Column

Print Friendly 

Weight Issues in Schizophrenia

Anita H. Clayton, MD

Return

Primary Psychiatry. 2006;13(3):22-24

 

Dr. Clayton is professor of psychiatric medicine at the University of Virginia in Charlottesville.

 

Disclosure: Dr. Clayton is a consultant to and on the advisory boards of Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pfizer, Vela, and Wyeth; is on the speaker’s bureaus of and receives honorarium from Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and receives grants and/or research support from Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Neuronetics, Pfizer, and Wyeth.


 

 

Disease-Related Concerns

 

Weight gain in adulthood appears to have significant negative effects on physical health. Among women, weight gain, regardless of baseline weight, is associated with decreased physical function, diminished vitality, and increased body pain.1 In a large naturalistic study,2 nearly 40% of women 45–72 years of age gained >5 lbs in 4 years, with the leanest women who gained >20 lbs having twice the likelihood of developing role limitations due to physical problems. No difference was seen between older and younger women. In addition, adults who gain >10 lbs are at increased risk for medical illnesses and premature death.2 Adults in this group have nearly twice the risk of type II diabetes mellitus and ischemic stroke and 1.25 times the risk of coronary heart disease, compared to adults who lose or maintain a stable weight. Breast cancer risk also appears to be increased with weight gain. Impairments in physical functioning, reduced quality of life, and poor mental health are also associated with weight gain and are an additional burden for patients with schizophrenia.

 

Among individuals with schizophrenia, effects of both the disease and its treatment may contribute to weight gain, metabolic syndrome, and subsequent other impairments and functional limitations. This may be particularly true for women, as women with schizophrenia (from the National Health Interview Survey) had a significantly higher mean body mass index (BMI) than women without schizophrenia (from the National Health and Nutrition Examination Survey III [NHANES III]), 27.36 versus 24.50, respectively (P<.001).3

 

Treatment-Related Issues

 

Very few studies have examined gender differences in weight and metabolic effects in patients with schizophrenia. In addition, separating out the effects of the illness from the effects of the antipsychotic agents has been difficult. It is clear that both men and women with severe and persistent mental illness (Maryland Medicaid recipients with severe and persistent mental illness) had a higher prevalence of obesity than individuals in the general population (NHANES III and Maryland Behavioral Risk Factor Surveillance System), but only men demonstrated a 4-fold greater association between atypical antipsychotics and prevalent obesity.4 However, in a study examining several antipsychotics in patients with schizophrenia, clinically significant weight gain (>7% of baseline body weight) was experienced by 46% of patients receiving olanzapine, 31% of patients receiving risperidone, and 22% of patients receiving haloperidol.5 No subjects treated with quetiapine gained >7% of their baseline body weight. The risk of weight gain was higher in women (odds ratio [OR] 4.4), overweight patients (OR 3.0), and in women receiving risperidone (OR 2.6). Perhaps women with schizophrenia have a greater risk of obesity related to their disease, whereas men may have that risk further increased by treatment with atypical antipsychotics not associated with elevations in prolactin levels.

 

To sort out the effect of disease versus treatment, 15 men and 4 women with drug-naïve, first-episode schizophrenia were evaluated for obesity/fat distribution parameters and 24-hour plasma cortisol levels, and compared to age- and sex-matched controls.6 Patients were treated with olanzapine or risperidone for 6 months, followed by reassessment of the adiposity parameters. At baseline, the patients with schizophrenia had significantly more intra-abdominal fat as measured by computerized tomography and anthropometry, which did not change with treatment. Higher baseline cortisol levels significantly decreased with antipsychotic treatment. No differences were demonstrated between the two antipsychotics. In an open-label study involving the use of olanzapine in six men and three women experiencing their first psychotic episode, a median increase in body weight of 4.7 kg was seen within 12 weeks, a significant increase of >7% from first assessment (within 7 weeks of diagnosis).7 Body fat also increased significantly, primarily as central fat deposits. Fasting insulin, C-peptide, and triglyceride levels significantly increased within 3 months of treatment initiation, but glucose levels did not. Neither did cholesterol or leptin levels. This may suggest insulin resistance, with a decrease in fat oxidation as a secondary or predisposing mechanism for weight gain with antipsychotics, explaining how weight gain and metabolic effects may occur together or independently in patients receiving antipsychotics. Similar outcomes were seen with clozapine in one study (11 women and 8 men),8 with early increases in circulating leptin levels inversely correlated with weight gain over the following 6–8 months (13 men and 9 women) in another trial.9

 

Long-term studies are important, as most patients with schizophrenia require life-long therapy. In one naturalistic 5-year study, patients with schizophrenia were at increased risk of weight gain through month 46 from initiation of clozapine, and of developing diabetes mellitus (36.6%). Weight gain was not a significant risk factor for the onset of diabetes, so these factors appear independent, but co-occurring.10 In addition, calculations reveal that the lives saved from suicide through treatment with clozapine are essentially offset by the additional deaths associated with a 10 kg weight gain.11

 

The Clinical Antipsychotic Trials of Intervention Effectiveness data support these concerns with some of the atypical antipsychotics, as 30% of patients receiving olanzapine gained >7% of their baseline body weight versus 7% to 16% with other antipsychotics.12 Average weight gain with olanzapine was 2 lbs/month. Comparable problems were seen with blood glucose, cholesterol, triglycerides, and hemoglobin A1c. Discontinuation secondary to weight gain and metabolic side effects over the 18 months of the trial was 9% with olanzapine versus 1% to 4% with the other drugs. Other differences among agents included improvement in metabolic effects with ziprasidone and an increase in prolactin levels with risperidone. However, only 25% of the subjects in the trial were women.

 

Women may have a different propensity for weight gain with antipsychotics than men because premenopausal women with schizophrenia require lower medication doses for effective treatment and because women have less of a predisposition for visceral fat storage. However, since 1987, the mean BMI for women with schizophrenia 18–30 years of age has increased dramatically and significantly when compared to women in the general population.13 One factor may be a combination of medications, which can further contribute to weight gain. Women are more likely to have an associated mood disorder requiring additional medication intervention, which may result in subsequent weight gain. However, in an 8-week trial of patients with borderline personality disorder, the combination of fluoxetine with olanzapine was associated with less weight gain than olanzapine alone.14 Women also appear more likely to suffer with hyperprolactinemia secondary to antipsychotics than men, and as a result may experience abnormal menstrual cycles and weight gain. However, iatrogenic weight gain (mean weight increase of 27%) does not explain the emergence of irregular menses (23%) among premenopausal women with psychotic illness taking clozapine.15 Other factors contributing to weight gain may include diet, smoking, exercise, substance use, and hormonal transitions.16

 

Management Options

 

Use of the lowest possible dose of antipsychotic medication may reduce the likelihood of weight gain, as insulin levels have been positively correlated to serum concentration of clozapine.17 Premenopausal women generally require lower doses than men or postmenopausal women. Minimizing additional concomitant medications will also reduce potential weight gain. When other medications are required, utilizing those not associated with weight gain is recommended. Such medications may include lamotrigine, bupropion, and topiramate. Education about interventions such as nutrition, exercise, and living a healthy lifestyle may limit weight gain, as a 6-month study demonstrated a mean weight change in the intervention group of -0.06 lbs versus +9.57 lbs in the standard care group.18 Good general health maintenance may also mitigate against weight gain, so routine monitoring of weight, blood pressure, fasting blood glucose, and lipids is recommended. Once problems with weight gain or metabolic syndrome have been identified, treatment should be instituted immediately, and consideration should be given to change of antipsychotic medication to ziprasidone, quetiapine, and possibly aripiprazole. A long-term view is required, as patients with schizophrenia will require life-long treatment with a goal to maintain general health status. PP

 

References

 

1. Fine JT, Colditz GA, Coakley EH, et al. A prospective study of weight change and health-related quality of life in women. JAMA. 1999;282(22):2136-2142.

