer advertising of pharmaceuticals. Am J Med. 2007;120(6):475-480.
12.    Mackenzie FJ, Jordens CF, Ankeny RA, et al. Direct-to-consumer advertising under the radar: the need for realistic drugs policy in Australia. Intern Med J. 2007;37(4):224-228.
13.     ‘t Jong GW, Stricker BH, Sturkenboom MC. Marketing in the lay media and prescriptions of terbinafine in primary care. Dutch cohort study. BMJ. 2004;328(7445):931.
14.    Gilbody S, Wilson P, Watt I. Benefits and harms of direct to consumer advertising: a systematic review. Qual Saf Health Care. 2005;14(4):246-250.
15.    Zachry WM 3rd, Shepherd MD, Hinich MJ, Wilson JP, Brown CM, Lawson KA. Relationship between direct-to-consumer advertising and physician diagnosing and prescribing. Am J Health Syst Pharm. 2002;59(1):42-49.
16.    Mintzes B, Barer ML, Kravitz RL, et al. How does direct-to-consumer advertising (DTCA) affect prescribing? A survey in primary care environments with and without legal DTCA. CMAJ. 2003;169(5):405-412.
17.    Hollon MF. Direct-to-consumer marketing of prescription drugs: a current perspective for neurologists and psychiatrists. CNS Drugs. 2004;18(2):69-77.
18.    Robinson AR, Hohmann KB, Rifkin JI, et al. Direct-to-consumer pharmaceutical advertising: physician and public opinion and potential effects on the physician-patient relationship. Arch Intern Med. 2004:164(4):427-432.

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Dr. Weisler is adjunct professor of psychiatry at the University of North Carolina Chapel Hill School of Medicine in Chapel Hill and adjunct associate professor of psychiatry and behavioral sciences at Duke University Medical Center in Durham, North Carolina. Dr. Goodman is director of the Adult Attention Deficit Disorder Center of Maryland at Johns Hopkins at Green Spring Station, assistant professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine, and director of Suburban Psychiatric Associates, LLC.

Disclosure: Dr. Weisler is/has been a consultant to Abbott, the Agency for Toxic Solvent Disease Registry/Centers for Disease Control, AstraZeneca, Biovail, Bristol-Myers Squibb, Corcept, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Novartis, Organon, Otsuka America Pharma, Pfizer, Sanofi-Synthelabo, Shire, Solvay, Validus, and Wyeth; is/has been on the speaker’s bureaus of Abbott, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Organon, Pfizer, sanofi-aventis, Shire, Solvay, Validus, and Wyeth; receives/has received grant support from Abbott, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cephalon, Ciba-Geigy, CoMentis, Duke University Medical Center/National Institute of Health, Eisai, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, McNeil, MediciNova, Merck, the National Institute of Mental Health, Neurochem, New River, Novartis, Organon, Parke Davis, Pharmacia, Pfizer, Pfizer Research, Saegis, Sandoz, Sanofi-Synthelabo, Schwabe/Ingenix, Sepracor, Shire, SmithKline Beecham, Solvay, Synaptic Pharmaceutical Inc., Takeda, TAP Pharmaceutical, UCB Pharma, Inc., Upjohn, Vela, and Wyeth; and has held or holds stock in Bristol-Myers Squibb, Cortex, Merck, and Pfizer. Dr. Goodman is/has been a consultant to GlaxoSmithKline, Eli Lilly, Forest, McNeil, New River Pharmaceuticals, Novartis, and Shire; is/has been on the speaker’s bureaus of GlaxoSmithKline, Forest, McNeil, Novartis, Shire, and Wyeth; receives/has received grant support from Cephalon, Eli Lilly, Forest, McNeil, New River Pharmaceuticals, and Shire; and receives/has received honoraria from Eli Lilly, Forest, McNeil, Novartis, Shire, and Wyeth.
Acknowledgments: Funding was provided by Shire Development Inc., Wayne, PA. Editorial assistance was provided by Robert Gregory, Timothy Coffey, and Rosa Real, MD, at Excerpta Medica in Bridgewater, NJ.

Please direct all correspondence to: Richard Weisler and Associates, 700 Spring Forest Rd, Suite 125, Raleigh, NC 27609; Tel: 919-872-5900; Fax: 919-878-0942; E-mail: RWeisler@aol.com.


 

Focus Points

• Adult attention-deficit/hyperactivity disorder (ADHD) has a profound effect on the lives of those with the disorder.
• There are numerous barriers to correctly diagnosing adult ADHD, including diagnostic criteria better suited to children, nonspecificity of symptoms, high incidence of comorbid disorders, and lack of definitive diagnostic instruments.
• Correctly diagnosing ADHD requires a multifaceted approach.
• Clinicians should maintain a high index of suspicion for ADHD in adults and include ADHD screening in all initial psychiatric evaluations.
• Stimulants are the first line of pharmacotherapy for ADHD in adults.
 

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is commonly perceived as a childhood disorder, but it persists into adulthood in 35% to 70% of affected people. The symptoms, deficits, and consequences associated with ADHD have a profound negative impact on the lives of patients and their families. Barriers to diagnosing ADHD in adults include diagnostic criteria developed and field-tested in children, nonspecificity of symptoms, high incidence of comorbid disorders that could mask or distract from the ADHD diagnosis, variation in presenting symptoms by gender and ethnicity, and lack of definitive diagnostic tools. Given the relatively high prevalence of ADHD compared with other psychiatric disorders, clinicians should maintain a high index of suspicion and integrate screening for ADHD into all routine psychiatric evaluations. Accurate diagnosis requires a comprehensive clinical interview, including evaluation of past and present symptoms and longitudinal course and assessment of functional impairment. It is often necessary to interview or obtain information from family, friends, coworkers, and old school or test records. A self-awareness of symptoms can be difficult for people who have lived most of their lives with the illness. Comorbid disorders may need to be treated before instituting treatment for ADHD. Education of patients and their families is an important facet of treatment that can improve adherence and optimize outcome. Pharmacologic therapy includes short- and long-acting stimulants as well as second-line nonstimulant medications. Short-acting stimulants may be inconvenient and have the potential for diversion and misuse. New treatments on the horizon may offer options better fitting the needs of adults with ADHD.

Introduction

Until recently, attention-deficit/hyperactivity disorder (ADHD) was perceived as primarily a disease of childhood.1 Thus, diagnostic criteria and guidelines for the assessment, diagnosis, and treatment of ADHD in children are well established.2-5 ADHD usually becomes evident during childhood, but it persists into adolescence and adulthood in an estimated 35%–70% of cases.6-8 A nationally representative household survey of adults 18–44 years of age conducted in the United States in 2001–2003 reported an estimated 4.4% prevalence for ADHD.9 In surveys conducted by the World Health Organization (WHO) from 2001–2003, the prevalence of adult ADHD ranged from 1.2% in Spain to 7.3% in France (and 5.2% in the US).10

According to national surveys of ambulatory care visits to physicians’ offices and outpatient and emergency departments of general and short-stay hospitals, the proportion of adult patients diagnosed with ADHD making these visits increased from 2.1% in 1996–1997 to 3.7% in 2000–2001, and to 6% in 2002–2003.11 The number of prescriptions for ADHD medications has also shown substantial increases. Using pharmacy claims data for 2.5 million participants in prescription benefit plans, Castle and colleagues12 reported that during the period from 2000–2005, the annual growth rate in ADHD prescriptions for young adults 20–44 years of age was 17% for men and 21.4% for women. In contrast, the increase among children and adolescents ≤19 years of age was 9.5%. Recent data from Verispan13 indicates that prescriptions for ADHD medications for adults ≥18 years of age grew steadily from January 2003 through October 2007.

Nevertheless, adult ADHD remains largely underdiagnosed and untreated.8-10,14,15 In the US household survey,9 only 10.9% of adults with ADHD received any treatment for the disorder during the preceding year.

In spite of the need for diagnosis and management of adult ADHD, primary care physicians (PCPs), who are often an adult’s main healthcare provider, have little training in the assessment of adult ADHD.16 Moreover, numerous psychiatrists have had no training regarding ADHD in adults, despite reports from the 1970s and onward of the persistence of ADHD into adulthood.17 In a recent survey of 400 PCPs who regularly treat mental health disorders, 48% reported that they were not confident diagnosing adult ADHD, 44% considered the diagnostic criteria for adult ADHD to be unclear, and 72% reported it was more difficult to diagnose ADHD in adults than in children. Two-thirds deferred to a specialist when diagnosing adult ADHD compared with 2% when diagnosing depression and 3% when diagnosing generalized anxiety disorder.18

ADHD exerts a substantial toll on the lives of its sufferers and their families.1,19 This article explores the social and personal impact of ADHD on the lives of adults with this disorder, and the clinical challenges and opportunities for improving patient care through appropriate diagnosis and treatment.

The Impact of Untreated ADHD on Adult Lives

Functional and Psychological Impairment

ADHD has a wide-ranging impact on adult lives, manifesting as educational, interpersonal, physical, emotional, and work-related difficulties. Controlled studies1,20 demonstrate that adults with untreated ADHD have poorer educational performance and attainment, significantly more marriages, greater likelihood of problems making friends, and a higher incidence of interpersonal problems than those without ADHD. Adults with ADHD are also reported to have more symptoms of psychological distress, including hostility, depression, and anxiety, than non-ADHD controls.1 In the workplace, adults with ADHD are more likely to be fired from or quit a job impulsively, hold a single job for less time, have more job changes in a 10-year period, receive a lower salary, and have poorer work performance scores than their non-ADHD peers.1,19-21 In a 2003 national survey of 500 adults with ADHD (mean age=32 years) and 501 sex- and age-matched controls, significantly more psychosocial, educational, and occupational impairments were seen in those with ADHD. They had higher rates of divorce/separation and arrests and were less likely to be optimistic about their futures than non-ADHD controls; 72% felt that ADHD had a lifelong detrimental impact.20

Risky Behaviors

Adults with ADHD may engage in risky or impulsive behaviors.22 They may demonstrate poor driving skills, have suspension or revocation of their driver’s license, receive more speeding tickets, and experience more motor vehicle accidents than those without ADHD.1,23,24 ADHD is recognized by the National Highway Traffic Administration as a contributing factor in motor vehicle accidents.25 Because accidents are the leading cause of death among people 16–30 years of age,26 the contribution of ADHD to these accidents adds to an already significant public health risk.

Tobacco use and drug and alcohol abuse are also more common in adults with ADHD than in the general population.9,27,28 A longitudinal study of the smoking status of 221 adults who had childhood ADHD reported a daily smoking rate of 35% compared with 16% of non-ADHD age-matched controls.27 In a study of 91 girls with ADHD 6–17 years of age, cigarette smoking was found to be a significant predictor of subsequent alcohol or drug use, abuse, and dependence.29 In the National Comorbidity Survey Replication (NCSR),9 those who satisfied criteria for ADHD were 3.0 times more likely to have a substance use disorder and 7.9 times more likely to be drug dependent than adults without ADHD; prevalence of substance use disorder was 15.2% for those with ADHD and 5.6% for those without ADHD (P<.05). Although the research is inconclusive, pharmacologic treatment for ADHD appears to reduce the risk of substance abuse.30-32

Adults with ADHD, especially those with comorbid conduct or oppositional defiant disorder histories, are more likely to engage in behaviors resulting in incarceration. In a study at the Utah State Prison of 102 randomized male inmates 16–64 years of age, 26 received a positive diagnosis of ADHD (having significant symptoms both as children and adults). An additional 22 inmates showed varying patterns of ADHD symptoms throughout childhood and adulthood, while seven had exhibited ADHD symptoms only during childhood, and seven showed ADHD symptoms only as adults.33 Of 129 inmates of a German prison for adolescent and young adult male prisoners, ADHD (using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition34 criteria) was diagnosed in 45%. Using International Classification of Diseases–Tenth Edition35 research criteria (“disturbance of activity and attention” or “hyperkinetic conduct disorder”), the prevalence was 21.7%.36 Conduct disorder and substance abuse are frequently seen with ADHD, but the risk of incarceration associated with ADHD appears to be independent of these comorbid conditions.37

The effects of ADHD may have a different impact on the lives of women than men. Women may receive the diagnosis later in life than men, perhaps because women tend to show more symptoms of inattention than of hyperactivity, the more conspicuous presentation.38 Women often blame themselves for their symptoms, damaging their self-esteem and resulting in depression.38,39 Traditional gender roles may also increase the impact of ADHD on women, as they are often employed in addition to being burdened with the multitasking role of family caretaker.38

Comorbidity and Economic Burden

Adults with ADHD are likely to have additional psychiatric and physical disorders.40 Comorbid conditions occurring frequently in adults with ADHD include substance/alcohol abuse, as well as mood, anxiety, learning, and personality disorders.9,10,41 The WHO epidemiologic surveys (n=11,422) reported that adults with ADHD were 4.0 times more likely to have an anxiety disorder, 3.9 times more likely to have a mood disorder, and 7.2 times more likely to have ≥3 psychiatric disorders than those without ADHD (P<.05).10 The NCSR (n=3,199) reported a prevalence of 38.3% for mood disorder and 47.1% for anxiety disorder among adults with ADHD.9 Among adults with bipolar disorder, those who also have ADHD are more likely to attempt suicide than those without ADHD.42 Rates of suicide in patients with bipolar disorder are estimated to be 15–22 times greater than in the general population,43 and ADHD can further compound the risks by increasing impulsivity, aggression, cigarette smoking, and substance abuse, which are independent risk factors for suicidality in patients with bipolar disorder.44-47 A history of suicide attempt was reported in 15% of 60 young adults with combined-type ADHD and in 3% of 36 young adults with inattentive-type ADHD.48 In an Austrian study,49 current suicidality was reported in 29% of incarcerated adolescent males diagnosed with ADHD.

Not surprisingly, ADHD poses a significant economic burden in terms of medical costs and work loss.21,41,50 Total excess healthcare and work-loss costs of childhood and adult ADHD in the US in 2000 were estimated to be $31.6 billion, of which $19.5 billion was directly attributed to excess healthcare costs for ADHD adults and their families, many of whom also incur additional healthcare expenses as a result of the ADHD of their impaired family member.50 Loss of workforce productivity due to ADHD among adults 18–64 years of age was estimated to be $67–$116 billion in 2003.21

Challenges in the Diagnosis of Adult ADHD

Shortcomings of DSM-IV-TR Criteria

There are numerous challenges to the correct diagnosis of ADHD in adults, particularly among those undiagnosed during childhood.51,52 Some of these challenges are related to the diagnostic criteria listed in the DSM-IV-TR.22 These require that patients have six of nine symptoms of either inattention or hyperactivity-impulsivity present for ≥6 months, have onset of symptoms before 7 years of age, impairment from the symptoms present in ≥2 settings (eg, work and home), and impaired social, academic, or occupational functioning (Table 1).22

 

The ADHD criteria of the DSM-IV-TR focuses on childhood expression of symptoms that may have limited applicability in adults; in fact, these criteria have never been validated in adults.14,15,53 Developmental, social, and environmental differences between children and adults affect the way in which symptoms manifest. For example, hyperactivity in children may be seen more as restlessness in adulthood; a child who squirmed, ran, or climbed might, as an adult, choose a physically demanding job or work excessively long hours.8,16,22 Thus, adult symptoms may be masked by compensatory choices in life situations or by development of coping skills that mitigate impairment. Further, symptoms may become apparent only in more challenging situations, such as at home with its demands for multitasking, and be less prominent in a work environment chosen for its suitability for ADHD.16,54 Adaptive skills, intelligence quotient, and environmental demands may make it difficult to enumerate the six of nine symptom criteria or to validate the two-domain criterion of the DSM-IV-TR. This adds to the need to revisit the conceptualization of ADHD subtypes in adults.

Because the DSM-IV-TR indicates that impairments from ADHD must have an onset during childhood, diagnosis involves establishing the presence of symptoms during childhood as well as assessing current impairment.22 The DSM-IV-TR requirement for manifestation of symptoms before 7 years of age relies on parental, peer, or self-memories of childhood occurrences or records for verification. Records, however, may be unclear, unavailable, or incomplete.22,51 Research indicates that retrospective diagnosis of childhood symptoms via self-rating by adults is a valid approach to meeting the DSM-IV-TR criterion of childhood onset.55,56 However, the necessity for symptoms before 7 years of age has come under question. A recent study identified a group of 79 adults who fulfilled all criteria for ADHD except for onset of symptoms before 7 years of age. Eighty-three percent recalled first symptoms between 7 and 12 years of age, and the other 17% had onset in adolescence or even adulthood.15 In a 20-year prospective follow up of adults diagnosed with ADHD by 6 years of age, their retrospective self-report age of onset was ≥4 years later than when it actually occurred.57 Thus, many adults with ADHD may not recall symptoms before 7 years of age, but most can recall symptoms by 12 years of age. The DSM-IV-TR would classify these patients as having a diagnosis of ADHD not otherwise specified (NOS) because they do not fulfill the age-at-onset criterion for ADHD.22 Gathering additional ADHD impairment data from family, friends, and school records from before 7 years of age can be helpful in many cases. It is important to remember that patients classified as having a diagnosis of ADHD NOS will also usually respond to approved treatments, as recently reported by Biederman and colleagues.58 In an open-label trial in 36 adults with late-onset ADHD NOS, an extended-release preparation of methylphenidate was associated with statistical and clinical improvement of ADHD symptoms.

Gender and Cultural Differences

Differences in ADHD presentation based on culture and gender pose another diagnostic challenge. As noted above, ADHD in adults occurs across ethnic groups and nationalities.9,10 However, the perceived importance of symptoms, or extent of impairment, may vary according to the cultural or family environment, and may affect what the patient and family consider problematic behaviors worth reporting to the clinician.8,59

Prevalence of ADHD is higher in boys than girls, with reported ratios of 2:1–9:1.22 Boys are more likely than girls to have the hyperactive subtype, learning disabilities, school behavior problems, and conduct or oppositional-defiant disorder.60 Among adults, the male to female ratio is reported to be approximately 3:2,9 and the expression of the disorder is similar in both sexes.61 However, because women may be less likely to have had ADHD diagnosed in childhood because of the absence or reduced intensity of hyperactive, disruptive behavior, they may require more effort to diagnose as adults. Moreover, numerous clinicians have a mistaken bias about ADHD being only a “male disease.”

Nonspecificity of Symptoms and Comorbidity

The diagnosis of ADHD requires the presence of six of nine symptoms of inattention or hyperactivity-impulsivity, but the individual symptoms in adults are nonspecific (ie, they are present in many healthy adults and may be seen in other psychiatric disorders such as major depressive disorder, mania, and generalized anxiety disorder).52 Shared and distinguishing features for ADHD and some common psychiatric illnesses are listed in Table 2.16,53 The presence of comorbid psychiatric disorders can mask or modify the presentation of ADHD symptoms, further complicating the diagnostic process.53,62 Adults may complain of symptoms of the comorbid disorder, which may be of new onset, while not mentioning symptoms of ADHD because these have been present since childhood and are not recognized as abnormal.16 Clinicians may then focus on the presenting diagnosed comorbid disorder and fail to identify or treat the underlying ADHD, potentially compromising treatment efficacy.

 

Inadequacy of Diagnostic Instruments

There is no accepted standardized diagnostic instrument for validation of adult ADHD compared with those available for other psychological disorders.9 Although current rating scales and neuropsychologic tests are cost-effective and helpful in assessing current symptoms in adults with suspected ADHD,8,51 results must be considered in light of the patient’s history. Interpretation of the self-report instruments requires proper training because adult psychopathology can distort perception on rating scales, and some self-report scales have poor specificity.52 Neuropsychologic testing, imaging, and laboratory tests can be helpful in understanding the cognitive and neural process underlying ADHD, but individual variability is such that they are not definitive for diagnosis and may add unnecessary costs.14,63,64

Making the Correct Diagnosis

Maintaining a high index of suspicion for the presence of ADHD in adults is a key aspect in making a correct diagnosis. Because of the high prevalence of adult ADHD relative to other major psychiatric disorders, screening for the disorder should be part of a comprehensive psychiatric evaluation.3 A useful screening tool is the WHO Adult ADHD Self-Report Scale Screener, a six-item subset (four inattentive and two hyperactive-impulsive) of the 18-question Adult Self-Report Scale (ASRS; Table 3).65 In a sample of 154 respondents who reported a diagnosis of childhood ADHD and persistence into adulthood, the six questions from Part A of the ASRS were found to be the most predictive of ADHD. This questionnaire has 65% sensitivity and 94% specificity for adult ADHD when a cut-off of 14 out of a total of 24 points is used.66

 

After screening, accurate diagnosis of ADHD requires a multifaceted approach including assessments of history, present symptoms, and functional impairment (Table 4).15,40,51,53 An accurate diagnosis requires sufficient presenting symptoms from the patient, with a pervasive course since childhood, and confirmation of childhood symptoms by an outside informant. Family history of ADHD further strengthens the diagnosis. The clinical interview should include a medical, educational, developmental, social, family, and psychological history. Interviewing family members greatly improves the clinician’s ability to correctly identify ADHD, as others often remember impairments that the patient has forgotten or failed to recognize. It can also be helpful to obtain school records to identify or corroborate childhood manifestations of ADHD.40 However, valuable supplementary information from family members or school records may often be somewhat difficult to obtain for adult patients no longer residing near their parents or schools.

 

 

Several standardized tools are useful in assessing adults with ADHD (Table 5).8,67 Diagnostic scales are either clinician administered (Conners Adult ADHD Diagnostic Interview, Brown ADD Scale Diagnostic Form, Brown ADD Scale) or self-reported (Barkley’s Current Symptoms Scales, which include evaluation by a family member). These tools vary with respect to whether they evaluate only current symptoms or include functional assessment and prior symptoms. Response to pharmacotherapy, psychotherapy, or both can be monitored by using the assessment scales through the course of treatment to evaluate target symptom changes.

 

Neuropsychologic deficits, including those of executive function, have been demonstrated in multiple studies of adults with ADHD, although results are heterogeneous across tests and patients.64,68,69 Executive dysfunction, evident in children with ADHD, has been shown to persist unchanged into young adulthood70 and has been reported to occur in adults with ADHD.71 Therefore, evaluation of adults with ADHD should include inquiries about deficits related to executive function such as difficulties in organization, working memory, time management, and ability to plan and think sequentially.64,72 Although neuropsychologic tests are not useful for diagnosis, evaluating these deficits may help clarify impairments of performance, guide treatment choices,64 and obtain work or academic accommodations.

Complete evaluation of an adult with suspected ADHD should also include assessment of comorbid psychiatric diagnoses and underlying medical conditions.52 Some medical conditions may have symptoms overlapping those of ADHD or can themselves account for certain attentional symptoms. These include impaired sight or hearing; medication side effects; and neurologic disorders such as sequelae of traumatic brain injury or cerebrovascular accidents, multiple sclerosis, or chemotherapy.73-76 Endocrine disorders such as thyroid diseases and diabetes, age-related conditions such as cognitive changes related to perimenopause, sleep disorders such as obstructive sleep apnea, and rare conditions such as Lyme disease should also be considered.77-83 Occasionally, treatable vitamin B12 or folate deficiencies are also found among adults with cognitive problems including ADHD84,85 when they are tested for serum levels of B12, methylmalonic acid (a more sensitive assay for B12 deficiencies), and folic acid. The critical factor in distinguishing many of these conditions from ADHD is the absence of childhood cognitive or behavioral symptoms consistent with ADHD.

Recommendations for Improving Care for Adult Patients With ADHD

Once the diagnosis is made, patient involvement is a key element in the success of managing ADHD in adults. Management can begin by educating patients and their families about ADHD.16,86 This includes discussion of the genetic contributions to ADHD, how ADHD is diagnosed, its presenting symptoms, and how comorbid conditions will be addressed in the treatment plan.16,87 The patient (and his or her family) can be taught to see ADHD as a treatable disorder rather than as an intrinsic part of their character, and they can begin to understand the impact that untreated ADHD has on their lives.16,86

After patient and family education, other treatment principles can help improve therapeutic outcomes. When significant psychiatric comorbidities such as affective, anxiety, or substance use disorders are present, it is best to treat them with appropriate therapies before targeting the symptoms of ADHD.87 In addition, once appropriate treatment options and objectives are identified, the clinician should explain the expected time course for symptom improvement, as well as potential adverse effects of prescribed medications, and emphasize that using prescribed medications on a consistent basis can improve and maintain the patient’s quality of life.16,40 The importance of involving family members in the overall management process should also be discussed, as should patient expectations and any reservations they have about treatment. Providing long-term support and encouragement at follow-up sessions is intrinsic to the treatment process and can also serve to significantly increase the often poor treatment adherence seen in ADHD.

Pharmacologic Treatment of Adult ADHD

Stimulants are the first line of treatment for ADHD.3 Stimulants, including methylphenidate and amphetamines, have been widely and successfully used in children for decades. Current pediatric guidelines recommend them as first-line therapy.2,3,5 Fewer controlled trials of stimulants have been conducted in adults than in children,88 but results of such studies in adults are similar to those in children and adolescents.89 Controlled trials in adults report significantly greater improvements with stimulants than with placebo, and response rates of 54% to 78% are seen using standard rating scales.89-94

Reported adverse events with stimulants are generally mild or moderate in severity and include reduced appetite, weight loss, anxiety, dry mouth, headache, and insomnia.89,94 Small increases in blood pressure and pulse have been reported in patients receiving stimulants. Cardiovascular status, especially blood pressure, should be monitored while the patient is receiving stimulants. Patients with poorly controlled hypertension may not be eligible for stimulant treatment until their blood pressure is well controlled.91,92 Before prescribing stimulants, clinicians should ensure that the patient has no structural cardiac abnormalities or other serious cardiac problems that may place him or her at increased vulnerability to the sympathomimetic effects of stimulant drugs.

Amphetamine and methylphenidate preparations are available in both immediate- and extended-release formulations. Immediate-release preparations require multiple daily dosing and are more likely to be diverted for misuse and abuse than extended-release formulations, a situation that is more common in adults and adolescents than in children.95,96 A recent study explored total retail prescriptions for long-acting and short-acting medications for ADHD by PCPs, pediatricians, and psychiatrists.96 Approximately 7 million patients in the US filled ≥1 prescription for their ADHD in 2007, with approximately 80% being written by PCPs (21%), pediatricians (28%), or psychiatrists (30%). The selection of short-acting or long-acting ADHD treatments varied by specialty, with long-acting agents representing 56% of primary care prescriptions, 64% of psychiatrist prescriptions, and 79% of pediatric prescriptions. When examined by patient age, long-acting agents accounted for 78% of ADHD prescriptions in pediatric patients (0–17 years of age), but only 49% of adult ADHD prescriptions. Extended-release preparations of methylphenidate, dexmethylphenidate, mixed amphetamine salts, and lisdexamfetamine are approved by the US Food and Drug Administration for use in adults without age restrictions.

Nonstimulants are used as second-line treatment of ADHD when the patient does not respond to first-line therapy, does not tolerate stimulants, or has an active substance use disorder.2,3,97 The nonstimulant atomoxetine is approved by the FDA for use in adults and has been shown to be effective in reducing symptoms of ADHD in adult placebo-controlled trials and in an open-label long-term study.98-101 A delayed time to onset (2 weeks) of a response to atomoxetine has been reported in adult patients.100 Atomoxetine is generally well tolerated and has no abuse potential; the most frequently reported adverse events in clinical trials were dry mouth, insomnia, and nausea.16 A few cases of serious liver injury have been reported in patients receiving atomoxetine, which should be used with caution in patients with cardiovascular or cerebrovascular disease because it can increase blood pressure and heart rate.102

In 2005, the possibility of suicidal ideation with atomoxetine led to an FDA boxed warning similar to that for antidepressant medications for children and adolescents, but no such warning was required in adults based on analysis of the adult studies. Nonetheless, it is prudent to be alert for suicidality in all patients with ADHD regardless of the choice of treatment and, in particular, in those patients with comorbid mood, anxiety, and substance use disorders. Double-blind studies in adults with ADHD have been positive for guanfacine, desipramine, and bupropion, but their use remains off label.103-107

The FDA has recently approved the use of two long-acting stimulants in adults with ADHD: a prolonged-release formulation of methylphenidate and lisdexamfetamine dimesylate, a long-acting prodrug.

In June 2008, the FDA approved the use in adults of a formulation of methylphenidate (MPH) in which the drug is released via an osmotic release oral system (OROS). The OROS-MPH formulation, which is designed to deliver MPH in a controlled manner for approximately 12 hours with a once-daily administration, has been shown to be efficacious and well tolerated in children and in several recent studies in adults with ADHD.108-110 In a double-blind study by Medori and colleagues,110 401 adults 18–63 years of age with ADHD  received 18 mg, 36 mg, 72 mg, or placebo daily for 5 weeks. The primary measure of treatment response was the Conners Adult ADHD Rating Scale. At treatment end point, significantly greater improvements in rating scale scores were seen in patients receiving each of the three doses of OROS-MPH than in the placebo patients (effect sizes of .38, .43, and .62, respectively). Most adverse events were mild or moderate in each treatment group and few patients discontinued treatment because of an adverse event.

In April 2008, the FDA approved the use in adults of a new once-daily stimulant, lisdexamfetamine dimesylate (LDX), the first long-acting prodrug indicated for the treatment of ADHD in children and adults. LDX is a therapeutically inactive molecule, but after oral ingestion it is converted to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, responsible for the drug’s activity. LDX was developed with the goal of providing a long duration of effect that is consistent throughout the day. Clinical trials of LDX in children have demonstrated significant improvements in ADHD rating scale scores compared with placebo and consistent times to maximum plasma LDX levels among the subjects.111,112 Similar results have been seen in adults. In a double-blind, placebo-controlled, parallel-group study in 420 adults 18–55 years of age with a primary diagnosis of ADHD, improvements from baseline in ADHD Rating Scale and Clinical Global Impressions scores throughout the 4-week study period and at endpoint were significantly greater with three doses of LDX than with placebo (P<.0001 and P<.01, respectively).113 In addition, the prodrug formulation was developed to offer reduced potential for abuse-related liking effects. In a double-blind crossover study114 (n=36) of substance-abusing adults, the increase in the “liking score” after 100 mg of oral LDX on the Drug Rating Questionnaire-Subject did not differ significantly from placebo and was significantly less than the liking score increase after an equivalent dose of immediate-release d-amphetamine (P<.04). However, at 40 mg of d-amphetamine and 150 mg of LDX, between-group differences in changes in liking scores were not significant.

Current FDA-approved medications for the treatment of ADHD in adults are listed in Table 6, together with their generic and trade names and dosing information.102,115-118

 

Nonpharmacologic Treatment of Adult ADHD

In addition to pharmacotherapy, nonpharmacologic interventions, such as helping the patient restructure their environment, develop organizational skills, and create better coping strategies, may be beneficial in adults with ADHD.16 Because ADHD affects the entire family, treatment interventions may involve the spouse and children in restructuring of task sharing, planning, and day-to-day functioning. Cognitive-behavioral psychotherapy and structured problem-solving and coping-skills training for ADHD may also improve residual deficits and symptoms that may persist in spite of medication therapy.119-125

The Algorithm presents a schematic to select a specific psychotherapy for target symptoms and impairments.87 A thoughtful conceptualization and application of psychotherapy will prevent the therapist from being distracted. Because it is the very nature of the patient to be disorganized and distractible, organization and focus on the part of the therapist will ensure adherence to the therapeutic pursuit.