 

2. Kawachi I. Physical and psychological consequences of weight gain. J Clin Psychiatry. 1999;60(suppl 21):5-9.

 

3. Allison DB, Fontaine KR, Heo M, et al. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry. 1999;60(4):215-220.

 

4. Daumit GL, Clark JM, Steinwachs DM, Graham CM, Lehman A, Ford DE. Prevalence and correlates of obesity in a community sample of individuals with severe and persistent mental illness. J Nerv Ment Dis. 2003;191(12):799-805.

 

5. Bobes J, Rejas J, Garcia-Garcia M, et al. Weight gain in patients with schizophrenia treated with risperidone, olanzapine, quetiapine or haloperidol: results of the EIRE study. Schizophr Res. 2003;62(1-2):77-88.

 

6. Ryan MC, Flanagan S, Kinsella U, Keeling F, Thakore JH. The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia. Life Sci. 2004;74(16):1999-2008. Erratum in: Life Sci. 2004;75(23):2851.

 

7. Graham KA, Perkins DO, Edwards LJ, Barrier RC Jr, Lieberman JA, Harp JB. Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis. Am J Psychiatry. 2005;162(1):118-123.

 

8. Kivircik BB, Alptekin K, Caliskan S, et al. Effect of clozapine on serum leptin, insulin levels, and body weight and composition in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(5):795-799.

 

9. Monteleone P, Fabrazzo M, Tortorella A, La Pia S, Maj M. Pronounced early increase in circulating leptin predicts a lower weight gain during clozapine treatment. J Clin Psychopharmacol. 2002;22(4):424-426.

 

10. Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry. 2000;157(6):975-981.

 

11. Fontaine KR, Heo M, Harrigan EP, et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res. 2001;101(3):277-288.

 

12. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.

 

13. Homel P, Casey D, Allison DB. Changes in body mass index for individuals with and without schizophrenia, 1987–1996. Schizophr Res. 2002;55(3):277-284.

 

14. Zanarini MC, Frankenburg FR, Parachini EA. A preliminary, randomized trial of fluoxetine, olanzapine, and the olanzapine-fluoxetine combination in women with borderline personality disorder. J Clin Psychiatry. 2004;65(7):903-907.

 

15. Feldman D, Goldberg JF. A preliminary study of the relationship between clozapine-induced weight gain and menstrual irregularities in schizophrenic, schizoaffective, and bipolar women. Ann Clin Psychiatry. 2002;14(1):17-21.

 

16. Seeman MV. Gender differences in the prescribing of antipsychotic drugs. Am J Psychiatry. 2004;161(8):1324-1333.

 

17. Melkersson KI, Hulting AL. Insulin and leptin levels in patients with schizophrenia or related psychoses—a comparison between different antipsychotic agents. Psychopharmacology (Berl). 2001;154(2):205-212.

 

18. Littrell KH, Hilligoss NM, Kirshner CD, Petty RG, Johnson CG. The effects of an educational intervention on antipsychotic-induced weight gain. J Nurs Scholarsh. 2003;35(3):237-241.

 

Return

 

Dr. Messer is physician of Behavioral Health at SMDC Medical Center in Duluth, Minnesota. Dr. Haller is senior research scientist of Education and Research at SMDC Health System.

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

Acknowledgments: The authors thank John Grabowski, PhD, for critical review of the manuscript and helpful suggestions.

Please direct all correspondence to: Irina V. Haller, PhD, MS, Senior Research Scientist, Division of Research, SMDC Health System, 503 E. Third Street, Duluth, MN 55805; Tel: 218-786-8185; Fax: 218-727-8159; E-mail: ihaller@smdc.org.


 

Abstract

Patients not responding to conventional treatment for depression are classified as having treatment-resistant depression (TRD). Electroconvulsive therapy is effective in ~50% of the patients diagnosed with TRD. Recent reports of rapid antidepressant effect with a single dose of ketamine suggest a potential benefit for TRD patients. However, there are no studies characterizing optimal dosing parameters (eg, frequency and inter-dose interval). The following case describes the effects of two ketamine administration regimens in a patient with a 15-year history of depression.

 

Focus Points

• Treatment-resistant depression affects up to 15% of patients with major depressive disorder, and there are few options after electroconvulsive therapy failure.
• Ketamine can be administered in an outpatient setting with nurse monitoring during the infusion.
• Adverse events associated with ketamine infusions are rare and can be avoided by using ideal body weight for dosing.
• Multiple infusions may increase the length of remission.  However, optimal dose, frequency, and inter-dose interval for ketamine administration require further study.

 

Introduction

Despite substantial advances in the therapeutic options for managing patients with major depressive disorder (MDD), treatment-resistant depression (TRD) continues to be a serious public health problem. It is estimated that up to 15% of patients diagnosed with MDD do not respond to conventional treatments and can be classified as treatment resistant.1 Attempting successive pharmacologic trials in the quest for an effective agent increases risk for the patient and can produce significant health, social, and economic burdens.2

A growing body of evidence indicates that N-methyl-d-aspartate (NMDA) receptor antagonists significantly and rapidly improve depressive symptoms in MDD patients. Two randomized controlled trials, one including TRD patients, reported a rapid antidepressant response from a single infusion of ketamine in patients with MDD.3,4 However, there are no available data or general guidelines on optimal dose, frequency, or inter-dose interval for ketamine administration to sustain remission. This case delineates a dosing regimen and may provide guidance to achieving sustained remission in TRD patients.

 

Case Report

In January 2008, a 46-year old female with MDD was hospitalized for a course of electroconvulsive therapy (ECT). Successive interventions over 15 years had included trials of 24 psychotropic medications and 273 ECT treatments, 251 of which were bilateral. No intervention had produced remission but only a short-lived response to treatment. She had no history of an Axis II diagnosis, chemical dependency or other major medical illnesses.

ECT during this admission was administered with ketamine as the anesthetic at 2 mg/kg given over 60 seconds. Surgical anesthesia occurred ~30 seconds after the end of intravenous injection and lasted ~10 minutes. There was no significant change in depression symptoms with the ketamine used as an anesthetic during the ECT treatment. Alternative treatments were reviewed for potential use. In addition to no significant recovery from her depression, the long-term use of ECT caused problems with memory loss and focused attention. She was unable to remember much of her history over the previous 15 years. Re-learning the information became futile since each course of ECT would eliminate what had been gained.