 

Conclusion

Adult ADHD remains under-recognized, underdiagnosed, and undertreated by clinicians in the US. Its prevalence and the absence of relevant professional clinical training indicate a need to educate physicians and other healthcare providers who encounter the challenging task of diagnosing ADHD in adults. Updated DSM-IV-TR diagnostic criteria that recognize adult-specific symptoms and reconsider age-threshold criteria for symptom onset are needed. Meanwhile, clinicians can improve patient care and provide a better quality of life for these patients and their families by maintaining a high index of suspicion for ADHD, making screening for the disorder an intrinsic part of the standard psychiatric evaluation, and implementing a multifaceted approach to the diagnosis and treatment of adult ADHD.

Stimulants that have been used in the pediatric ADHD population for decades are effective and well tolerated in adults. Management of ADHD in adulthood requires the clinician to rule out fairly common medical conditions, such as hypertension, that may be exacerbated by stimulant treatment. Significant cardiac disease in most cases precludes the use of stimulants in both adults and children. However, risk/benefit assessment and a cardiologic consultation may be necessary when the severity of ADHD leads to severe life impairments. Longer-acting forms of stimulants and nonstimulants can improve convenience and extend control of ADHD symptoms in challenging adult environments and potentially may help decrease, but by no means eliminate, the likelihood of stimulant abuse and diversion. In a recent analysis96 of US prescribing patterns, long-acting medications were still being used more commonly to treat ADHD in children and adolescents (78%) than in adults (49%), though adults may have even greater problems with treatment adherence and drug abuse and diversion than those ≤18 years of age. Alternative medications offer options to those patients with stimulant intolerance or special clinical circumstances such as active substance abuse.

The development of diagnostic tools and treatment guidelines, coupled with the use of effective and tolerable medications and effective management of comorbid conditions, should improve the quality of care for adult patients with ADHD. Improved recognition and treatment of ADHD should result in improved productivity in academic, work, and home environments, and should enhance quality of life for both patient and family. Future research may demonstrate whether intervention for ADHD can reduce morbidity and mortality from tragic outcomes associated with ADHD such as increased rates of motor vehicle accidents, suicide, and substance abuse and dependence. PP

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4. American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Attention-Deficit/Hyperactivity Disorder. Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Pediatrics. 2000;105(5):1158-1170.
5. American Academy of Pediatrics, Subcommittee on Attention-Deficit/Hyperactivity Disorder, Committee on Quality Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108(4):1033-1044.
6. Barkley RA, Fischer M, Smallish L, Fletcher K. The persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder. J Abnorm Psychol. 2002;111(2):279-289.
7. Kessler RC, Adler LA, Barkley R, et al. Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the National Comorbidity Survey Replication. Biol Psychiatry. 2005;57(11):1442-1451.
8. Adler L, Cohen J. Diagnosis and evaluation of adults with attention-deficit/hyperactivity disorder. Psychiatr Clin North Am. 2004;27(2):187-201.
9. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716-723.
10. Fayyad J, De Graaf R, Kessler R, et al. Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry. 2007;190:402-409.
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51. Murphy KR, Adler LA. Assessing attention-deficit/hyperactivity disorder in adults: focus on rating scales. J Clin Psychiatry. 2004;65(suppl 3):12-17.
52. McCann BS, Roy-Byrne P. Screening and diagnostic utility of self-report attention deficit hyperactivity disorder scales in adults. Compr Psychiatry. 2004;45(3):175-183.
53. Searight HR, Burke JM, Rottnek F. Adult ADHD: evaluation and treatment in family medicine. Am Fam Physician. 2000;62(9):2077-2086,2091-2092.
54. Culpepper L. Primary care treatment of attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2006;67(suppl 8):51-58.
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56. De Quiros GB, Kinsbourne M. Adult ADHD: analysis of self-ratings on a behavior questionnaire. Ann N Y Acad Sci. 2001;931:140-147.
57. Barkley RA, Murphy KR, Fischer M. ADHD in Adults: What the Science Says. New York, NY: Guilford Press; 2007.
58. Biederman J, Mick E, Spencer T, et al. An open-label trial of OROS methylphenidate in adults with late-onset ADHD. CNS Spectr. 2006;11(5):390-396.
59. Livingston R. Cultural issues in diagnosis and treatment of ADHD. J Am Acad Child Adolesc Psychiatry. 1999;38(12):1591-1594.
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61. Biederman J, Faraone SV, Monuteaux MC, Bober M, Cadogen E. Gender effects on attention-deficit/hyperactivity disorder in adults, revisited. Biol Psychiatry. 2004;55(7):692-700.
62. Kalbag AS, Levin FR. Adult ADHD and substance abuse: diagnostic and treatment issues. Subst Use Misuse. 2005;40(13-14):1955-1981.
63. Casey BJ, Durston S. From behavior to cognition to the brain and back: what have we learned from functional imaging studies of attention deficit hyperactivity disorder [editorial]? Am J Psychiatry. 2006;163(6):957-960.
64. Seidman LJ. Neuropsychological functioning in people with ADHD across the lifespan. Clin Psychol Rev. 2006;26(4):466-485.
65. Adult ADHD Self-Report Scale-V1.1 (ASRS-V1.1) Screener from WHO Composite International Diagnostic Interview. 2003.
66. Kessler RC, Adler LA, Gruber MJ, Sarawate CA, Spencer T, Van Brunt DL. Validity of the World Health Organization Adult ADHD Self-Report Scale (ASRS) Screener in a representative sample of health plan members. Int J Methods Psychiatr Res. 2007;16(2):52-65.
67. Weisler RH, Goodman DW. Understanding adult ADHD: treatment adherence and rationale for treatment selection. Psychiatric Times Reporter. 2007;(suppl):2-5.
68. Hervey AS, Epstein JN, Curry JF. Neuropsychology of adults with attention-deficit/hyperactivity disorder: a meta-analytic review. Neuropsychology. 2004;18(3):485-503.
69. Boonstra AM, Oosterlaan J, Sergeant JA, Buitelaar JK. Executive functioning in adult ADHD: a meta-analytic review. Psychol Med. 2005;35(8):1097-1108.
70. Biederman J, Petty CR, Fried R, et al. Stability of executive function deficits into young adult years: a prospective longitudinal follow-up study of grown up males with ADHD. Acta Psychiatr Scand. 2007;116(2):129-136.
71. Seidman LJ. ADHD neuropsychology and executive function deficits. Paper presented at: 159th Annual Meeting of American Psychiatric Association; May 20-25, 2006; Toronto, Canada.
72. Wilens TE, Dodson W. A clinical perspective of attention-deficit/hyperactivity disorder into adulthood. J Clin Psychiatry. 2004;65(10):1301-1313.
73. Pinkston JB, Kablinger A, Alekseeva N. Multiple sclerosis and behavior. Int Rev Neurobiol. 2007;79:323-339.
74. Ahles TA, Saykin A. Cognitive effects of standard-dose chemotherapy in patients with cancer. Cancer Invest. 2001;19(8):812-820.
75. Drew M, Tippett LJ, Starkey NJ, Isler RB. Executive dysfunction and cognitive impairment in a large community-based sample with multiple sclerosis from New Zealand: a descriptive study. Arch Clin Neuropsychol. 2008;23(1):1-19.
76. Vardy J, Wefel JS, Ahles T, Tannock IF, Schagen SB. Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. Ann Oncol. 2008;19(4):623-629.
77. Stein MA, Weiss RE. Thyroid function tests and neurocognitive functioning in children referred for attention deficit/hyperactivity disorder. Psychoneuroendocrinology. 2003;28(3):304-316.
78. Wessels AM, Rombouts SA, Remijnse PL, et al. Cognitive performance in type 1 diabetes patients is associated with cerebral white matter volume. Diabetologia. 2007;50(8):1763-1769.
79. Tager FA, Fallon BA, Keilp J, Rissenberg M, Jones CR, Liebowitz MR. A controlled study of cognitive deficits in children with chronic Lyme disease. J Neuropsychiatry Clin Neurosci. 2001;13(4):500-507.
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81. Markou A, Duka T, Prelevic GM. Estrogens and brain function. Hormones (Athens). 2005;4:9-17.
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85. Elias MF, Robbins MA, Budge MM, et al. Homocysteine, folate, and vitamins B6 and B12 blood levels in relation to cognitive performance: the Maine-Syracuse study. Psychosom Med. 2006;68(4):547-554.
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88. Wilens TE, Spencer TJ, Biederman J. A review of the pharmacotherapy of adults with attention-deficit/hyperactivity disorder. J Atten Disord. 2002;5(4):189-202.
89. Spencer TJ. ADHD treatment across the life cycle. J Clin Psychiatry. 2004;65(suppl 3):22-26.
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91. Spencer T, Biederman J, Wilens T, et al. Efficacy of a mixed amphetamine salts compound in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2001;58(8):775-782.
92. Spencer TJ, Adler LA, McGough JJ, Muniz R, Jiang H, Pestreich L. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61(12):1380-1387.
93. Weisler RH, Biederman J, Spencer TJ, et al; on behalf of the SLI381.303 Study Group. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr. 2006;11(8):625-639.
94. Biederman J, Spencer TJ, Wilens TE, Weisler RH, Read SC, Tulloch SJ. Long-term safety and effectiveness of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr. 2005;10(12 suppl 20):16-25.
95. Wolraich ML, McGuinn L, Doffing M. Treatment of attention deficit hyperactivity disorder in children and adolescents: safety considerations. Drug Saf. 2007;30(1):17-26.
96. Cascade E, Kalali AH, Weisler RH. Short-acting versus long-acting medications for the treatment of ADHD. Psychiatry. 2008;5(8):24-27.
97. Lopez FA. ADHD: new pharmacological treatments on the horizon. J Dev Behav Pediatr. 2006;27(5):410-416.
98. Simpson D, Plosker GL. Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder. Drugs. 2004;64(2):205-222.
99. Faraone SV, Biederman J, Spencer T, et al. Efficacy of atomoxetine in adult attention-deficit/hyperactivity disorder: a drug-placebo response curve analysis. Behav Brain Funct. 2005;1:16.
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109. Reimherr FW, Williams ED, Strong RE, Mestas R, Soni P, Marchant BK. A double-blind, placebo-controlled, crossover study of osmotic release oral system methylphenidate in adults with ADHD with assessment of oppositional and emotional dimensions of the disorder. J Clin Psychiatry. 2007;68(1):93-101.
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Dr. Carroll is clinical assistant professor of Psychiatry at Ohio University College of Osteopathic Medicine in Athens, and chief of Psychiatry Service at the Chillicothe VA Medical Center in Ohio. Dr. Appiani is assistant professor of Pharmacology at Universidad de Buenos Aires, Facultad de Medicina, and Director of ACEDEN in Buenos Aires, Argentina.

Disclosures: Dr. Carroll is a consultant to NMSIS; is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Pfizer, and Janssen; and receives grant support from Pfizer. Dr. Appiani reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Brendan T. Carroll, MD, Chief, Psychiatry Service, MHCL, Chillicothe VA Medical Center, 116A, 17273 State Route 104, Chillicothe, OH 45601; Tel: 740-773-1141, x7871; Fax: 740-772-7179; E-mail: btcarroll1@cs.com.


 

Catatonia is currently viewed as a neuropsychiatric syndrome of diverse etiology.1 However, there has been a steady decline in the diagnosis of catatonic schizophrenia over the last 50 years.2 Recent studies, however, showed that catatonia was diagnosed in ~10% of patients admitted to acute psychiatric facilities.3,4 When methodically assessed, catatonic signs and symptoms are prevalent in schizophrenia (18% of newly admitted patients with psychoses3 and 38% of patients with chronic schizophrenia).4 There are different types of catatonia (eg, acute and chronic) that show different responses to treatment. Catatonia in children and adolescents occurs frequently and may benefit from established treatments with electroconvulsive therapy (ECT) and benzodiazepines. Catatonia may present with psychogenic polydipsia or ingestion of foreign bodies with medical complications. Some patients with catatonia may be resistant to treatments with ECT and benzodiazepines, and alternative pharmacotherapy must be considered. This issue of Primary Psychiatry addresses the treatment of catatonia in these populations.

Catatonia is a clinical syndrome characterized by a range of psychomotor abnormalities that occur in the context of a wide variety of both psychiatric and medical conditions. In children and adolescents it occurs in affective, psychotic, autistic, developmental, and medical disorders. Catatonia may present with unusual stereotypies and medical comorbidities. Consequently, it is under-recognized and under-diagnosed. This issue offers a collection of several articles to help readers understand more about the unique presentations and varied treatment approaches to catatonia. Each article includes case vignettes to aid the clinician in the recognition of catatonia in daily practice. The diagnosis and treatment recommendations are still undergoing modification with the development of new rating scales and new treatments.

William W. McDaniel, MD, MS, and David R. Spiegel, MD, present case vignettes of patients who required treatment for low sodium and catatonia. The definition of stereotypy from the KANNER scale is repetitive, non-goal-directed movements.5 The scale range is from 0 (absent) to 8 (present, with severe self-injury). The ingestion of non-food items and polydipsia would be included as catatonic signs. The basic tenants for the treatment of medical catatonias are to: treat the underlying medical condition, treat medical catatonia with treatments used for psychiatric catatonias, and treat the comorbid diagnoses to improve the patient’s outcome. In their study, hyponatremia is the co-occurring medical condition.

In their article on catatonia in children and adolescents, Dirk M. Dhossche, MD, PhD, and colleagues present data to support the use of benzodiazepines and ECT. They provide a treatment algorithm that includes careful assessment and judicious use of a lorazepam challenge test. The case vignettes support this approach. They also discuss the importance of the classification of catatonia in the upcoming Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.6 They emphasize the need for greater independence of the diagnosis of catatonia “for the sake of the children”.

Finally, Brendan T. Carroll, MD, and colleagues, demonstrate the wide variety of pharmacologic treatments. It is difficult to construct a pharmacologic algorithm for the treatment of catatonia. This literature is extensive and the clinician may be distracted by the latest case report. This attempt is to organize the pharmacotherapy along neurochemistry and the known mechanisms of action of the medications. The case vignettes were included to show the presentation of catatonia in the hospital setting. They also underscore the need to use a combination of medications to treat these patients with catatonia. Perhaps the great divide in catatonia is that between g-aminobutyric acid (GABA) and glutamate mechanisms in catatonia. This has been discussed by Northoff7 and has been investigated, usually when benzodiazepines and ECT are not available or not effective.7

The most compelling reason for diagnosing catatonia is its exquisite responsiveness to treatment, particularly to benzodiazepines. During the last 2 decades, other compounds like zolpidem and glutamate antagonists were used with success in the treatment of this syndrome.7 Modern neuroimaging techniques allow findings of cortical involvement in catatonia, but the primary findings come from pharmacology response to treatment.7 Benzodiazepines are effective in 60% to 80% of patients with acute catatonia.8 It has been described that ~75% of patients can achieve sustained improvement with continuous treatment.9 Zolpidem, a non-benzodiazepine GABAA agonist, also relieves catatonia. There are reports of cases of clinical durable improvement in patients with treatment resistance to ECT and benzodiazepines. These facts give clues about GABAA involvement in the pathophysiology of catatonia.8 Moreover, GABAA receptor binding in right lateral orbitofrontal and right posterior parietal cortex is diminished. There is also a report that correlates catatonic stupor with GABAA binding decrease with flumazenil positron emission tomography scan.9 This gabaergic binding normalized after the treatment with diazepam.9 Another research performed with Spect with iodine-123-iomazenil showed lower cerebral perfusion in the right lower prefrontal cortex and parietal cortex in catatonic patients. In this group of patients the decrease of GABAA receptor binding correlated positively with motor and affective symptoms.10 In summary, catatonic reaction to benzodiazepines and GABAA agonists seems to be paradoxical. Patients treated with lorazepam tend to react with activation rather with sedation, even in those with a post-acute catatonic state. Lorazepam and GABAA agonists show that the principal dysfunction in catatonia may be related to GABA depletion.