Based on recent reports of rapid antidepressant effect of single dose ketamine in MDD patients,3,4 the authors of this case report reviewed the information available with the patient and obtained her consent. They discussed potential side effects known to be associated with the anesthetic dose of ketamine, such as psychosis during or after the treatment, elevations in liver enzymes, hypertension, a harlequin-like skin change, and malignant hyperthermia. At lower doses used for antidepressant treatment4 reported in the literature, side effects included perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness, and increased libido, as well as gastrointestinal distress, increased thirst, headache, metallic taste, and constipation. These side effects appeared to abate within 80 minutes after the infusion. Ketamine was administered at 0.5 mg/kg of ideal body weight (IBW) over 40 minutes on February 28, 2008.

The first ketamine treatment led to a dramatic remission of depressive symptoms: the Beck Depression Inventory (BDI) score decreased from 22 to 6 (Figure). Three additional infusions administered every other day over 5 days produced remission lasting 17 days after the last infusion in this series. Three series of six ketamine infusions given every other day except weekends were repeated over the next 16 weeks (Figure). Each infusion sequence produced remission lasting 16, 28, and 16 days, respectively, followed by a relapse. After three remission/relapse cycles and before relapse could occur after the fourth infusion series, a maintenance ketamine regimen was established on August 27, 2008 using 0.5 mg/kg IBW at a 3-week inter-dose interval. The authors’ estimation for the maintenance dosing interval was based on the time frame between remission and relapse for this patient. Relapse to depression was prevented by treating prior to the onset of a relapse.

 

As shown in the Figure, with maintenance infusions the patient has been in remission for >15 months. No concurrent pharmacotherapeutic agents have been administered or required during this time period, no adverse events have emerged, and there has been no cognitive impairment as is typical with ECT, polypharmacy, or from MDD itself.

Generally, weight-based dosing (eg, mg/kg) is a sound pharmacologic strategy. However, data and experience with weight-based dosing in a previous patient who was substantially overweight5 resulted in perceptual distortion, though antidepressant benefit was evident. In consultation with the authors’ Anesthesia department, they selected IBW to establish the dosing regimen. The Metropolitan Life Insurance weight tables6 can be used to determine IBW based on sex, age, height, and body frame.

For this case, ketamine infusions were administered with nursing supervision as a day patient procedure and treatment was well tolerated. Vital signs were monitored during the infusion. No psychotic or dissociative symptoms were noted during or after the ketamine infusions and no other adverse events occurred. Ketamine was safe in an outpatient setting without cognitive or physical impairment once ketamine was metabolized (usually within 2 hours post infusion). Repeated administration did not produced tachyphylaxis or tolerance.

Maintenance ketamine treatments described here continue to sustain this patient’s recovery from depression. Moreover, in this patient, maintenance treatments were more effective than the recurrent series of infusions for maintaining recovery.

 

Conclusion

While there is no consensus regarding the definition of TRD,2,7 it is generally regarded as a resistance to treatment when the patient has not experienced a 50% reduction in depressive symptoms after ≥2 courses of appropriate antidepressant, given in an adequate dose and duration.

As indicated by the designation TRD, there are no consistently effective interventions. Options include medications from various classes of antidepressants either alone or in combination with other psychotropics, or ECT alone or in combination with a range of medications. ECT is given in a series of treatments and with TRD may also be given as a maintenance treatment. Most current treatments for TRD take several weeks to achieve full clinical effect. In comparison, ketamine in this case had a rapid onset of action.

The cost implications of ECT must also be taken into consideration when this becomes the primary antidepressant intervention. Ketamine treatments require infusion capability and ongoing nursing observation. The cost and personnel needed for a ketamine treatment are far less than that of ECT since no charges associated with anesthesia or operating room use are needed. The data from our institution suggest that the charges associated with one ketamine treatment are ~33% of the charges for one ECT.

The combination of ketamine and ECT has received very little attention in the literature. Although others have noted a potential benefit from using ketamine during ECT either as induction treatment8 or an anesthetic,9 the authors did not see any changes in mood symptoms in this patient when ketamine was used as an anesthetic to ECT. This lack of response could be attributed to the patient’s significant exposure to ECT. Alternatively, antidepressant benefit may be attenuated by the amnestic effect of ECT or anesthetic doses, with the latter suggesting a “state-dependent” effect.

A growing body of evidence suggests that the glutamatergic system, known to play a role in neuronal plasticity and cellular resilience, is also involved in the pathophysiology and treatment of MDD.10-12 Ketamine, an NMDA receptor antagonist with rapid antidepressant effect, emerged as a potential agent for treatment of mood disorders,3,4 specifically TRD. Zarate and colleagues12 have described the putative mechanism of action of NMDA receptor antagonists. It is postulated that the NMDA-glutamate receptor complex signals morphologic changes that produce cell loss or atrophy. Ketamine, a high-affinity NMDA-receptor antagonist, causes the release of brain-derived neurotrophic factor (BDNF). The presence of BDNF increases the size of cells and increases arborization of dendrites which is reduced under circumstances of stress in animal models that are analogous to depression. The function of BDNF is considered to be a part of the antidepressant effect of electroconvulsive treatments, antidepressants, and ketamine.

Optimal ketamine regimens to sustain remission have not been defined. Previously, the authors successfully treated two patients with TRD using a series of ketamine infusions5 over a 12-day period. The patient who received two ketamine treatments separated by 6 days was symptom-free for 18 days and the patient who received six ketamine treatments (every other day over 12-day period) was symptom-free for 29 days.5 As reported by others, remission was followed by relapse.

In the case described here, a maintenance ketamine treatment was more successful in preventing relapse of depression than repeated series of infusions. It may also have some economic and quality of life advantages compared to ECT. As NMDA receptor antagonist action on TRD is explored, a maintenance treatment protocol requires further investigation as a means to sustain recovery from depression.  PP

 

References

1.    Burrows GD, Norman TR, Judd FK. Definition and differential diagnosis of treatment-resistant depression. Int Clin Psychopharmacol. 1994;9(suppl 2):5-10.
2.    Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):26-31.
3.    Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.
4.    Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.
5.    Messer MM, Haller IV, Larson P, Pattison-Crisostomo J, Gessert CE. The use of a series of ketamine infusions in two patients with treatment resistant depression. J Neuropsychiatry Clin Neurosci. In press.
6.    Metropolitan Life Insurance Company. Weight Charts. Available at: www.coping.org/weightmgt/strategies/Weight%20Charts.doc. Accessed February 23, 2010.
7.    Berlim MT, Turecki G. What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials. Eur Neuropsychopharmacol. 2007;17(11):696-707.
8.    Ostroff R, Gonzalis M, Sanacora G. Antidepressant effect of ketamine during ECT. Am J Psychiatry. 2005;162(7):1385-1386.
9.    Okamoto N, Nakai T, Sakamoto K, Nagafusa Y, Higuchi T, Nishikawa T. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: Comparing ketamine and propofol anesthesia. J ECT. November 19, 2009 [Epub ahead of print].
10.    Paul IA, Skolnick P. Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci. 2003;1003:250-272.
11.    Rot M, Chaney D, Mathew S. Intravenous ketamine for treatment-resistant major depressive disorder. Primary Psychiatry. 2008;15(4):39-47.
12.    Zarate CA Jr, Du J, Quiroz J, et al. Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system. Ann N Y Acad Sci. 2003;1003:273-291.