Glutamate transmission and N-methyl-d-aspartate (NMDA) antagonists may be involved in the pathophysiology of catatonia through NMDA receptors.11 It has been hypothesized that the decrease in gabaergic tone in prefrontal areas released the supplementary motor areas, resulting in glutamate disinhibition. Thus, the glutamatergic hyperfunction in the striatum may be related to the development of catatonic symptoms.10 There are reports of successful treatments with glutamate antagonists: amantadine, topiramate, and memantine in patients who failed to respond to established treatment, including lorazepam and ECT.11 With these compounds, clinical improvement seems to be gradual. This difference in the time response between GABA agonists and glutamatergic antagonists may suggest that glutamate hyperactivity may be a secondary reaction to gabaergic depletion.11 When these findings are connected, catatonic syndromes are in part due to gabaergic hypoactivity and glutamate hyperactivity, and it seems that in this disorder it is necessary to have a balance between GABA and glutamate concentrations. When this balance is broken catatonia may appear. According to current pharmacology, catatonia may be relieved by diminishing glutamate hyperactivity or by augmenting gabaergic tone.  PP

 

References

1.    Taylor MA. Catatonia: a review of a behavioral neurologic syndrome. Neuropsych, Neuropsych Behav. 1990;3:48-72.
 2.    Mahendra B. Where have all the catatonics gone? Psychol Med. 1981;11(4):669-671.
 3.    van der Heijden FM, Tuinier S, Arts NJ, et al. Catatonia: disappeared or under-diagnosed? Psychopathology. 2005;38(1):3-8.
 4.    Ungvari GS, Leung SK, Ng FS, et al. Schizophrenia with prominent catatonic features (‘catatonic schizophrenia’): I. Demographic and clinical correlates in the chronic phase. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(1):27-38.
 5.    Carroll BT, Kirkhart R, Ahuja N,  et al.  Katatonia – a new conceptual understanding of catatonia. Psychiatry (Edgemont). 2008;5(12):42-50.
6.    Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; In press.
7.  Northoff G. What catatonia can tell us about “top down modulation”: a neuropsychiatric hypothesis.  Behav Brain Sci. 2002:25(5):555-577.
8.    Seethalakshmi R, Dhavale S, Suggu K, et al. Catatonic syndrome: importance of detection and treatment with lorazepam. Ann Clin Psychiatry. 2008;20(1):5-8.
9.    Iseki K, Ikeda A, Kihara T, et al. Impairment of the cortical Gabaergic inhibitory system in catatonic stupor: a case report with neurimaging. Epileptic Disord. 2009;11(2):126-131.
10.    Northoff G, Steinke R, Czcervenka C, et al. Decreased density of GABA A receptors in the left sensorimotor cortex in akinetic catatonia: investigation of in vivo benzodiazepine receptor binding. J Neurol Neurosurg Psychiatry. 1999;67(4):445-450.
11.    Carroll BT, Goforth HW, Thomas C, et al. Review of adjunctive glutamate antagonist therapy in the treatment of catatonic syndromes. J Neuropsychiatry Clin Neurosci. 2007;19(4):406-412.

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The Unusual Side Effect of Excessive Sexual Desire with Paroxetine Use

Roger Z. Samuel, MD

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Primary Psychiatry. 2006;13(3):40-42

 

Dr. Samuel is president and medical director at the Boca Raton Psychiatric Group in Florida.

 

Disclosure: Dr. Samuel is on the speaker’s bureau of Pfizer.

Please direct all correspondence to: Roger Z. Samuel, MD, President and Medical Director, Boca Raton Psychiatric Group, 7284 W. Palmetto Park Rd, Suite 201S, Boca Raton, FL 33433; Tel: 561-368-8998; Fax: 561-392-9170; E-mail: brpg7284@lycos.com.


 

 

 

Focus Points

  • Serotonin reuptake inhibitors are associated with a 22% to 43% risk of sexual side effects.
  • While diminished sexual dysfunction is the most common form of sexual side effect, excessive sexual desire and hypersexuality are rare but possible adverse effects.
  • Over-the-counter remedies can have independent as well as interaction-based risks in patients with psychiatric disorders.
 
 

 

Abstract

 

Increased arousal and sexual desire in patients on antidepressants do not always signify the presence of mania or hypomania. While serotonin reuptake inhibitors have frequently been associated with decreased sexual function (eg, decreased libido or arousal; erectile and orgasmic dysfunction), and while paroxetine is notorious for being the worst offender, there are rare occurrences of hypersexuality associated with antidepressant treatment. The following case report examines a female patient who developed increased sexual arousal with the use of paroxetine for depressive symptoms. The presence of other manic symptoms was ruled out and the implications of drug-supplement interactions were examined.

 

Introduction

 

This case report discusses the incidence of sexual dysfunction with antidepressant therapy, and examines the causes and postulated mechanisms by which it occurs. Possible forms of sexual dysfunction, including the rare side effect of hyperarousal in connection with paroxetine use, are discussed. Other reported cases of hypersexuality and drugs associated with them are reviewed. The importance of a careful evaluation of treatment-emergent symptoms and the need to keep an open mind to a broad differential diagnosis will be emphasized. This case report also highlights the necessity of keeping track of over-the-counter remedies and watching out for their side effects and interactions with prescription drugs.

 

Case Report

 

A 56-year-old white female was referred to the Boca Raton Psychiatric Group by her psychotherapist out of concern that the sudden appearance of hypersexuality might be due to new-onset mania. The patient’s 5-month history of depressed mood associated with worthlessness, insomnia, fatigue, impaired concentration, anhedonia, and anxiety, was consistent with a major depressive episode (MDE).

 

Her past psychiatric history was significant, as follows. Zolpidem twice per week was initiated in 1997 by her gynecologist for the treatment of middle insomnia. Her gynecologist then prescribed nefazodone 100 mg QD from 1996–1998 for perimenopausal symptoms. The patient engaged in purging throughout her 40s. She became depressed after stock market losses in 2002, and experienced interrupted sleep and diminished energy and activity levels; however, there were no other MDE symptoms. Without seeing a psychiatrist, she took paroxetine 20 mg QD, which she obtained from a friend. After improving, she stopped the paroxetine in autumn 2004, which preceded her current episode by 9 months. Careful questioning revealed no history of manic or hypomanic episodes in the past.

 

The patient put herself back on paroxetine 10 mg QD 10 days prior to her referral. She developed new-onset sexual arousal 3 days later, which persisted after she increased the paroxetine to 20 mg QD. She was otherwise anhedonic. She did not have spontaneous orgasms or clitoral changes, and refrained from engaging in sexual activity. A detailed inquiry revealed no evidence of mania or hypomania. There was no reduction in sleep nor increase in energy, activities, spending, rate of speech, or thoughts. Her affect, psychomotor activity, and mood were consistent with depression. There were no manic symptoms in the preceding months nor was there a family history of mania or bipolar disorder. The absence of other manic/hypomanic symptoms was corroborated by her therapist.

 

The patient’s medications consisted of paroxetine 20 mg QD, zolpidem 10 mg 2/3 tab HS PRN, and supplements (red yeast rice, milk thistle, flax seed oil, and vitamin C). She was drinking one half to two thirds a bottle of wine daily; her alcohol consumption had increased over the last decade.

 

She was diagnosed with major depressive disorder and alcohol abuse. Thyroid-stimulating hormone was normal. She was tapered off paroxetine over the course of 3 days, and abstinence was advised. Clorazepate 3.75 mg prn and 7.5 mg HS was prescribed.

 

At 1-week follow-up the patient was off the paroxetine for 3 days and using clorazepate occasionally in the day and QHS. She had markedly reduced her alcohol consumption. Her libido/sexual arousal had returned to its normal level and her mood had improved such that she chose to avoid antidepressant use. No manic or hypomanic symptoms ever occurred.

 

One month later, due to anxiety over a new breast lump and persisting depression, the patient agreed to a trial of citalopram, starting at 10 mg QD for 4 days, and then 20 mg QD. At 2-week follow-up, her mood had improved but she had the side effect of heightened libido, albeit less than with paroxetine. Two weeks later, her libido had returned to normal while still on citalopram 20 mg QD. She did not display manic or hypomanic symptoms at any time.

 

Discussion

 

Serotonin reuptake inhibitors (SRIs), such as paroxetine and citalopram, are known to cause sexual side effects. However, these are usually diminution of sexual function such as hyposexuality, erectile dysfunction, and orgasmic difficulty. SRIs are known to have a deleterious effect on sexual function through increased serotonin effects as well as increased prolactin, opioid, and cortisol effects.

 

SRIs were initially reported to have lower rates of sexual side effects than are currently believed to be accurate, due to study and surveillance reporting defects1 (eg, fluoxetine was listed as having a 2% rate of sexual side effects). More recent reports suggest sexual side-effect rates of 22% to 43% for all antidepressants (with paroxetine having the highest rate of 43%),2 and paroxetine has been reported to cause diminished sexual desire at a 9% rate.3

 

A review of the literature revealed a report of yawning, clitoral engorgement, and orgasm associated with fluoxetine,4 as well as of yawning associated with clomipramine.5 There is also a report of sexual stimulation in three women treated with the SRIs fluoxetine, paroxetine, and fluvoxamine. Two of the women experienced undesirable sexual arousal, and the third had increased sexual desire, arousal, and hypersexuality. The woman on paroxetine was also prescribed methylphenidate.6 Anecdoctal reports (in lay media, the Internet) of hypersexuality related to SRIs do occur, some of which refer to this phenomenon as a SRI-discontinuation symptom. A persistent sexual arousal syndrome7 as well as premenstrual hypersexuality have been reported,8 but these are unrelated to SRI use.

 

Among other things, sexual function is affected by dopamine-serotonin balance,9 ie, dopamine being excitatory and serotonin being inhibitory in nature. Dopamine mechanisms are important in libido function. Stimulation of serotonin 2A receptors in mesocortical centers by SRIs may reduce libido by diminishing dopamine activity.10 Nitric oxide and acetylcholine are important in arousal.10 The arousal pathway travels from the brain to the spinal cord, and then to nerve fibers of the peripheral autonomic system and the sexual tissue. By reducing nitric oxide synthesis, SRIs cause sexual dysfunction (ie, arousal dysfunction). Drugs with anticholinergic activity can also inhibit sexual functioning.10

 

There is conflicting data about whether the effect of serotonin on sexual response is primarily inhibitory, excitatory, or mixed, depending on the receptor subtype stimulated.4 Serotonin agonism occurs with acute administration of SRIs and hypersexual responses have been reported secondary to acute increases in central serotonergic neural activity.4 The spontaneous sexual response and yawning associated with clomipramine use was attributed to corticotropin-releasing factor (CRF)-activated neural circuits resulting from clomipramine’s effect on serotonin reuptake, which causes increased brain serotonin levels and releases hypothalamic CRF.11

 

Animal studies implicate an association between altered norepinephrine transmission and the hormonal changes associated with female sexual behavior. Systemic treatment with α- and β-receptor agonists and antagonists modulate such behavior.12 Studies have shown that stimulation of α1 receptors in certain parts of the brain plays a role in hormonal facilitation of female animal sexual behavior, whereas stimulation of β-receptors seems to inhibit this behavior.

 

Paroxetine is a potent SRI with some norepinephrine reuptake inhibition at higher doses as well as muscarinic cholinergic antagonism.10-13 Citalopram, on the other hand, has been called a “true selective serotonin reuptake inhibitor” because it functions as a “selective” SRI without other significant activity.

 

The sequence of hypersexuality onset with initiation of paroxetine, combined with resolution with discontinuation and later re-emergence with initiation of citalopram, suggests a side effect of SRI use. No other causes explain this phenomenon. A review of the supplements red yeast rice, milk thistle, and flax seed oil14 revealed no evidence for instigating hypersexuality, except that flaxseed is reported to have weak antiestrogenic, estrogenic, and steroid-like activity. However, as the patient had been on these supplements for months prior to and after the 10 days of hypersexuality, this symptom was deemed unrelated to the supplement use.

 

Conclusion

 

It can be postulated that this patient’s hypersexuality was connected in some complex but unclear way to paroxetine’s norepinephrine effects; however, the occurrence of a similar reaction with citalopram and the reports of hypersexuality with fluoxetine, paroxetine, and fluvoxamine4,6 argue against it. Rather, it might make more sense to suggest that initial serotonin agonism caused by SRI administration in a subgroup of susceptible females can provoke hypersexuality due to increased central serotonergic activity. It is also possible that there was an interaction between flaxseed oil and SRI effects. PP

 

References

 

1. Goldstein B, Goodnick P. Selective serotonin reuptake inhibitors in the treatment of affective disorders—III. Tolerability, safety and pharmacoeconomics. J Psychopharmacol. 1998;12(3 suppl B):S55-S87.

 

2. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366.

 

3. Agren H, Aberg-Wistedt A, Akerblad AC. Sertraline vs paroxetine in major depression—a multicenter, double-blind, 24 week comparison. Poster presented at: 151st Annual Meeting of the American Psychiatric Association; May 30-June 4, 1998; Toronto, Ontario, Canada.

 

4. Modell JG. Repeated observations of yawning, clitoral engorgement, and orgasm associated with fluoxetine administration. J Clin Psychopharmacol. 1989;9(1):63-65.

 

5. McLean JD, Forsythe RG, Kapkin IA. Unusual side effects of clomipramine associated with yawning. Can J Psychiatry. 1983;28(7):569-570.

 

6. Elmore JL, Quattlebaum JT. Female sexual stimulation during antidepressant treatment. Pharmacotherapy. 1997;17(3):612-616.

 

7. Leiblum SR. Sexual problems and dysfunction: epidemiology, classification, and risk factors. J Gend Specif Med. 1999;2(5):41-45.

 

8. Riley A. Premenstrual hypersexuality. J Sex Mar Ther. 1994;9(1):87-93.

 

9. Crenshaw TL, Goldberg JP. Sexual Pharmacology: Drugs That Affect Sexual Functioning. New York, NY: Norton; 1996.

 

10. Stahl S. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. New York, NY: Cambridge University Press; 2000.

 

11. Harrison W, Stewart J, McGrath PJ, Quitkin F. Unusual side effects of clomipramine associated with yawning. Can J Psychiatry. 1984;29(6):546.

 

12. Bloom FE, Kupfer DJ. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995.

 

13. Frazer A. Norepinephrine involvement in antidepressant action. J Clin Psychiatry. 2000;61(suppl 10):25-30.

 

14. Fetrow CW, Avila JR. Professional’s Handbook of Complementary & Alternative Medicines. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.

 

 

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Psychiatric Dispatches: Noteworthy Briefs from the Field: April 2009

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Primary Psychiatry. 2009;16(4):17-18
 

Depression Linked to Increase in Harmful Type of Body Fat

While obesity and weight gain have been known to be a common link to depression, depression is also actually proven to increase fat. Nicole Vogelzangs, doctoral student at VU University Medical Center in Amsterdam, and colleagues, studied >2,000 patients 70–79 years of age in Memphis, Tennessee and Pittsburgh, Pennsylvania. The study initially evaluated participants and then re-assessed them 5 years later to conclude any information correlating to obesity in general and abdominal obesity in particular. After 5 years, the evaluation consisted of determining whether or not there was a correlation between overall obesity and abdominal obesity while also considering other factors such as an individual’s lifestyle, history of diseases, and other information that could interfere with the outcome.

They found no substantial causation linked to baseline depression. However, there was a significant difference between abdominal obesity and depression. One possible theory why depressed people are more likely to have abdominal obesity is because their lifestyle is most likely unhealthy. However, this assumption is not very strong, as the researchers had factored in the additional affects of alcohol use, exercise patterns, smoking and other illnesses.

“Previous studies have reported clinically relevant depressive symptoms in 10% to 15% of older persons,” said Ms. Vogelzangs. “Physicians should be alert of the fact that persons with depressive symptoms are more prone to gain visceral fat, as this increases their risk for heart diseases. Therefore, it would be good to monitor the metabolic status of (older) persons with depressive symptoms.”

According to Vogelzangs and colleagues, the most important finding was that older individuals with depressed symptoms were twice as likely to gain visceral fat as were non-depressed older people. Although there was an increase in visceral fat, there was no change in overall obesity, such as body mass index. This implies a biologic explanation more so than poor diet as the cause.

One of the most challenging factors they found was that they did not analyze psychiatric diagnoses of depression. Instead, they used a questionnaire to calculate the symptoms.

“However, previous studies have shown that the questionnaire we used (The Center for Epidemiologic Studies Depression Scale) gives a good indication of the presence of clinically relevant depressive symptoms,” Ms. Vogelzangs said.

Funding for this research was provided by the National Institutes of Health and the Young Academy of the Royal Netherlands. (Arch Gen Psychiatry. 2008;65(12):1386-1393.) –AC

Genetic Marker Discovered to Be Strongly Associated with Delusions in Schizophrenia

Patients with schizophrenia may present with various symptoms, including delusions, hallucinations, and declines in motor and cognitive function. According to the National Institute of Mental Health, among the 1.1% of the United States population affected by the disorder, some may present with some but not all of the common symptoms of schizophrenia. Due to the varied network of symptoms associated with schizophrenia, the identification of particular genes that may be associated with the disorder is difficult. Currently, researchers have identified certain genes that may contribute to the development of schizophrenia, such as neuregulin (NRG) 1, but lack a more complete understanding of the genetic make-up for the disorder.

David Valle, MD, of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues, studied the genetic make-up of 1,515 people with and without schizophrenia in the Ashkenazi Jewish population for genetic differences that may highlight particular genes involved in schizophrenia. In prior gene linkage studies, researchers have identified a schizophrenia susceptibility locus gene in Ashkenazi Jewish and Han Chinese from Taiwan populations.

Valle and colleagues studied 458 patients with schizophrenia (including 285 parent-child trios) and compared their genetic composition to 487 healthy controls. In addition, the authors identified 73 different symptoms of schizophrenia and separated symptoms into nine heritable quantitative disorder traits: delusion, prodromal, negative, affective, scholastic, adolescent sociability, disorganization, disability, and hallucination. Patients with schizophrenia were evaluated for presence of these traits. Focusing on the region previously implicated in schizophrenia—chromosome 10—researchers analyzed 1,414 single nucleotide polymorphisms (SNPs) to determine if any SNPs were more common among patients with schizophrenia than healthy controls.

Although they did not find any genetic markers directly related to the complete spectrum of schizophrenia symptoms, the authors did find three SNPs (rs10883866, rs10748842, and rs6584400) strongly associated with the “delusion” quantitative trait when comparing genetic differences from healthy controls. Each SNP was located at NRG3, which is primarily expressed in the central nervous system and is related to NRG1. In addition, researchers identified 20 additional SNPs that may play a role in schizophrenia development; 13 of those SNPs, which were associated with scholastic, disorganization, and hallucination traits, were located at or near NRG3.

They concluded that these biologic properties along with prior linkage studies and these association results strongly support NRG3 as a gene involved in the development of schizophrenia. Additional studies could begin sequencing the NRG3 gene to uncover any genetic variants that may contribute to schizophrenia development in affected patients.

Funding for this research was provided by the National Alliance for Research on Schizophrenia and Depression, the National Institute of Mental Health, the National Institutes of Health, and the Wasie Foundation. (Am J Hum Genet. 2009;84(1):21-34.) –CP

Bipolar Mania Symptoms Associated with Treatment-emergent Mania

Manic phases of bipolar disorder have been shown to respond to mood stabilizer treatment, but treating bipolar depression can be more complex. Prescribing an antidepressant for bipolar depression can sometimes lead to treatment-emergent mania (TEM), a rapid switch from depression to mania following the introduction of an antidepressant.

Mark A. Frye, MD, at the Mayo Clinic in Rochester, Minnesota, and colleagues, recently published a study focusing on the factors leading and related to the emergence of TEM in bipolar disorder. They analyzed data from a previous study, led by Robert Post, MD, of the Bipolar Collaborative Network in Chevy Chase, Maryland. This second study included 176 adult outpatients with bipolar disorder, enrolled in a 10-week trial. Participants were divided into three groups, according to the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N=85), those who did not respond to antidepressant treatment (N=45), and those who had TEM or hypomania (N=46).

Using factor analysis, researchers compared the TEM group to the favorable and the non-favorable antidepressant response groups. Some components of the Young Mania Rating Scale—which was included in patients’ baseline testing—were identified as correlates of TEM, including increased motor activity and speech and language-thought disorder. It is suggested, therefore, that minimal manic symptoms at baseline in otherwise full syndromal bipolar disorder are indicative of risk for TEM. (Am J Psychiatry. 2009;166:164-172.) –LS

Psychiatric dispatches is written by Amanda Cuomo, Carlos Perkins, Jr., and Lonnie Stoltzfoos.
 

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Dr. Kimhy is assistant professor of clinical psychology in the Department of Psychiatry at Columbia University, Ms. Durbin is research assistant at the New York State Psychiatric Institute, and Dr. Corcoran is director of the Center of Prevention and Evaluation clinic at the New York State Psychiatric Institute, all in New York City.

Disclosure: Drs. Kimhy and Corcoran receive grant support from the National Institute of Mental Health. Ms. Durbin reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: David Kimhy, PhD, Department of Psychiatry, Unit 55, Columbia University, 1051 Riverside Dr, New York, NY 10032; Tel: 212-543-6817; Fax: 212-543-6176, E-mail: dk553@columbia.edu.


 

Focus Points

• Psychosis onset has been associated with cannabis use.
• The causal relationship between cannabis and psychosis remain unclear.
• Retrospective assessments cannot determine the temporal direction of this link.
• Daily diaries can clarify the directionality of this link during “real world” daily functioning.

 

Abstract

The association between cannabis use and the initial development of psychotic symptoms has attracted increased interest over the past decade. In particular, researchers have attempted to elucidate whether cannabis use increases the risk of psychosis among vulnerable individuals or may just represent attempts to self-medicate distressing symptoms. While a growing literature suggests that cannabis use may contribute to the development of psychotic symptoms, these findings are based primarily on retrospective assessments that have limited ability to clarify the temporal link between cannabis use and psychotic symptoms. The authors review the literature regarding the link between cannabis use and psychotic symptoms; point out the limitations associated with retrospective assessments; and discuss advantages of incorporating daily diary methods, such as Experience Sampling Method (ESM), to study cannabis use and symptoms during daily functioning in “real world” environments. The authors also discuss potential future applications of ESM in research and clinical practice that may inform the identification of individuals vulnerable to develop psychotic symptoms, as well as the development of treatments that target this population.

Introduction

The association between cannabis use and psychotic symptoms has attracted increased interest over the past decade.1-3 A multifarious body of research has been conducted to characterize this link, including cohort, epidemiologic, challenge, and genetic studies. A primary focus of these inquiries has been the potential causal role cannabis use may play in the initial development of psychotic symptoms and schizophrenia. In particular, researchers have attempted to elucidate whether cannabis use increases risk of psychosis among vulnerable individuals or may just represent attempts to self-medicate distressing symptoms.4 The increased interest in this link is rooted, in part, in cannabis being potentially one of a few modifiable risk factors of schizophrenia,5 with an estimated 8% of the attributable risk for this disorder being accounted for by cannabis use.

Previous reports indicate that the prevalence of cannabis use in a first episode of psychosis (~20% to 40%)6-8 is comparable to rates reported among individuals at high risk of psychosis (17% to 41%).9-12 Cross-sectional studies in genetic high-risk individuals indicate a link between cannabis use and positive symptoms, with an increase in use and symptoms during the months leading to the development of frank psychosis.13,14 Similarly, individuals with psychosis vulnerability were more likely to report abnormal perceptions and thought influence when they used cannabis4,15 and were more likely to develop psychosis.2,16 Evidence from challenge,17,18 genetic,19-21 and epidemiologic studies22 provide further support for this link. However, the support for cannabis playing a causal role in the development of psychosis is not universal. Opponents of this position point to evidence of increased use of cannabis in the general population (eg, Australia) without corresponding elevations in cases of schizophrenia,23 as well as a lack of association between cannabis use and later development of psychosis in some clinical high-risk cohort studies.9  While a growing literature suggests that cannabis use may play a role in the development of psychosis, these findings are based primarily on retrospective assessments that have limited ability to clarify the temporal link between cannabis use and psychosis. The use of daily diary methods may potentially elucidate this link. Thus, the primary aims of this article are to review the literature regarding the link between cannabis use and psychotic symptoms; identify the limitations associated with retrospective assessments; and discuss advantages of incorporating daily diary methods, such as Experience Sampling Method (ESM), to study cannabis use and symptoms during daily functioning in “real world” environments.

Link Between Cannabis Use and Initial Development of Psychotic Symptoms: Methodologic Limitations

A growing body of literature suggests cannabis is associated with the initial development of psychotic symptoms. However, the literature remain inconclusive regarding the causal direction of this link due to numerous methodologic limitations. First, most studies to date in high-risk individuals have employed single assessments or cross-sectional designs. Thus, evidence of the co-evolution of cannabis use and symptoms over time remains unclear. Corcoran and colleagues12 recently published the first prospective longitudinal report on cannabis use and symptoms in individuals at clinical high risk of psychosis. Subjects were assessed prospectively every three months for up to 2 years. Data indicated that periods characterized by increased cannabis use were associated with significantly more perceptual disturbances and worse functioning, controlling for medications and use of other drugs. However, the 3-month assessment intervals in this study did not permit time-lag analyses, precluding the evaluation of causality between cannabis use and symptoms. 

Another limiting factor is the use of retrospective measures of cannabis use and symptoms. Such assessments are vulnerable to the influence of memory difficulties, affective states at assessment time, and cognitive biases and reframing. Even when prospective designs are used (eg, conducting assessments prospectively every 3 months for up to 2 years), these assessments are still based on the participants’ retrospective recollection of cannabis use and symptoms from the past week, from the past month, or since the previous assessment. These difficulties are particularly critical given the substantial memory deficits experienced by many individuals at high risk for psychosis,24,25 making the use of retrospective assessments potentially problematic in this population. This view is echoed in the preliminary assessment guidelines for the pharmaceutical industry published by the United States Food and Drug Administration.26 Accordingly, Patient-Reported Outcome (PRO) instruments that:

…require patients to rely on memory, especially if they must recall over a period of time, or to average their response over a period of time may threaten the accuracy of the PRO data. It is usually better to construct items that ask patients to describe their current state than to ask them to compare their current state with an earlier period or to attempt to average their experiences over a period of time.26 (p. 11)

A third limiting factor is rooted in the relatively brief impact period (minutes to hours) of Delta 9-tetrahydrocannabinol, the active ingredient of Cannabis sativa.27 Retrospective assessments that are completed days, weeks, or even months after the actual cannabis use are limited in their ability to provide information about the co-evolution of mood, symptoms, and drug use over the brief periods before and after the actual cannabis use. As a result, the determination of the temporal link between mood, symptoms, and cannabis use remains unclear.

Finally, the use of retrospective assessments may provide only limited information about the social and environmental context associated with cannabis use, as well as motivation for use. Thus, the current literature based on retrospective assessments of cannabis use and symptoms may have limited ecological validity to determine the temporal relationship between cannabis use and development of psychotic symptoms.

Diary Methods

To overcome some of these difficulties, researchers have employed daily diary methods to study cannabis use and symptoms during daily functioning in “real world” environments. Diary methods such as ESM is an ecologically valid time sampling of self-reports developed to study the dynamic process of person-environment interactions.28 Subjects in ESM studies are typically supplied with a digital wristwatch and booklets containing questionnaires about current mood, symptoms, activities, and social context. The subjects are instructed to complete a questionnaire upon hearing beeps from the wristwatches, which are typically preprogrammed to beep randomly numerous times a day to elicit experience samples. ESM offers numerous advantages over retrospective assessments including: the ability to record experiences, behavior, and context using high time-resolution measurement (over minutes to hours) that permits time-lag analyses; assessment of current experiences with limited need of episodic memory input; the potential for inclusion of minor/transient experiences that may not be recalled later, but may still have an impact on mood and behavior; the ability to assess motivation in vivo; and the possibility to analyze in high time-resolution the daily fluctuations and patterns of change across activities, social contexts, and time of day.

Spearheaded by researchers from the Maastricht group,28-31 ESM has been used extensively to study psychosis during the flow of daily functioning in individuals with schizophrenia spectrum disorders. More recently, the authors of this study demonstrated the feasibility and validity of using ESM with Palm computers in hospitalized individuals with schizophrenia32 and in young people identified as at heightened clinical risk for psychosis,33 allowing researchers to link these data to concurrent ambulatory physiologic measures.

A handful of attempts have been made to apply ESM to study cannabis use and psychosis. The Table lists peer-reviewed publications of studies using daily diary methods (such as ESM) to investigate cannabis use and psychosis.20,21,34,35 Among individuals with established psychosis, ESM has been used to investigate the link between psychosis, cannabis use, and the functional polymorphism in the catechol-O-methyltransferase gene (COMT Val(158)Met).20,21 Only two studies34,35 to date have used ESM to elucidate the link between cannabis use and psychotic symptoms in individuals with psychosis proneness. Verdoux and colleagues34 and Tournier and colleagues35 investigated this link in undergraduate university students. They reported that subjects with high vulnerability for psychosis were more likely to report unusual perceptions, as well as feelings of thought influence compared to subjects with low vulnerability.34 In contrast, cannabis use did not increase subsequent occurrences of psychotic experiences. Similarly, individuals with a diagnosis of agoraphobia were significantly more likely to use cannabis (regardless of state anxiety; however, overall, there was no evidence for anxiolytic or anxiogenic effect of cannabis use in this agoraphobia sample.35 These findings were interpreted as inconsistent with the self-medication model.34

 

 

While these findings35 shed light as to the temporal link between cannabis use and psychosis, the study included a nonclinical sample of college students. No study to date has used ESM to characterize prospectively in high time-resolution the temporal link between cannabis use and positive symptoms during the flow of daily functioning among individuals at clinical high risk for psychosis. Such a study may offer unique and vital information that may not be possible to collect using retrospective assessments. Such a study will permit the conduct of time-lag analyses that will shed light about the directionality of the cannabis use—positive symptom link, informing causality; will allow the collection of data as to motivation for use within close temporal proximity to time of use; and will provide information about the social and environmental context of cannabis use in the flow of daily functioning in this population. Understanding the motivation for and context in which individuals at clinical high risk for psychosis use cannabis could inform the development of preventive interventions to reduce exposure, and delay or possibly prevent psychosis onset. Numerous investigators, notably Barrowclough and colleagues,36 have demonstrated the safety and efficacy of psychological treatments aimed at reducing the use of cannabis and other drugs in patients with schizophrenia, including first-episode patients.37,38 Treatments include motivational models,39 cognitive-behavioral therapy (CBT), family intervention,36 and antipsychotics.9 With an understanding of motives for use, these programs for first-episode dual-diagnosis patients could be piloted in substance-using prodromal patients. Miller and colleagues40 is currently developing a study using ESM with Palm computers in a sample of urban, help-seeking adolescents and young adults who have been determined to be at clinical high-risk for psychosis using the Structured Interview for Prodromal Syndromes and Scale of Prodromal Symptoms–the diagnostic “gold standard” in psychosis high-risk research. Figure 1 presents screen shots of questions to be presented on the Palm computers as part of this study.