Return

 

Dr. Feusner is psychobiology research fellow, Dr. Cameron is associate clinical professor, and Dr. Bystritsky is professor of psychiatry and behavioral sciences and director of the Anxiety Disorders Program at the David Geffen School of Medicine at the University of California–Los Angeles.

Disclosure: Dr. Feusner receives grant support from the National Institutes of Health. Dr. Cameron reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Bystritsky is a consultant to Jazz; on the speaker’s bureau of Forest; and receives grant support from Cephalon, GlaxoSmithKline, Merck, Pfizer, and Wyeth.

Please direct all correspondence to Alexander Bystritsky, MD, PhD, Department of Psychiatry and Biobehavioral Sciences, 300 UCLA Medical Plaza, Rm. 2335,

Los Angeles, CA 90095-8346; Tel: 310-206-5133; Fax: 310-206-8387; E-mail: abystritsky@mednet.ucla.edu.


 

 

Abstract

Panic disorder affects millions of people worldwide, causing considerable suffering and loss of productivity. It is often associated with other psychiatric and substance use disorders. Fortunately, understanding the neurobiological, behavioral, and psychological factors involved in panic disorder has helped guide the development of effective pharmacotherapies and psychotherapies. The antidepressant class of selective serotonin reuptake inhibitors is a first-line defense, based on efficacy data, safety, and ease of use. However, there is also strong evidence for the efficacy of tricyclic antidepressants, benzodiazepines, and monoamine oxidase inhibitors. Cognitive-behavioral therapy (CBT) is most evidently the psychotherapy of choice for panic disorder, and can result in the maintenance of long-term improvements. Selection of treatment for the individual patient depends on the severity of illness, comorbid conditions, patient choice, and availability of psychotherapy. Pharmacotherapy and CBT combined in a rational and coordinated manner provides the best outcome.  

 

Introduction

Panic disorder is a prevalent and disabling condition, affecting 3% to 8% of the world’s population.1 The hallmark of the disorder is recurrent panic attacks, which are sudden episodes of acute apprehension or intense fear that occur without any apparent cause. During the panic attack, any of the symptoms listed in Table 1 can occur. These intense attacks usually last no more than a few minutes, but, in rare instances, can return in waves for up to 2 hours. In order to meet  Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)2 criteria for panic disorder, an individual must experience panic attacks as well as at least 1 month of persistent fear of having an additional attack, worry about the implications of the attack, or have a significant change in behavior as a result of the attacks.

Panic disorder often affects individuals in early to mid adulthood. The median onset is 24 years of age, although most do not seek treatment until their mid 30s.3,4 However, panic attacks can also begin in late adolescence. Twice as many women as men suffer from panic disorder.5 The course is typically chronic, although often waxing and waning.2

Agoraphobia is a common complication and consequence that occurs in approximately 50% of people with panic disorder. In the United States, an estimated 5.3% of the population, mostly women, suffer from agoraphobia.6 Patients suffering from agoraphobia are afraid of being in situations from which escape might be difficult, or in which help might be unavailable or embarrassing if they suddenly had a panic attack.2 In addition to the fear of experiencing a panic attack, many agoraphobics are afraid of what others will think of them after witnessing them having an attack. It is common for the agoraphobic to avoid crowded public places such as grocery stores, department stores, or restaurants. Enclosed or confined places, such as tunnels, bridges, or the hairdresser’s chair, may also be avoided. Individuals may feel trapped when using public transportation, such as trains, buses, subways, and planes, and may therefore avoid them. Individuals with panic and agoraphobia may also fear being at home alone in case a panic attack occurs and they will need help. The fears usually result in travel restrictions, the need to be accompanied by others when leaving home or staying at home, and being partially or completely house bound.

Panic disorder is associated with high comorbidity. Common comorbid conditions are major depressive episodes, specific phobias, obsessive-compulsive disorder (OCD), social anxiety disorder (SAD), generalized anxiety disorder, and posttraumatic stress disorder (PTSD).5,7 There are also high rates of substance use disorders, including alcohol, drugs, and both prescribed and non-prescribed medication. Panic disorder co-occurring with major depressive disorder (MDD), alcohol/substance abuse, and personality disorder, considerably increases the probability of a suicide attempt.5,7

Panic disorder often results in a diminished capacity for employment, especially for those with agoraphobia.8 Those who are financially dependent and those who receive either welfare or disability benefits constitute 27% of all panic disorder patients.9 Clearly, panic disorder is a relatively common psychiatric disorder that, especially when accompanied by agoraphobia, can result in considerable suffering and loss of productivity. Fortunately, in the past few decades there have been advances in the recognition and diagnosis of panic disorder as well as development of effective pharmacotherapy and psychotherapy.

 

Assessment

A comprehensive assessment is important in evaluating panic disorder and distinguishing it from other conditions, as panic attacks can occur in other psychiatric and medical disorders. The conditions that most likely need to be considered in assessing patients with panic disorder are listed in Table 2. A thorough medical history as well as a physical exam, laboratory tests, and an electrocardiogram if appropriate can help rule out any causative or concurrent medical problems related to the panic attacks.10 Certain medical problems that may cause panic-like symptoms or trigger panic attacks include, but are not limited to, complex partial seizures, hyperthyroidism, hyperparathyroidism, arrhythmias, asthma, withdrawal from drugs or alcohol, or use of psychostimulants, including caffeine. It is important to assess the presence of medications used for the treatment of medical illnesses as some of them (ie, antiasthmatics) may provoke panic. Assessment of medical status of panic patients who may undergo behavior therapy is specifically important for patients with cardiovascular problems. Collaborative work with the patient’s primary care physician is highly recommended.

 

Other psychiatric conditions are also part of the differential diagnosis, including MDD, bipolar disorder, SAD, specific phobias, OCD, and PTSD. Panic attacks can occur as symptoms of these disorders, or the disorders may exist as comorbidities. Panic attacks that seem to occur spontaneously or in the middle of the night as opposed to being triggered by specific situations or thoughts (such as with a traumatic reminder in someone with PTSD or fearing humiliation in SAD) can help distinguish panic disorder from its counterparts. Another distinguishing feature of panic disorder is fear of internal symptoms rather than fear of an external threat.

 

Theoretical Framework for Treatment

Cognitive-behavioral and biomedical theories have attempted to describe the mechanisms of panic and panic disorder.11,12 A brief synthesis of these theories reveals that panic disorder is likely a combination of an increase in alarm reaction, error in information processing (catastrophic thinking), and abnormal coping strategies to relieve anxiety and provide a sense of security (safety rituals and avoidance). The disorder represents a sequential process where the symptoms start with panic attacks and progress through the stages of abnormal thinking, rituals, and avoidance. These symptom clusters may be “wired” through different neuronal circuits and respond preferentially to different treatments.

Neuroanatomical areas of the brain responsible for alarm reactivity receive an abundance of projections from neurons having their origins in noradrenergic and serotonergic nuclei. Medications that affect serotonergic and noradrenergic systems are likely to influence the structures that are responsible for the alarm reactions and primitive defensive responses (ie, periaqueductal gray, septal areas, amygdala, and parts of orbital frontal cortex). Medications that affect serotonergic and dopaminergic pathways are capable of influencing systems involved in information processing of dangerous stimuli. These include the rostral cingulum and the basal ganglia, and their interaction with limbic areas. γ-aminobutyric acid (GABA)-receptor agonist medications are capable of slowing general reactivity of neurons. However, they can negatively affect information processing and cortical and hippocampal information retention that is necessary for forming new noncatastrophic memories important for deconditioning and desensitization.

Unfortunately, there are currently no Food and Drug Administration-approved medications that directly affect formation of new coping behaviors. It is highly unlikely that the current medications could directly affect complex behaviors such as safety rituals and avoidance. Rather, current medications influence alarm reactivity directly, and these effects over time may indirectly improve patient coping. Conversely, cognitive-behavioral therapy (CBT) directly affects coping strategies and modifies negative thinking. CBT is also capable of influencing alarm reactivity.

Pharmacotherapy and CBT, rationally applied in combination and taking into account their direct and indirect effects, should be more effective than either treatment alone. However, this theoretical framework is incomplete. The intricacy of the neuronal circuits and neurotransmitters and their relation to complex behaviors is not yet fully understood.

 

Pharmacotherapy

Selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatment for panic disorder based on their efficacy, tolerability, ability to treat common comorbid depression and anxiety disorders, and lack of abuse potential. Sertraline, fluoxetine, and paroxetine all have FDA indications for the treatment of panic disorder, but fluvoxamine, citalopram, and escitalopram are considered equally effective.   

Several meta-analyses have demonstrated that SSRIs are generally as or more effective than other pharmacotherapies.13 Boyer14 analyzed 27 randomized, placebo-controlled studies and found that SSRIs were superior to imipramine and alprazolam. Otto and colleagues13 performed an effect-size analysis of 12 placebo-controlled trials of SSRIs for the treatment of panic and compared it to a meta-analysis on non-SSRI antidepressants. They found that SSRIs were as effective as other antidepressants (both with effect sizes of 0.55), and dropout rates were similar. Another meta-analysis examined 43 randomized and open, nonrandomized trials and compared effect sizes between SSRIs and tricyclic antidepressants (TCAs). Effect sizes were similar but dropout rates were lower for SSRIs (18%) versus TCAs (31%).15 TCAs and clomipramine have been demonstrated to be efficacious in panic patients but are generally less tolerated than SSRIs.16,17

Benzodiazepines have the longest history of proven efficacy in panic disorder. In several controlled trials, alprazolam, lorazepam, and clonazepam were effective for panic disorder.18-21 Meta-analyses show benefits of benzodiazepines.22-27 Most studies, with the exception of a study by van Balkom and colleagues,25 showed similar effect sizes as the antidepressants. However, outcome measures were not consistent across studies. The benefits of the benzodiazepines are that they have a rapid onset of action and generally favorable side-effect profile. They can be used in maintenance, regular dosing, or on an as-needed basis. The downsides are the propensity for development of physiological dependence, tolerance, and cognitive side effects at higher doses. Compared to the antidepressants, they are not able to treat common comorbid depressive disorders.

Several older controlled studies have shown monoamine oxidase inhibitors (MAOIs) to be efficacious for panic disorder treatment.28,29 Sheehan and colleagues,29 in a placebo-controlled, double-blind study, found that phenelzine and imipramine groups showed significant improvement, with phenelzine superior to imipramine on some measures. MOAIs, however, are often problematic due to a heavy burden of side effects and dietary restrictions. The reversible monoamine oxidase inhibitors (RIMAs) such as moclobemide and brofaromine, do not require dietary restriction, and have been demonstrated in some (but not all30) controlled studies to be beneficial in panic disorder.31-34 Neither are currently available in the US.

Other pharmacologic agents may also be effective in panic disorder, although they have not yet been studied as extensively. Two small, controlled trials showed benefits in treatment with mirtazapine.35,36 GABA-ergic anticonvulsants, such as valproic acid37,38 and gabapentin,39 have shown promise in small trials, although gabapentin was more effective than placebo only for more severely ill patients.

 

Medication Treatment Considerations

Clinical trial data assist in understanding which group of medications are effective for panic disorder, and serve as a starting point for which medication is likely to benefit a particular patient. Selection of specific medications frequently depends on whether patients have received prior pharmacotherapy for the treatment of a mood and anxiety disorder, on previous reaction to medication, and on severity and acuity of their illness state.

SSRIs are currently the treatment of choice for patients who have never received prior pharmacotherapy and have at least moderate severity of illness. In addition to treating anxiety, SSRIs treat the frequently present comorbid MDD and lower the risk of future MDD. All SSRIs are thought to be effective in treating panic disorder and differ only in subtle side-effect profile and in their effects on the cytochrome P450 liver enzyme systems. In general, selection among antidepressants should be based on the patient’s anxiety symptom profile (one should avoid medications with side effects similar to their anxiety symptoms) and history of prior medication side effects. For example, paroxetine, fluvoxamine, or citalopram are more sedating medications and would be preferable SSRIs for patients with prominent activation. In the patient with severe insomnia one might select a sedating tricyclic antidepressant, such as nortriptyline or mirtazapine. Use of a dual-acting medication, such as venlafaxine, may be considered in the early stages of the treatment; however, at present there is no strong evidence from clinical research to support their early use. The clinical experience of the authors of this article is that treatment of uncomplicated panic may be started with small doses and increased to higher doses in patients with more obsessive thought patterns and avoidance.

Patients with panic disorder are often fearful of medication side effects or medications in general. They also have a tendency to have heightened side effects and reactions to side effects.10 This can be particularly problematic with the SSRIs, which often cause transient increases in anxiety, jitteriness, or exacerbation of panic attacks at initiation of treatment. For these reasons, and to minimize the likelihood of patients discontinuing the medications early, it can be helpful to start at very low doses and titrate upwards slowly. If needed, liquid formulations of most SSRIs are available to facilitate starting at very low doses, (eg, as low as fluoxetine 1 mg). However, the patient will at some point most likely need to achieve a dose in the range of what is required for the treatment of MDD.15

Benzodiazepines are not the first choice of treatment for panic disorder because of tolerance, dependency potential, and possible interference with CBT (especially with as-needed use). Therefore, these medications should be reserved for the “emergency” situations (eg, initial panic attacks) or for the reduction of anxiety in extreme or infrequent phobic situations (eg, airplanes, elevators) when the patient has not yet begun CBT. Finally, benzodiazepines can be used for maintenance of the chronic patients with refractory anxiety. If used chronically, these agents should be prescribed using a pharmacokinetically appropriate schedule in order to minimize daily withdrawal or interdose anxiety. Prior history of alcohol and drug abuse should be assessed before beginning treatment, as this may preclude their use.

Benzodiazepines can be initiated concurrently with an antidepressant. This strategy is particularly useful for patients with a history of increased anxiety with initiation of antidepressants or for acute anxiety in need of rapid relief. The benzodiazepine can be initiated with a planned treatment duration of approximately 4 weeks (to allow the antidepressant to take effect), followed by a flexible taper of the benzodiazepine over several weeks. This strategy was tested by Goddard and colleagues,40 who found that the combination of clonazepam and sertraline for 4 weeks followed by a 3-week taper of the clonazepam resulted in more responders than with sertraline and placebo by the first and third week. However, by the end of the 12-week trial there were no differences in the number of responders, and the dropout rates were similar.