 

 

Daily diary methods such as ESM may also be used as a tool to identify in treatment the clinical correlates of psychosis, including cannabis use, during the flow of daily functioning in individuals at high risk of psychosis. Kimhy and colleagues32 has used ESM with Palm computers to collect information about stress and psychotic symptoms in hospitalized psychotic patients as part of their daily functioning. For example, Figure 2 presents the mean ratings of subjective stress and suspiciousness across time of day in this population. Such information may allow identifying associations between stress, symptoms, and specific activities or social context (in this example, lunch and dinner time on the unit). In this case, lunch and dinner times on the inpatient unit are temporally linked with lower ratings stress and suspiciousness by patients. In particular, use of ESM may elucidate the link between cannabis use and exacerbation of attenuated psychotic symptoms that may not be recognized or recalled retrospectively by patients during treatment session. As such, they may allow clinicians to identify individuals in whom the use of cannabis may increase psychotic symptoms. Kimhy and Corcoran33 recently published a case report in which ESM with a Palm computer was incorporated into CBT with an individual at clinical high risk of psychosis. The authors of this article are currently developing software for mobile devices that will allow data collection and homework completion as part of CBT treatment.

 

Conclusion

The use of daily diary methods offers a novel and unique way to gather information on the temporal link between cannabis use and psychosis; motivation for use; and the clinical, social and environmental correlates of psychosis. As such, they may inform the discussion about the putative causal role of cannabis use on the initial development of psychosis and schizophrenia. PP

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2.    Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systemic review. Lancet. 2007;370(9584):319-328.
3.    Murray RM, Morrison PD, Henquet C, Di Forti M. Cannabis, the mind and society: the hash realities. Nat Rev Neurosci. 2007;8(11):885-895.
4.    Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ. 2005;330(7481):11.
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6.    Pencer A, Addington J. Substance use and cognition in early psychosis. J Psychiatry Neurosci. 2003;28(1):48-54.
7.    Van Mastrigt S, Addington J, Addington D. Substance misuse at presentation to an early psychosis program. Soc Psychiatry Psychiatr Epidemiol. 2004;39(1):69-72.
8.    Sevy S, Robinson DG, Holloway S, et al. Correlates of substance misuse in patients with first-episode schizophrenia and schizoaffective disorder. Acta Psychiatr Scand. 2001;104(5):367-374.
9.    Phillips LJ, Curry C, Yung AR, Yuen HP, Adlard S, McGorry PD. Cannabis use is not associated with the development of psychosis in an ‘ultra’ high-risk group. Aust N Z J Psychiatry. 2002;36(6):800-806.
10.    Rosen JL, Miller TJ, D’Andrea JT, McGlashan TH, Woods SW. Comorbid diagnoses in patients meeting criteria for the schizophrenia prodrome. Schizophr Res. 2006;85(1-3):124-131.
11.    Haroun N, Dunn L, Haroun A, Cadenhead KS. Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research. Schizophr Bull. 2006;32(1):166-178.
12.    Corcoran CM, Kimhy D, Stanford A, et al. Temporal association of cannabis use with symptoms in individuals at clinical high risk for psychosis. Schizophr Res. 2008;106(2-3):286-293.
13.    Miller P, Lawrie SM, Hodges A, Clafferty R, Cosway R, Johnstone EC. Genetic liability, illicit drug use, life stress and psychotic symptoms: preliminary findings from the Edinburgh study of people at high risk for schizophrenia. Soc Psychiatry Psychiatr Epidemiol. 2001;36(7):338-342.
14.    Miller PM, Johnstone EC, Lawrie SM, Owens DGC. Substance use, psychiatric symptoms and the onset of schizophrenic illness. J Subst Use. 2006;11(2):101-113.
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16.    Kristensen K, Cadenhead KS. Cannabis abuse and risk for psychosis in a prodromal sample. Psychiatry Res. 2007;151(1-2):151-154.
17.    D’Souza DC, Perry E, MacDougall L, et al. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004;29(8):1558-1572.
18.    Koethe D, Gerth CW, Neatby MA, et al. Disturbances of visual information processing in early states of psychosis and experimental delta-9-tetrahydrocannabinol altered states of consciousness. Schizophr Res. 2006;88(1-3):142-150.
19.    Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005;57(10):1117-1127.
20.    Henquet C, Di Forti M, Morrison P, Kuepper R, Murray RM. Gene-environment interplay between cannabis and psychosis. Schizophr Bull. 2008;34(6):1111-1121.
21.    Van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull. 2008;34(6):1095-1105.
22.    Thomas H. A community survey of adverse effects of cannabis use. Drug Alcohol Depend. 1996;42(3):201-207.
23.    Degenhardt L, Hall W, Lynskey L. Exploring the association between cannabis use and depression. Addiction. 2003;98(11):1493-1504.
24.    Brewer WJ, Francey SM, Wood SJ, et al. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry. 2005;162(1):71-78.
25.    Lencz T, Smith CW, McLaughlin D, et al. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biol Psychiatry. 2006;59(9):863-871.
26.    Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Rockville, MD; 2006.
27.    Curran HV, Brignell C, Fletcher S, Middleton P, Henry J. Cognitive and subjective dose-response effects of acute oral Delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology. 2002;164(1):61-70.
28.    Delespaul P. Assessing Schizophrenia in Daily Life. Maastricht, The Netherlands: The International Institute for Psycho-Social and Socio-Ecological Research; 1995.
29.    Delespaul P, deVries M, van Os J. Determinants of occurrence and recovery from hallucinations in daily life. Soc Psychiatry Psychiatr Epidemiol. 2002;37(3):97-104.
30.    Myin-Germeys I, Nicolson NA, Delespaul PA. The context of delusional experiences in the daily life of patients with schizophrenia. Psychol Med. 2001;31(3):489-498.
31.    Myin-Germeys I, Delespaul P, van Os J. Behavioural sensitization to daily life stress in psychosis. Psychol Med. 2005;35(5):733-741.
32.    Kimhy D, Delespaul P, Corcoran C, Ahn H, Yale S, Malaspina D. Computerized experience sampling method (ESMc): assessing feasibility and validity among individuals with schizophrenia. J Psychiatr Res. 2006;40(3):221-230.
33.    Kimhy D, Corcoran CM. Use of palm computer as an adjunct to cognitive behavior therapy with an ultra high risk patient-a case report. Early Interv Psychiatry. 2008;2:234-241.
34.    Verdoux H, Gindre C, Sorbara F, Tournier M, Swendsen JD. Effects of cannabis and psychosis vulnerability in daily life: an experience sampling test study. Psychol Med. 2003;33(1):23-32.
35.    Tournier M, Sorbara F, Gindre C, Swendsen JD, Verdoux H. Cannabis use and anxiety in daily life: a naturalistic investigation in a non-clinical population. Psychiatry Res. 2003;118(1):1-8.
36.    Barrowclough C, Haddock G, Tarrier N, et al. Randomized controlled trial of motivational interviewing, cognitive behavior therapy, and family intervention for patients with comorbid schizophrenia and substance use disorders. Am J Psychiatry. 2001;158(10):1706-1713.
37.    Edwards J, Maude D, McGorry PD, Harrigan SM, Cocks JT. Prolonged recovery in first-episode psychosis. Br J Psychiatry Suppl. 1998;172(33):107-116.
38.    Addington J, Addington D. Impact of an early psychosis program on substance use. Psychiatr Rehabil J. 2001;25(1):60-67.
39.    Spencer C, Castle D, Michie PT. Motivations that maintain substance use among individuals with psychotic disorders. Schizophr Bull. 2002;28(2):233-247.
40.    Miller TJ, McGlashan TH, Rosen JL, et al. Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability. Schizophr Bull. 2003;29(4):703-715.

Return

 

Dr. Vadhan is assistant professor of clinical psychology and Dr. Haney is associate professor of clinical neurobiology at Columbia University College of Physicians and Surgeons at the New York State Psychiatric Institute in New York City. Dr. Serper is professor of psychology at Hofstra University in Hempstead, New York. 

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Acknowledgments: The authors thank Cheryl M. Corcoran, MD, for comments on an earlier version of this manuscript, and Elysia Michaels and Eliezer Pickholtz for assistance with the literature search.

Please direct all correspondence to: Nehal P. Vadhan, PhD, Assistant Professor of Clinical Psychology, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY 10032; Tel: 212-543-5489; Fax: 212-543-6018; E-mail: npv2101@columbia.edu.


 

Focus Points

• Working memory deficits are a hallmark feature of schizophrenia.
• Delta 9-tetrahydrocannabinol acutely impairs working memory in marijuana smokers.
• An association between early marijuana abuse and adulthood schizophrenia has been reported.
• To help clarify this relationship, the acute working memory effects of smoked marijuana should be examined in marijuana smokers who are already at heightened risk for schizophrenia.
 

Abstract

This article reviews the literature on the acute effects of Delta 9-tetrahydrocannabinol, the primary psychoactive component of marijuana, on working memory, and the implications for schizophrenia. Working memory deficits are a hallmark feature of schizophrenia, and have been implicated as an etiologic mechanism contributing to the onset of the disorder. Regular marijuana smokers may also exhibit subtle working memory impairment relative to healthy controls, and an association between marijuana abuse and subsequent development of schizophrenia, though controversial, has been reported in the literature. The causal role that marijuana plays in working memory impairment related to schizophrenia, however, remains unclear. Thus, this article specifically considers the acute effects of marijuana on working memory performance. The ecologic relevance and clinical significance of these findings will be examined, and directions for future research will be recommended.

Introduction

The purpose of this article is to examine the relationship between marijuana use, working memory, and schizophrenia. In young individuals at risk to develop schizophrenia, marijuana abuse has been reported to be associated with the onset of adulthood schizophrenia. Deficits in working memory are a hallmark feature of schizophrenia and have been implicated as an etiologic mechanism contributing to the onset of the disorder. Therefore, an examination of the effects of marijuana on working memory may shed light on the link between marijuana abuse and schizophrenia. In this article, working memory will first be defined, and theory and findings regarding working memory performance in schizophrenia patients and marijuana smokers will be briefly examined. Second, the association between marijuana smoking and schizophrenia will be considered. Third, selected acute effects of Delta 9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive component of marijuana, will be reviewed; findings from studies on working memory effects and findings from studies on other psychotomimetic effects will be examined. Finally, the relevance and implications of these effects on the development of schizophrenia as well as recommendations for future research will be discussed. Clinical issues related to prevention and treatment are discussed elsewhere in this issue of Primary Psychiatry.1

Working Memory

Working memory refers to the ability to mentally store and manipulate representations of stimuli over a short duration to execute a response.2 Working memory is distinguished from other forms of memory, such as immediate memory and delayed memory, both of which refer to the storage of information without manipulation. One prototypical working memory task is the Digits Backward condition of the Digit Span subtest. In its classic form,3 the participant is orally presented with increasingly long strings of digits (eg, 1–5–3–7) and is required to repeat them back to the examiner backwards (eg, 7–3–5–1). A more difficult variant of this task is the Letter-Number Sequencing task,3 which requires a reorganization of both numbers (in order) and letters (alphabetically). These tasks measure verbal working memory. Various digit recall tasks have been computerized and employ visually-presented digits, which retain the stimuli’s semantic but not auditory properties.

Another common working memory task is the spatial n-back task, during which the participant views an array on a computer screen that includes a fixation point and a dot set at one of a series of fixed points around the fixation point. The location of the dot changes on each trial, and the participant must decide if the position of the dot on the current trial (target stimulus) matches the position of the dot at a certain number of trials preceding the target (comparison stimulus). The number of trials preceding the target stimulus that the comparison stimulus resides at (n) can be altered, with a higher n-value indicating greater difficulty. This task measures visuospatial working memory.

These are two exemplars of primary working memory tasks since they both directly measure the storage and mental manipulation of stimuli representations. Many other tasks have been employed in neurocognitive studies that are primary measures of other cognitive functions, such as attention or executive functions, but require a significant contribution from working memory to perform them; these are considered secondary working memory tasks. These include the Wisconsin Card Sorting test,4 the Trailmaking test, the Tower of London task,5 and the Iowa Gambling task,6 which are described below.

Intact working memory—the ability to mentally hold and manipulate information—is necessary for the performance of many activities of daily life, including holding conversations, running errands, and performing academic and vocational tasks.2 Working memory is also highly correlated with measures of overall intelligence.7 As such, individuals whose working memory is impaired may appear distracted, impulsive, and forgetful, and may exhibit decreased academic, vocational, and interpersonal functioning. Thus, working memory is a clinically relevant cognitive function and may be impaired in individuals with a variety of neuropsychiatric conditions.

Working Memory and Schizophrenia

Individuals with schizophrenia have been found to exhibit impaired performance on tests of working memory in multiple modalities, including visuospatial,8,9 auditory verbal,10 and auditory nonverbal domains,11 relative to healthy control participants. Additionally, greater decrements in cognitive performance have been found in participants with schizophrenia, relative to control participants, as the response delay and size of the stimulus set increased.8,12 This suggests that the performance of schizophrenia patients is particularly susceptible to increased working memory requirements. Working memory performance has been found to be broadly correlated with performance on tests of other cognitive functions, such as delayed memory and motor functions, in participants with schizophrenia, but not in healthy control participants13; thus, working memory deficits have been hypothesized to play a central role in the other cognitive impairments commonly exhibited by schizophrenia patients. Visuospatial working memory impairments have been found to remain present even after psychotic symptoms have been stabilized,9 indicating that working memory deficits in schizophrenia are stable across phases of the disorder.

In terms of clinical relevance, primary and secondary working memory performance has been reported to be predictive of aspects of functional outcome in schizophrenia14,15 and symptom formation,16 respectively. Additionally, in young individuals at heightened risk for schizophrenia, working memory performance has been found to be impaired17,18 and to be a sensitive predictor of the development of schizophrenia-related psychosis in adulthood.18 In sum, deficits in working memory represent a core feature of schizophrenic illness19 and, therefore, have been proposed to be a clinically relevant area to target for remediation.20 

Working Memory and Marijuana Use

The relationship between marijuana use and working memory deficits in the nonpsychiatric population is complex. Reviews21,22 of working memory function in psychiatrically healthy individuals who smoke marijuana regularly concluded that such individuals exhibit performance impairment on primary and secondary working memory tasks relative to healthy controls, and such impairments have been found to be associated with the self-reported frequency of marijuana smoking.23,24 However, such deficits have been found less consistently than in participants with schizophrenia only. When present in non-schizophrenic marijuana users, the impairment is generally of a less severe degree21,22 and is less stable25 than is typically seen in participants with schizophrenia only. Thus, regular marijuana use in the natural ecology may be associated with modest and short-term deficits in working memory performance when participants are not acutely intoxicated.

Of note, young marijuana smokers were found to exhibit alterations in activation of the prefrontal and parietal cortices in response to working memory tasks during functional magnetic resonance imaging (under conditions of short-term marijuana abstinence) relative to non-using controls.26,27 This indicates functional alteration in brain regions relevant to the development of psychopathology in young marijuana smokers while they engaged their working memory.

Although these studies of the residual sequelae of marijuana smoking suggest that marijuana smoking contributes to working memory deficits, the cross-sectional and correlational nature of the studies reviewed thus far do not allow an assessment of marijuana’s direct effects on working memory.

Marijuana Use and Schizophrenia

Marijuana is the most prevalent illicit substance used by schizophrenia patients, with lifetime marijuana use estimated at 30%, and lifetime marijuana dependence (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition28) estimated at 28%.29 Marijuana is also the most commonly used illicit substance among youths identified as prodromal, or at heightened clinical risk, for psychosis.30,31 However, the link between marijuana smoking and the development of schizophrenia is highly controversial. An association between marijuana abuse and subsequent development of schizophrenia has been reported in epidemiologic and longitudinal observational studies,32,33 with several studies showing that the risk associated with marijuana smoking may be limited to young individuals predisposed towards schizophrenia.34,35 However, some studies have found no association between marijuana smoking and the onset of schizophrenia,36 and past and recent marijuana use may actually be associated with enhanced neurocognitive performance on secondary measures of working memory in nonintoxicated schizophrenia patients.37,38 As such, the interaction between marijuana use, working memory, and schizophrenia remains unclear.

Studies employing real-time experience-sampling methodology may help to clarify these associations.39,40 However, knowledge of the direct effects of Δ9-THC on the component processes of schizophrenia, such as working memory, may help to clarify the causal relationships between these variables. For example, if Δ9-THC were found to acutely decrease working memory performance, this would be consistent with a causal link between regular marijuana smoking and impairment of a cognitive function centrally related to schizophrenia. However, a finding that Δ9-THC had a negligible or beneficial impact on working memory performance would be inconsistent with such a role. Therefore, this article primarily reviews studies of the acute effects of smoked marijuana, conducted under controlled laboratory conditions, on working memory.

Acute Effects of Δ9-THC on Working Memory

Acute effects refer to those effects that occur while the participant is directly intoxicated from Δ9-THC administration (ie, within 4 hours of drug administration). Ranganathan and D’Souza41 conducted a comprehensive review of studies of the acute Δ9-THC effects on memory and concluded that Δ9-THC acutely impaired immediate, delayed, and working memory in psychiatrically healthy marijuana smokers. Given the hypothesized centrality of working memory to schizophrenia, this article focuses more narrowly on working memory, considering both primary and secondary measures. Additionally, since smoking is the method by which marijuana is typically used in the natural ecology, this article primarily focuses on studies of the effects of smoked marijuana. Given the overall similarity of time course effects between smoked marijuana and intravenous (IV) Δ9-THC on subjective ratings (eg, “I feel high”) and physiologic measures (eg, heart rate),42,43 studies that employed an IV route of administration were also considered. Since oral Δ9-THC does not share this similarity,44 studies that employed this route were not reviewed.

There are many factors to consider when examining the literature on acute effects of Δ9-THC on working memory performance. One variable that may moderate the acute effects of Δ9-THC is tolerance, with less frequent users thought to be more susceptible to cognitive effects than more frequent users.45 Thus, attempts were made to examine studies in daily and near-daily marijuana smokers separately from studies in relatively less frequent marijuana smokers, although this was difficult since marijuana use frequency was characterized differently across studies, and some studies employed participants with a wide range of use frequency. One similarity between these studies is that they were generally conducted in relatively young marijuana smokers (≤30 years of age), potentially a useful feature when considering the implications for the emergence of schizophrenia in youths.

In the studies reviewed, only the effects of single marijuana cigarettes or deliveries of Δ9-THC, with varying concentrations of Δ9-THC across sessions, were examined, unless otherwise noted. In such studies, it is considered ideal to employ at least two active Δ9-THC concentrations and a placebo, since this allows for the analysis of Δ9-THC concentration-dependent functions.42 However, not all studies relevant to working memory employed this methodology, so studies that compared at least one concentration of Δ9-THC to placebo were also reviewed. However, caution must be exercised in interpreting the results of these studies. All studies that were reviewed incorporated counterbalancing of Δ9-THC concentrations across sessions, unless otherwise noted, and provided independent verification of participants’ Δ9-THC intoxication via subjective-effect ratings and/or physiologic measures. All smoked marijuana studies employed some form of standardized marijuana smoking (eg, paced puffing).46 The Figure47 shows typical acute subjective and cardiovascular effects of single active marijuana cigarettes (closed symbols) relative to placebo marijuana cigarettes (open circles), produced under these controlled laboratory conditions. Based on this figure, it can be seen that subjective and cardiovascular effects peak within 7–10 minutes after marijuana smoking, and are Δ9-THC concentration dependent (eg, 3.9%>1.8%>placebo). 

 

 

While most of these studies employed task batteries that measured a wide range of cognitive functions, this article focuses on the working memory performance data from those studies. Regarding measurement of working memory, there are several caveats to this review. First, since all of the studies that were reviewed employed working memory tasks that were visuomotor in nature (including digit recall tasks), this review cannot speak to Δ9-THC effects on auditory working memory. Second, the amount of training on the working memory tasks prior to the experimental sessions, which may influence the baseline level of performance during the sessions, differed across studies. Third, since the motivation for participants to perform cognitive tasks effortfully while intoxicated from Δ9-THC is unclear,48 some investigators provided monetary payment that was performance-contingent (noted below), while others did not. These studies are summarized in the Table and reviewed below.43,47,49-58

 

Visuospatial Working Memory

Ilan and colleagues49 investigated the effects of smoked marijuana on working memory performance in infrequent marijuana smokers (1–4 times/month). In this study, the effects of active marijuana (3.5% Δ9-THC) on spatial n-back task performance (n=2 trials) were compared to placebo marijuana in 10 college-aged individuals. Relative to baseline performance, active marijuana significantly reduced the accuracy and increased the response time on this task, compared to placebo. For example, participants performed within a 96% to 97% accuracy range at baseline, but performed at ~94% accuracy 20 minutes after active marijuana, relative to 97% accuracy 20 minutes after placebo marijuana. After 1 more hour, performance under the active marijuana condition began to trend back towards baseline performance. This pattern of results was replicated when two Δ9-THC concentrations (1.8 and 3.6%) were tested in more frequent marijuana smokers (15–17 marijuana cigarettes/month).50 Therefore, these two studies indicated that smoking a single marijuana cigarette, relative to placebo, acutely impaired spatial n-back performance to a mild degree in non-daily marijuana smokers. 

D’Souza and colleagues43 examined cognitive performance after administration of IV Δ9-THC (2.5 or 5.0 mg Δ9-THC) in participants with varied reported lifetime exposures to marijuana (<5 uses [n=7], 11–100 uses [n=9], >100 times [n=6]); current use frequency was not reported. Working memory was assessed using a computerized delayed matching-to-sample task, during which a series of geometric shapes were presented consecutively, and participants were required to indicate when a repeated shape was shown. Performance on this task was assessed before and after Δ9-THC administration. The results indicated that active Δ9-THC decreased accuracy on this task, with a trend towards increased response time. Consistent with these results, it has also been found that smoked marijuana decreased performance accuracy and increased response time on a simpler delayed matching-to-sample task in infrequent marijuana smokers (2–10 days/month), despite performance accuracy being reinforced with monetary earnings.51

Thus, it appears that single administrations of marijuana or Δ9-THC acutely impaired visuospatial working memory performance in relatively infrequent marijuana smokers. Further, since this impairment occurred whether or not participants were being reinforced for accuracy with monetary payment, performance motivation did not appear to play a role.

Verbal Working Memory

Marijuana-related effects on verbally based working memory have also been studied. The effects of single marijuana cigarettes were tested in marijuana smokers (n=10) who reported infrequent weekly use of marijuana (0.5–3.0 times/week).52 Working memory was primarily measured by a digit recall task, during which participants were first presented with a string of nine digits, and then a string of eight of the same digits in a random order after a delay. Participants were asked to identify the missing digit, thus requiring encoding and storage of the initial string, a mental reorganization of the new digit string, and a comparison of the two strings. Performance was reinforced with money earnings. The results indicated that, relative to placebo, marijuana (1.8 or 3.6% Δ9-THC) had no effect on accuracy or response time on digit recall, or on serial addition/subtraction, a task that requires a significant contribution from working memory. Consistent with these results, another study53 found that single marijuana cigarettes (3.6% Δ9-THC) had no impact on the accuracy of backwards digit recall in a comparable group of 14 marijuana users. However, in a smaller study54 of similar marijuana smokers (n=3), smoking two consecutive marijuana cigarettes (2.6% Δ9-THC) did impair accuracy of digit recall and accuracy and response time on serial addition/subtraction, despite task performance being reinforced with monetary earnings.

These studies suggest that smoking a single marijuana cigarette had no impact on accuracy or speed of verbal working memory when measured by digit storage/manipulation and mental arithmetic, regardless of the incentive to perform, whereas smoking two marijuana cigarettes did have a negative effect. Also, one of the studies with negative results52 employed forced-randomization for session order (ie, the lower-strength marijuana always preceded the higher-strength marijuana), which may have produced some state-dependent practice effects under the higher strength marijuana.

Secondary Working Memory Measures

In addition to the studies that have directly assessed working memory in infrequent smokers, investigators have employed executive function tasks that are secondary measures of working memory.59-61 The computerized version of the Tower of London task62 displays both starting and ending arrangements of colored balls on sticks, and requires participants to judge the fewest movements of the balls it would take to arrive at the end arrangement without violation of certain rules. The Iowa Gambling task requires participants to repeatedly select cards from four decks, each associated with a different pattern of winnings and losses in hypothetical money, which must be learned and kept in mind while choosing cards. In terms of overall winnings and losses, two of the decks are considered disadvantageous (“risky”), and two of the decks are considered advantageous.

Performance on these tasks during intoxication from single Δ9-THC-infused nicotine cigarettes (250 or 500 mg/kg cigarettes with 13.0% Δ9-THC) was examined in 20 participants who reported ~3.4 marijuana uses/month.55 The results indicated that the number of correct choices on the Tower task was decreased and response time was increased to a mild degree following active marijuana relative to placebo. Marijuana did not alter card selection on the Gambling task. However, single marijuana cigarettes (3.6% Δ9-THC) increased “risky” selections for real money on a different decision-making task, relative to placebo, in participants with comparable marijuana use.56 In sum, it appears that single marijuana cigarettes generally impaired performance on secondary measures of working memory in relatively infrequent marijuana smokers.

Generally, the studies reviewed above indicate that single administrations of smoked marijuana and IV Δ9-THC acutely impaired visually-based working memory function in marijuana smokers whose reported use frequency ranged from a handful of lifetime exposures to multiple times per month or week, but not near-daily or greater. Performance accuracy or strategy as well as response time (when measured) were affected, and these effects did not seem to be due to decreased performance motivation. However, impairments were temporary and generally of a mild degree. Accuracy and speed of verbal working memory were not affected by single marijuana cigarettes but were impaired by two cigarettes, suggesting that verbal working memory was more resistant than visuospatial working memory to marijuana-related impairments. Though not reviewed, other functions such as immediate memory and attention were also acutely impaired by Δ9-THC in these studies. Although this indicated that Δ9-THC did not selectively impact working memory, it should be noted that deficits in these other cognitive domains have been widely observed in schizophrenia patients.63

Relatively fewer studies have been conducted to examine Δ9-THC’s effects on working memory in more experienced marijuana smokers, such as those who smoke on a daily or near-daily basis. Hart and colleagues47 investigated the effects of single marijuana cigarettes (1.8 or 3.9% Δ9-THC) on a broad range of cognitive functions in 18 participants who reported smoking marijuana 6 days/week. In this study, working memory was assessed with a computerized backwards Digit Span test from the MicroCog test battery.64 The results showed that while participants required greater amounts of time to complete the task after active marijuana, relative to placebo, accuracy was not altered. The same pattern of effects was seen on a test of mental arithmetic. Thus, consistent with studies in less experienced marijuana smokers, marijuana slowed performance on tests of working memory; however, in contrast, it did not disrupt accuracy in frequent smokers.

This was the only study found that directly measured working memory performance under conditions of marijuana intoxication in near-daily marijuana smokers. However, similar to studies in less-frequent smokers, investigators have also examined performance on secondary measures of working memory. Employing a comparable group of participants (n=36) and similar marijuana administration procedures as the study by Hart and colleagues,47 another study57 found that smoked marijuana had no effect on Gambling task performance for real money in terms of card selection or money earned, but did increase the time required to complete the Gambling task, relative to placebo. Δ9-THC-infused nicotine cigarettes (13 and 17 mg Δ9-THC) were also found to have no effect on Gambling task card selection for hypothetical earnings, nor on performance speed, in daily marijuana smokers (n=14).58 However, in this study, Δ9-THC increased errors on the Wisconsin Card Sorting Task, which requires participants to sort cards according to implicit rules that covertly shift, relative to placebo. In sum, data from studies in relatively frequent marijuana smokers indicate that accuracy or strategy on primary and secondary tests of working memory was not disrupted during Δ9-THC intoxication, except on a measure of categorization and cognitive flexibility. Most studies did indicate a slowing effect of Δ9-THC on working memory tasks in this population.

The studies reviewed here varied considerably in participant characteristics, route of drug administration, and the tasks used to measure working memory. Nevertheless, this review indicated, although not unequivocally, that Δ9-THC acutely impaired accuracy and response time on tests of working memory function in occasional marijuana smokers. Acute marijuana-related impairment was generally limited to response time in relatively more frequent smokers. None of the studies revealed any beneficial impact of marijuana smoking on working memory. Although there is some controversy over the potency of the marijuana administered in the smoked marijuana studies, as compared to the marijuana smoked in naturalistic settings,65 several lines of evidence are inconsistent with this concern.45 For example, the marijuana cigarettes employed in these studies produced robust Δ9-THC concentration-dependent changes in mood and cardiovascular measures, and the upper levels of Δ9-THC were within the range of Δ9-THC found in American street marijuana.66 Therefore, the marijuana employed in these studies appears to be relevant and meaningful. In conclusion, if one considers both accuracy and response time as meaningful components of working memory function, it appears that Δ9-THC acutely decreases working memory function in marijuana smokers. As such, this review is consistent with the conclusions of Ranganathan and D’Souza.41

Acute Δ9-THC Effects and Schizophrenia

The conclusion that Δ9-THC acutely impairs working memory in psychiatrically healthy participants may suggest that marijuana smoking is a mechanism by which individuals already vulnerable to schizophrenia may further impair this critical function, albeit acutely. However, the working memory deficits acutely induced by Δ9-THC in psychiatrically healthy marijuana smokers appear to be fairly mild49 relative to those reported in nonintoxicated schizophrenia patients.67 Additionally, schizophrenia is a disorder with multiple classes of symptoms, some of which appear to be related to working memory deficits,19,68,69 but some of which may not be.13,70,71 In other words, the presence of co-occurring working memory impairment, while suggestive, does not necessarily indicate an etiologic relationship. Therefore, the relevance of marijuana-related effects on working memory to the development of schizophrenia may become clearer still when studied in concert with other aspects of psychosis.72

Accordingly, studies have been conducted specifically to investigate the effects of Δ9-THC on cognitive functions simultaneously with other psychotomimetic experiences, such as positive and negative psychiatric symptoms and perceptual disturbances.41,73 For example, in addition to the working memory effects in psychiatrically healthy individuals described above, IV Δ9-THC also acutely increased global clinician ratings of positive and negative symptoms and perceptual alterations, as well as participant-rated anxiety, and decreased performance on other neurocognitive measures.43 These findings suggest that Δ9-THC acutely produces numerous effects qualitatively similar to psychiatric symptoms of schizophrenia, in addition to working memory deficits.

Expanding the clinical relevance of this work, IV Δ9-THC was administered to participants diagnosed with schizophrenia who reported a minimum of one lifetime exposure to marijuana.74 The results of this study essentially replicated the findings of these investigators’ earlier study43: Δ9-THC acutely increased global ratings of positive, negative, and general symptoms; perceptual disturbances; and global ratings of extrapyramidal symptoms in schizophrenia patients, although the magnitude of these increases did not differ from those seen in the healthy participants from D’Souza and colleagues.43 Working memory was not directly assessed in the schizophrenia patients, but verbal list-learning was found to be disrupted to a greater extent by Δ9-THC in the schizophrenia patients than in the controls. Additionally, Δ9-THC did not increase subjective ratings of euphoria in the schizophrenia patients, as it had in the healthy participants. Thus, Δ9-THC did not have a unique impact on participants with fully developed schizophrenia, except for verbal learning and possibly euphoria.