 

Psychotherapy

Of the psychotherapeutic modalities, CBT has received the most widespread empirical and theoretical support in controlled studies for panic disorder.12,41-43 CBT is associated with low dropout rates, maintained long-term improvements, and the largest within-group and between-group effect sizes relative to all other comparison conditions.44,45

A recent long-term follow-up found treatment gains were maintained when reassessed at 6–8 years.46

CBT for panic disorder with and without agoraphobia has been described in manuals which have both patient and therapist guide versions.47 The goal of the treatment is to change catastrophic thinking that results when patients misinterpret internal bodily sensations as dangerous. First, the patient is guided through a psychoeducational process of understanding the panic process and the self-regulating nature of the physiology of anxiety. The patient is instructed on breathing and muscle relaxation techniques, which must be practiced at home between sessions. Next, the patient is engaged in monitoring his or her thinking, toward identifying and reappraising anxiety and panic-generating thoughts (cognitive restructuring). Finally, the patient is exposed, both in session and out of session, to bodily sensations that have become conditioned to fear. Through repeated exposure the patient habituates to the feared bodily sensations, thereby unlearning the fear response. The patient learns to confront possible agoraphobic avoidance of situations associated with previous panic attacks and anxiety.

Although considerable and growing research continues to demonstrate that CBT is well tolerated, cost effective, and efficacious in the short and long term, some patients do not benefit from it and there is still a need to improve the treatment.48 Efforts have been made to make CBT more efficient and to dismantle and identify its efficacious treatment components.

Data on utilization of healthcare services and medication have shown significant reductions in costs following CBT for panic disorder.49 CBT for panic disorder has been effectively and efficiently transported to the primary care setting. In a randomized, controlled study, mid-level behavioral health specialists trained to deliver CBT and pharmacotherapy were significantly more effective in treating primary care panic disorder than treatment as usual.50

Recent research has been conducted to increase self-directed therapy, reduce therapy frequency, and further streamline CBT delivery in innovative ways. Forty patients with panic disorder with agoraphobia were randomly assigned to either a traditional 12-session CBT group or a 4-session traditional treatment group plus a virtual reality component.51 Both groups were equally effective at treatment end, although the virtual reality group was less effective at 6-month follow-up. Using a manualized treatment program, panic disorder patients received either four sessions of group CBT or one meeting with a therapist plus three telephone contacts.52 Although the authors suggested that certain comorbid conditions negatively impacted self-directed treatment outcomes, the findings of the study (ie, higher end-state functioning in telephone condition) add to the viability of self-directed treatment options. An international multicenter trial reported that CBT delivered by brief computer-augmentation was as effective as extended therapist-delivered CBT, providing some support for the use of computers as an adjunct to effective CBT.53

A final emerging area in the evolution of CBT are mindfulness-based approaches. Mindfulness- or acceptance-based approaches are being hailed as the third wave in CBT54 (the first wave was strict behavioral approaches; the second wave was cognitive approaches). Mindfulness is a type of meditation that has been adapted from Buddhist psychology. One definition of mindfulness is “awareness of present experience with acceptance.”55 Mindfulness-based CBT has been applied to the treatment of panic disorder and other anxiety disorders,56 but it requires further carefully controlled research.57

CBT currently provides well-established treatments for panic disorder. It continues to be developed and evaluated, spawning innovating treatments that await further evaluation.

 

Combining Treatment Modalities

Several studies have been conducted to understand the importance of combined medication and CBT, versus either alone. A meta-analysis found combination treatments of CBT and medication, including benzodiazepines and/or antidepressants, superior to control groups, while exposure was not effective alone.25 In addition, the combined behavioral therapy and antidepressant group was superior to medications alone or psychotherapeutic interventions alone for agoraphobic avoidance. In another meta-analysis, Gould and colleagues24 showed that pharmacologic and CBT treatments were superior to control conditions, but that CBT had the largest effect sizes and the lowest attrition rates. A 1-year follow-up study, employing a time-series design, found that 89% of the participants were symptom free after receiving CBT, and that they also reduced their use of benzodiazepines. A study comparing CBT and pharmacologic treatment found all treatments effective, but the CBT group treatment was the most cost effective.58

In a clinic where CBT was accepted as the basic treatment for panic disorder with agoraphobia, it was suggested that psychiatrists appeared to rationally choose whether to add a benzodiazepine or antidepressant, either alone or in combination with each other and the CBT. Psychiatrists generally used combination treatments for more severe disorders, while CBT alone was often chosen when cognitive components were more pronounced than other symptoms. Benzodiazepines were often chosen for more somatically oriented patients with prominent panic attacks. Those choices resulted in substantial clinical improvements.59

If both CBT and medication are being used, coordination between the treatments is crucial. Completely blocking anxiety may prevent patients from receiving benefits from therapy and does not promote development of new ways of coping. Gradual reduction and stopping of medication can be attempted after 2–3 months of complete resolution of symptoms.

 

Treatment Algorithm

The treatment of panic disorder can proceed in a stepwise process, starting with treatments of proven efficacy and low rates of adverse events. Full response should be defined as not only a resolution of panic attacks, but also a resolution of the fear of panic and avoidant behaviors. The steps of the treatment are listed in the suggested (but not empirically tested) Algorithm.

 

Step 1

Education is the important first step in treatment, whether the treatment is pharmacotherapy, CBT, or the combination. At the most basic level, this involves explanations that the panic attacks do not signify that something is wrong with the body, and that the panic attacks are not dangerous. As primary care providers and the public are currently more aware of panic attacks, patients may already know that what they are experiencing is anxiety rather than a life-threatening condition such as a heart attack or stroke. The education should include explanations of how the cycle of panic attacks and fear of panic operates, and what kinds of behaviors reinforce the fear of the attacks. The clinician can also educate the patient on expectations regarding medication treatment; panic attacks may resolve, but the avoidance behavior may not change unless addressed directly with the help of a CBT therapist. Useful resources are available on the Internet and information in the form of pamphlets can be ordered from the Anxiety Disorders Association of America (www.adaa.org) and the National Institute of Mental Health (www.nih.nimh.gov). Involving the family can be helpful, especially when avoidance behavior is prominent and/or a family member misinterprets and is fearful of the patient’s panic attacks.

 

Step 2

Step 2 begins with a first-line of medication (SSRI) or CBT. The treatment choice is made during the initial patient session with the physician, in which the patient’s preference for either medication or psychotherapy is taken into consideration, along with the acuity of their current condition and availability of CBT. Patients who have very severe panic disorder accompanied by depression or other anxiety disorders are often less able to initially engage in CBT, and need to be started on antidepressants early. When availability or cost of CBT for the individual patient is problematic, medication treatment may be the only option.

 

Step 3

Step 3 begins after two trials of an SSRI are deemed to be unsuccessful. This step should start with a discussion with the patient about their preferences for switching to another medication or another treatment modality (eg, CBT) or augmenting the current modality by adding another medication or CBT. If the patient has had nonresponse or side effects to two prior SSRIs, the next choice is between other antidepressants (eg, venlafaxine, mirtazapine, or a TCA). A GABA-ergic strategy, such as benzodiazepines or gabapentin, can be used as augmentation if there is a partial response. Alternatively, a sedating atypical antipsychotic, such as olanzapine or quetiapine, can be used concomitantly. These medications are not ordinarily first-line treatments for anxiety disorders. If the patient continues to be treatment refractory, MAOIs may also be tried. MAOIs require dietary restrictions as well as first tapering off other antidepressants.