A different study75 examined the role of genetic factors in Δ9-THC’s acute effects. Δ9-THC-infused nicotine cigarettes were administered to psychotic participants, first-degree relatives of psychotic patients, and healthy controls, and psychiatric and cognitive measures were taken. Results indicated that acute effects in these areas were genetically moderated by the same functional polymorphism in the catechol-O-methyltransferase gene that was found in an epidemiologic study35 to have moderated the relationship between reported early onset marijuana smoking and subsequent emergence of adult psychosis. This suggests a common mechanism for both the acute and long-term psychosis-related responses to marijuana, highlighting the value of studying the acute psychotomimetic effects of marijuana in the laboratory with respect to the broader question of the development of schizophrenia.

Both of these studies represent significant progress in terms of expanding the clinical relevance of Δ9-THC administration studies. However, interpretations of the data are constrained by several methodologic limitations. While D’Souza and colleagues’43 study compared two doses of Δ9-THC to placebo, as is ideal, the investigators administered Δ9-THC intravenously, which may be limited in terms of its ecologic relevance. Specifically, it does not allow participants the opportunity to titrate their intake of Δ9-THC to produce desired effects, as smoked marijuana does.76 This may help explain why this study consistently found increases in psychotic symptoms and aversive feeling states in both the psychiatric and nonpsychiatric groups, but did not find similarly consistent increases in euphoria. In other words, this methodology may have concealed any acutely positive or beneficial effects of marijuana in the schizophrenia patients, such as has been shown for nicotine and working memory.77 Another concern was the use of clinician-rated measures of symptomatology to measure acute drug effects, which have unknown sensitivity and reliability for this purpose. The study by Henquet and colleagues75 employed a more ecologically relevant route of drug administration, but only compared one Δ9-THC dose to placebo. Further, the participants in both of these studies appeared to have a wide range of previous experience with marijuana, and neither study examined working memory directly.

Acute Δ9-THC effects in individuals at risk for schizophrenia?
Since the clinical impact of Δ9-THC is of the most concern in relatively young individuals who smoke marijuana regularly and are at risk for schizophrenia, acute studies of Δ9-THC in individuals already diagnosed with schizophrenia may have limited relevance to the broader question of marijuana’s relationship to the development of schizophrenia. Testing smoked marijuana’s acute effects in marijuana smokers who are at risk to develop schizophrenia would address this concern. Given that first-degree relatives of schizophrenia patients share some latent liability for schizophrenia, they constitute one potential group for examination.75 However, the group with perhaps the most clinical relevance would be those identified as prodromal for schizophrenia, eg, those individuals who experience subthreshold psychotic symptoms such as suspiciousness, overvalued ideation, and illusions.78 Marijuana use disorders have been found to be one of the most common comorbid psychiatric diagnoses in these individuals,30,31 and naturalistic studies31,79 have demonstrated an association between marijuana smoking and psychotic-like experiences in psychosis-prone participants. Yet, no controlled laboratory studies have been conducted to date to test the acute effects of smoked marijuana on working memory and other psychotomimetic experiences in a group of psychosis-prone marijuana smokers, an empirically, clinically, and ecologically meaningful endeavor.

Conclusion

This article argues for the centrality of working memory function in schizophrenia, examines the association between marijuana smoking and schizophrenia, and reviews studies of the acute effects of Δ9-THC on working memory in psychiatrically healthy participants. The authors generally found that in psychiatrically healthy marijuana smokers, Δ9-THC acutely decreased working memory performance, including speed and/or accuracy, regardless of route of Δ9-THC administration (smoked or IV), with more prominent effects on visuospatial working memory. Thus, Δ9-THC acutely impairs a critical cognitive function that is associated with the development of schizophrenia. The authors have also reviewed studies that specifically targeted the psychiatric features of schizophrenia, which suggested that Δ9-THC may acutely produce or exacerbate these features in healthy participants and schizophrenia patients, respectively, although these studies were constrained by methodologic limitations. Lastly, the authors proposed future directions that may improve the ecologic and clinical relevance of such research. PP

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Return

 

Dr. Downey is assistant professor at the School of Policy Studies at Roosevelt University; Dr. Zun is chairman and professor of Emergency Medicine in the Department of Emergency Medicine at Finch University/Chicago Medical School and chairman of the Department of Emergency Medicine at Mount Sinai Hospital; and Ms. Gonzales is researcher at Mount Sinai Hospital, all in Chicago, Illinois.

Disclosure: Dr. Downey and Ms. Gonzales report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Zun is a consultant to Alexa and sanofi-aventis and is on the the speaker’s bureaus of Eli Lilly and sanofi-aventis.

Please direct all correspondence to: La Vonne A. Downey, PhD, Assistant Professor, Roosevelt University, School of Policy Studies, Chicago, IL, 430 Michigan Ave, Chicago, IL 60605;
Tel/Fax: 847-360-1003; E-mail: LDowney@roosevelt.edu.


 

Abstract

Objective: The primary objective of this study was to determine what types of psychiatric patients utilize the emergency departments (EDs) for their psychiatric care. The secondary purpose was to identify reasons for the change in utilization.
Methods: A convenience study was conducted in an urban, Level I pediatric and adult trauma center with 45,000 annual visits. A portion of the National Health Access survey was administered to all consenting psychiatric patients who presented to the ED between May 2006 to February 2007 with a psychiatric issue as their chief complaint. The survey asked questions regarding healthcare resources used within the last year and the last 2 years, changes in psychological illness, sources of payments for services, reasons for changes in utilization of health care, and satisfaction with healthcare resources and who delivers the health care. The study was institutional review board approved.
Results: Of the 310 patients approached, 294 agreed to answer the survey. There was a difference in the types of psychiatric patients that utilize the ED for psychiatric care. The significant difference between patients was found within the following variables: those with a regular physician and regular health source (F=6.531, <.01), those with a regular health source whom the patient has visited for the most recent care (F=17.99, <.01), patients who were delayed in receiving psychiatric drugs (F=11.240, <.01), those who used the ED in the last 12 months (F=6.75, <.01), number of times of psychiatric evaluation in the ED in last 2 years (F=7.44, <.01), and number of hospitalizations (F=6.40, <.01).
Discussion: There are two different types of psychiatric patients who use the ED. Those with a regular PCP use the ED primarily for psychiatric reasons versus those without  a PCP who use the ED for a variety of health and psychiatric complaints.
Conclusion: There appears to be two different types of psychiatric patients using the ED for care. One group has a regular source of care for physical and psychiatric care from a PCP. These patients, however, have used the ED more in the last 12 months, present to the ED with a higher level of prior hospitalization, and had the a higher number of psychiatric evaluations in the ED within the last 2 years. Their referral to the ED was made by a primary care physician (PCP) or social worker. The other group is less likely to have a PCP and is referred to the ED primarily by self, family, or police. They have fewer prior psychological-based hospitalizations, have used the ED less in the last 12 months, and had fewer psychiatric evaluations in the ED within the last 2 years.

Introduction

The purpose of this study was to determine what type of psychiatric patient is using the emergency department (ED) for their care. Approximately 4.3 million psychiatric-related ED visits occurred in the United States in 2000, resulting in a rate of 21 visits per 100 adults.1,2 The number of psychiatric-related ED visits has increased 15% between 1992–2000.2 This increase was most commonly seen in disorders that used to be relatively scarce in the ED, such as mood and anxiety disorders.1,2 That finding may indicate that the clinical profiles of psychiatric patients entering an ED may be under a progressive change. The ED seems to have become the central entry point for a wider range of patients.3-5

Previous research identified patients who repeatedly visit the ED as people who have high unemployment rates and lower social profiles; are younger; depend on some type of public assistance; reside alone; or are more likely to be homeless, self referred, and have substance abuse as at least a portion of the secondary diagnosis if not the primary one.6-8 Many repeat visitors exhibit a less structured symptom profile than most patients, leading them to seek help in an easily accessible health service with low demands such as an ED. An important aspect of the emergency room situation is its impersonal and transient nature, but, paradoxically, the loosely structured care environment is favored by these patients who are undecided about their commitment to treatment.7-11

The cost of treating these patients is extremely high, thus putting additional strain on the ED’s already constrained resources. According to the national average, 74% of visits are compensated and 26% are uncompensated. Rotarius and colleagues12 found that this resulted in Boston hospitals providing $400 million in uncompensated care. The increases have been attributed to numerous factors.

Summers and colleagues13 stated that one of the contributing factors to the overuse of hospital EDs is the level of satisfaction patients have with the quality of care they have received in the ED. Many findings show that patients who received care in an ED reported being satisfied with the care they received. However, as one study7 of psychiatric patients satisfaction with ED care illustrates, “The majority of patients appeared to have been satisfied with the psychiatric service provided. Ninety-four percent felt they received information, 93% felt that the staff listened to their problems and 97% felt the staff were professional in their manner.” Patients considered the following characteristics of the staff as being helpful: being easy to talk to, providing reassurance, providing direction, projecting a calm manner, and providing information and explanations as required.7,9 Those researchers, however, believe that this phenomenon is multi-dimensional and that very little is known about the other reasons people with mental illness are choosing the ED.

This leads to the hypothesis that there may be distinct types of psychiatric patients that use the ED for their care. In order to address this gap in our understanding, more research is necessary to understand the impact of patient characteristics such as type of insurance, race, access to health care, understanding of diagnosis, and ability to tolerate treatment regimens when choosing the ED for care.12,14,15 The knowledge of this will allow hospitals that house these overburdened EDs a better understanding of the role they play in delivery of health care to the mentally ill.

Methods

A convenience study was conducted in an urban, Level I pediatric and adult trauma center with 45,000 annual visits. A portion of the National Health Access survey (2006 version) was administered by research fellows in the treatment area to all consenting psychiatric patients who presented to the ED from May 2006–February 2007 with a psychiatric-related chief complaint. The survey asked questions regarding healthcare resources used within the last year and last 2 years, changes in psychological illness, sources of payments for services, reasons for changes in utilization of health care, and satisfaction with healthcare resources and who delivers the healthcare. Information regarding psychiatric diagnosis and medications given or currently prescribed were taken from the charts after the patient was seen by a clinician. Patients were excluded from the study if they presented with a non-psychiatric chief complaint, were not medically stable, and were either physically or chemically restrained. The study was institutional review board approved.

Results

A total of 310 subjects were approached and 291 subjects were enrolled in the study. The sample consisted of 133 males, 152 females, and the count of 6 missing genders. The educational levels varied from 31% who completed ninth to twelfth grade, 21% who graduated high school, and 23% who experienced some college. The top four diagnoses were 25% depression, 20% personality disorders, 15% bipolar disorder, and 13% schizophrenia. The majority (58%) took antidepressants and 10% reported taking no medication.

Fifty-five percent of the patients had a regular medical doctor and 42% did not (the remaining 3% did not respond to that question when asked). Insurance was cited as the reason for the change in ED use over the last year by 36% versus the 50% who stated the change in ED use was due to better access.

The source of payment for their medical care was varied. However, it was overwhelmingly government funded. The majority, at 40% within the study, had Medicaid and 15% had Medicare; 10% used both as their source of payment for medical services. The other sources of payment were out of pocket at 16% and no source of payment public or private at 16%; 3% did not answer the question. Tables 1 and 2 show the responses.

 

An analysis of variance test with significance at ≤.05 was used in order to determine if there was a difference between types of patients that used the ED for their psychiatric care versus those who used it for psychiatric and general healthcare. The significant difference between patients was found within the following variables: those with a regular physician and regular health source (F=6.531, <.01), those with a regular health source whom the patient has visited for the most recent care (F=17.99, <.01), patients who were delayed in receiving psychiatric drugs (F= 11.240, <.01), those who used the ED in the last 12 months (F=6.75, <.01), number of times of psychiatric evaluation in the ED in last 2 years (F= 7.44, <.01), and number of hospitalizations (F= 6.40, <.01).

There were no significant differences between the two groups based on race, gender, education, age, or types of psychiatric illness.

Within this study, there were two distinct types of psychiatric patients that use the ED for their care. One group, who made up 45% of those in the study, used the ED for the majority of their healthcare needs within the last 12 months. Twenty-five percent of them used the ED exclusively for care of physical and psychiatric health problems; they do not have a regular primary care physician (PCP). Those that used the ED rated the care that they received as good to excellent. The majority have not had a psychiatric hospitalization within the last 2 years.

The second group, who made up 55% of the study, consisted of individuals who used their physician for the majority of their psychiatric and physical health problems. When they did go to the ED for mental health concerns it was because their doctor or social worker recommended it. This group had a higher level of hospitalizations within the last 2 years (Table 3). They were also less likely to delay purchasing drugs due to cost. The types of healthcare professionals they saw most recently were different. Over 33% of those with a PCP had most recently been seen in their doctor’s office versus only 9% of those without a PCP. Those with mental health issues that have a regular PCP seem to be those with a higher need for hospitalizations related to their illness. The PCP and or social worker they used for their psychiatric services were the individuals who recommended and referred these patients to use the ED for services.

 

 

Discussion

It is difficult to assess why there is an increase in the numbers of psychiatric patients using the ED for their psychiatric complaints. Although these patients were very satisfied with their ED care, the study does illustrate some concerning findings. Thirty-three percent of the patients were delayed in obtaining psychiatric care and many of these patients used the ED frequently. They saw the ED as a more accessible place to receive care.

Those patients with a PCP appeared to use the ED only for psychiatric reasons. However, those who did use the ED appeared from the data to have mental illness with higher levels of previous hospitalizations due to their illness and more psychiatric evaluations in the ED within the last 2 years.

It is uncertain why there is a breakout of patients with a PCP that implies a worse clinical condition. There is a subset of these patients that get admitted frequently to psychiatric facilities. It brings up the question of whether patients with a PCP have a worse clinical condition or whether the care provided by the PCP has a limitation to how much it can address and treat the clinical conditions (and therefore the PCP refers the patient to the ED). Further study needs to be conducted to explain why this relationship occurs.

There are certain limitations to this research. First, it only examines an inner city ED. A stronger and differing pattern in usage might be seen if a suburban ED was used as a comparison group. The sample size overall was large enough to make comparisons between the two groups in some but not all cases. A much larger sample would allow for a more robust and reliable analysis of inter- and intra-group differences and similarities.

Second, the use of the National Health Access survey meant that the time it took to answer all the questions was long. At least 80% of those that refused did so due to the length of time it took to answer the survey. With the exception of using medical charts to confirm diagnosis and medication regimes, there is often no other way to confirm patients truthfulness to the questions. The tool also did not adequately assess all potential reasons that have influenced the increased ED utilization for psychiatric complaints.

Conclusion

There appears to be a range of clinical profiles among the patients using the ED for care.4 In this study, there were two different types of psychiatric patients using the ED for care. The patients that use the ED frequently are using it as an access point to in-patient psychiatric treatment. They have been referred by another healthcare professional and are getting psychiatric evaluations.

This makes for a diverse mixture of psychological patients who come into the ED doors. It is also what has been seen on a national level with not just an overall increase in the number of patients but also in the range of services needed once they are being treated in the ED.5 Summers and colleagues13 found those using the ED also rated the services they received as good to excellent. Although not directly examined in this study, this could be one of the reasons for their continued use of the ED for services, especially for those patients without a regular PCP, psychologist, and/or social worker. The less frequent users of the ED in this study do directly fit those seen in other studies in that they were not committed to a treatment plan and/or provider in part due to presenting with a less structured or dual diagnosis.10

This study did help identify factors that contribute to increased utilization of the ED by those with psychiatric complaints. Those factors are varied and include not just costs and form of payment for treatment but perceived intensity of illness, use of a PCP and/or other psychiatric healthcare provider, lack of available community services, and the high level of satisfaction with the care they receive in the ED. This mixture of factors will need to be studied further in the future to more fully explain the implication of these results and the real impact they are having in contributing to ED overcrowding. For solutions to be devised and significant impacts on the system to be made, all components feeding the problem must be investigated. With that knowledge, we can understand and investigate which viable solutions can be devised and implemented. PP

References

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