 

Step 4

Step 4 involves treatments with more intensive CBT or with medications or combinations of treatments that have not yet been tried. An expert consultation is usually recommended. Treatments with less established evidence could be attempted at this step. Combining an intensive CBT program (several times a week) with medication augmentation strategies may also result in a desired effect. Electroconvulsive therapy may be helpful for comorbid panic and depression but not for panic alone.60 Other strategies are under development for the treatment-resistant population, but they have yet to move past early experimental stages.

 

Long-Term Management

While in some patients panic attacks remit in the course of a few months, panic disorder is usually a chronic, waxing and waning condition. However, some patients can achieve complete remission. As per expert consensus guidelines, after 12–24 months of remission (defined as absence of panic attacks, fear of panic, and avoidance, as well as overall well being and lack of disability) the clinician may discuss with the patient the risks and benefits of continuing versus tapering off the medication.61 The risk of relapse may be reduced if the patient has undergone CBT.62 If a course of CBT has been successful, the individual may benefit from once monthly sessions for 3–6 months and “booster” CBT sessions as needed thereafter. Other patients may be left with the symptoms of other disorders, initially masked by the panic attacks. Approximately 20% of patients will not respond to any treatment and need to be maintained in the most comfortable state with medication, therapy, or their combination.63

 

Conclusion

Panic disorder (and the often accompanying agoraphobia) is a relatively common condition that can significantly disrupt the patient’s life in many ways. Knowledge of neuroanatomy and neuropharmacology of these conditions can assist us in better understanding current treatments of these disorders and in selecting the appropriate treatment choices. However, knowledge of neuropharmacology is not enough in selecting treatment for a particular patient. A thorough assessment and understanding of the interplay of multiple psychological and biological factors together with a deep knowledge of evidence from contemporary clinical research can assist the effective management of an individual patient. For the best possible results, psychotherapy (CBT) and pharmacologic treatment may need to be used individually or in a rationally chosen combination for the best possible results.  PP

 

References

1. Wittchen HU, Essau CA, von Zerssen D, Krieg JC, Zaudig M. Lifetime and six-month prevalence of mental disorders in the Munich Follow-Up Study. Eur Arch Psychiatry Clin Neurosci. 1992;241(4):247-258.

2. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

3. Burke KC, Burke JD Jr, Regier DA, Rae DS. Age at onset of selected mental disorders in five community populations. Arch Gen Psychiatry. 1990;47(6):511-518.

4. Breier A, Charney DS, Heninger GR. Agoraphobia with panic attacks. Development, diagnostic stability, and course of illness. Arch Gen Psychiatry. 1986;43(11):1029-1036.

5. Weissman MM, Bland RC, Canino GJ, et al. The cross-national epidemiology of panic disorder. Arch Gen Psychiatry. 1997;54(4):305-309.

6. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(1):8-19.

7. Weissman MM. The hidden patient: unrecognized panic disorder. J Clin Psychiatry. 1990;51(suppl):5-8.

8. Roy-Byrne PP, Stang P, Wittchen HU, Ustun B, Walters EE, Kessler RC. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. Br J Psychiatry. 2000;176:229-235.

9. Leon AC, Portera L, Weissman MM. The social costs of anxiety disorders. Br J Psychiatry Suppl. 1995(27):19-22.

10. Pollack MH, Marzol PC. Panic: course, complications and treatment of panic disorder. J Psychopharmacol. 2000;14(2 suppl 1):S25-30.

11. Gorman JM, Kent JM, Sullivan GM, Coplan JD. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry. 2000;157(4):493-505.

12. Barlow DH. Cognitive-behavioral therapy for panic disorder: current status. J Clin Psychiatry. 1997;58(suppl 2):32-36; discussion 36-37.

13. Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry. 2001;158(12):1989-1992.

14. Boyer W. Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic attacks: a meta-analysis. Int Clin Psychopharmacol. 1995;10(1):45-49.

15. Bakker A, van Balkom AJ, Spinhoven P. SSRIs vs. TCAs in the treatment of panic disorder: a meta-analysis. Acta Psychiatr Scand. 2002;106(3):163-167.

16. Klein DF. Anxiety reconceptualized. Gleaning from pharmacological dissection–early experience with imipramine and anxiety. Mod Probl Pharmacopsychiatry. 1987;22:1-35.

17. Papp LA, Schneier FR, Fyer AJ, et al. Clomipramine treatment of panic disorder: pros and cons. J Clin Psychiatry. 1997;58(10):423-425.

18. Beauclair L, Fontaine R, Annable L, Holobow N, Chouinard G. Clonazepam in the treatment of panic disorder: a double-blind, placebo-controlled trial investigating the correlation between clonazepam concentrations in plasma and clinical response. J Clin Psychopharmacol. 1994;14(2):111-118.

19. Charney D, Woods S. Benzodiazepine treatment of panic disorder: a comparison of alprazolam and lorazepam. J Clin Psychiatry. 1989;50(11):418-423.

20. Noyes R Jr, Burrows GD, Reich JH, et al. Diazepam versus alprazolam for the treatment of panic disorder. J Clin Psychiatry. 1996;57(8):349-355.

21. Schweizer E, Pohl R, Balon R, Fox I, Rickels K, Yeragani V. Lorazepam vs. alprazolam in the treatment of panic disorder. Pharmacopsychiatry. 1990;23(2):90-93.

22. Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Panic Disorder and Agoraphobia. Australian and New Zealand clinical practice guidelines for the treatment of panic disorder and agoraphobia. Aust N Z J Psychiatry. 2003;37(6):641-656.

23. Bakker A, van Balkom A, Spinhoven P, Blaauw B, van Dyck R. Follow-up on the treatment of panic disorder with or without agoraphobia: a quantitative review. J Nerv Ment Dis. 1998;186(7):414-419.

24. Gould RA, Otto MW, Pollack MH. A meta-analysis of treatment outcome for panic disorder. Clin Psychol Rev. 1995;15(8):819-844.

25. van Balkom A, Bakker A, Spinhoven P, Blaauw B, Smeenk S, Ruesink B. A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral, and combination treatments. J Nerv Ment Dis. 1997;185(8):510-516.

26. Mattick R, Andrews G, Hadzi-Pavlovic D, Christensen H. Treatment of panic and agoraphobia. An integrative review. J Nerv Ment Dis. 1990;178(9):567-576.

27. Wilkinson G, Balestrieri M, Ruggeri M, Bellantuono C. Meta-analysis of double-blind placebo-controlled trials of antidepressants and benzodiazepines for patients with panic disorders. Psychol Med. 1991;21(4):991-998.

28. Tyrer P, Candy J, Kelly D. A study of the clinical effects of phenelzine and placebo in the treatment of phobic anxiety. Psychopharmacologia. 1973;32(3):237-254.

29. Sheehan DV, Ballenger J, Jacobsen G. Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Arch Gen Psychiatry. 1980;37(1):51-59.

30. Loerch B, Graf-Morgenstern M, Hautzinger M, et al. Randomised placebo-controlled trial of moclobemide, cognitive-behavioural therapy and their combination in panic disorder with agoraphobia. Br J Psychiatry. 1999;174:205-212.

31. Kruger M, Dahl A. The efficacy and safety of moclobemide compared to clomipramine in the treatment of panic disorder. Eur Arch Psychiatry Clin Neurosci. 1999;249(suppl 1):S19-S24.

32. Tiller J, Bouwer C, Behnke K. Moclobemide and fluoxetine for panic disorder. International Panic Disorder Study Group. Eur Arch Psychiatry Clin Neurosci. 1999;249(Suppl 1):S7-S10.

33. Bakish D, Saxena B, Bowen R, D’Souza J. Reversible monoamine oxidase-A inhibitors in panic disorder. Clin Neuropharmacol. 1993;16(suppl 2):S77-82.

34. van Vliet I, Westenberg H, Den Boer J. MAO inhibitors in panic disorder: clinical effects of treatment with brofaromine. A double blind placebo controlled study. Psychopharmacology (Berl). 1993;112(4):483-489.

35. Ribeiro L, Busnello J, Kauer-Sant’Anna M, et al. Mirtazapine versus fluoxetine in the treatment of panic disorder. Braz J Med Biol Res. 2001;34(10):1303-1307.

36. Boshuisen M, Slaap B, Vester-Blokland E, den Boer J. The effect of mirtazapine in panic disorder: an open label pilot study with a single-blind placebo run-in period. Int Clin Psychopharmacol. 2001;16(6):363-368.

37. Lum M, Fontaine R, Elie R, et al. Divalproex sodium’s antipanic effect in panic disorder. Biol Psychiatry. 1990;27(suppl 1):164A-165A.

38. Woodman CL, Noyes R Jr. Panic disorder: treatment with valproate. J Clin Psychiatry. 1994;55(4):134-136.

39. Pande A, Pollack M, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 2000;20(4):467-471.

40. 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.

41. van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM, Smeenk S, Ruesink B. A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral, and combination treatments. J Nerv Ment Dis. Aug 1997;185(8):510-516.

42. Craske MG. Anxiety Disorders: Psychological Approaches to Theory and Treatment. Boulder, CO: Westview Press; 1998.

43. Craske MG, Roy-Byrne P, Stein MB, et al. Treating panic disorder in primary care: a collaborative care intervention. Gen Hosp Psychiatry. 2002;24(3):148-155.

44. Borkovec TD, Ruscio AM. Psychotherapy for generalized anxiety disorder. J Clin Psychiatry. 2001;62(suppl 11):37-42; discussion 43-45.

45. Ladouceur R, Dugas MJ, Freeston MH, Leger E, Gagnon F, Thibodeau N. Efficacy of a cognitive-behavioral treatment for generalized anxiety disorder: evaluation in a controlled clinical trial. J Consult Clin Psychol.  2000;68(6):957-964.

46. Kenardy J, Robinson S, Dob R. Cognitive Behaviour therapy for panic disorder: long-term follow-up. Cogn Behav Ther. 2005;34(2):75-78.

47. Barlow DH, Craske MG. Mastery of Your Anxiety and Panic. 3rd ed. San Antonio, TX: The Psychological Corporation; 2000.

48. Landon T, Barlow DH. Cognitive-behavioral treatment for panic disorder: current status. J Psychiatr Pract. 2004;10(4):211-226.

49. Roberge P, Marchand A, Reinharz D, et al. Healthcare utilization following cognitive-behavioral treatment for panic disorder with agoraphobia. Cogn Behav Ther. 2005;34(2):79-88.

50. Roy-Byrne P, Craske M, Stein M, et al. A randomized effectiveness trial of cognitive-behavioral therapy and medication for primary care panic disorder. Arch Gen Psychiatry. 2005;62(3):290-298.

51. Choi Y, Vincelli F, Riva G, Wiederhold B, Lee J, Park K. Effects of group experiential cognitive therapy for the treatment of panic disorder with agoraphobia. Cyberpsychol Behav. 2005;8(4):387-393.

52. Hecker J, Losee M, Roberson-Nay R, Maki K. Mastery of your anxiety and panic and brief therapist contact in the treatment of panic disorder. J Anxiety Disord. 2004;18(2):111-126.

53. Kenardy J, Dow M, Johnston D, Newman M, Thomson A, Taylor C. A comparison of delivery methods of cognitive-behavioral therapy for panic disorder: an international multicenter trial. J Consult Clin Psychol. 2003;71(6):1068-1075.

54. Germer C. Mindfulness. What is it? What does it matter? In: Germer CK, Siegel RD, Fulton PR, eds. Mindfulness and Psychotherapy. New York, NY: Guilford Press; 2005:3-27.

55. Germer CK, Siegel RD, Fulton PR. Mindfulness and Psychotherapy. New York, NY: Guilford Press; 2005.

56. Kabat-Zinn J, Massion AO, Kristeller J, et al. Effectiveness of a meditation-bases stress reduction program in the treatment of anxiety disorders. Am J Psych. 1992;149(7):936-943.

57. Baer R. Mindfulness training as a clinical intervention: a conceptual and empirical review. Clin Psych: Science Prac. 2003;10(2):125-143.

58. Otto M, Pollack M, Maki K. Empirically supported treatments for panic disorder: costs, benefits, and stepped care. J Consult Clin Psychol. 2000;68(4):556-563.

59. Starcevic V, Linden M, Uhlenhuth E, Kolar D, Latas M. Treatment of panic disorder with agoraphobia in an anxiety disorders clinic: factors influencing psychiatrists’ treatment choices. Psychiatry Res. 2004;125(1):41-52.

60. Mathew SJ, Coplan JD, Gorman JM. Management of treatment-refractory panic disorder. Psychopharmacol Bull. 2001;35(2):97-110.

61. Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 1998;59(suppl 8):47-54.

62. Otto MW, Pollack MH, Sachs GS, Reiter SR, Meltzer-Brody S, Rosenbaum JF. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. Am J Psychiatry. 1993;150(10):1485-1490.

63. Pollack MH, Otto MW. Long-term course and outcome of panic disorder. J Clin Psychiatry. 1997;58(suppl 2):57-60.

Return

Journal CMEs

Print Friendly 

Post-Deployment Violence and Antisocial Behavior: The Influence of Pre-Deployment Factors, Warzone Experience, and Posttraumatic Stress Disorder

David M. Benedek, MD, DFAPA, and Thomas A. Grieger, MD, DFAPA

Needs Assessment: In combat veterans, violent or aggressive behavior emerging as an adaptive response on the battlefield often persists upon homecoming. Clinical and empirical studies of combat veterans from Vietnam demonstrate that post-deployment antisocial behavior correlates with a number of pre-military experiences, certain aspects of warzone exposure, and the development of posttraumatic stress disorder. The lessons learned from these studies, as well as an understanding of the limitations of these studies, will help in assessing and mitigating violence and antisocial behavior in returning service members.

 

Learning Objectives:

 
  • Discuss major study findings of the effects of combat deployment on post-deployment violence and antisocial behavior.
 
  • Identify the limitations of these studies concerning post-deployment behavior of service members returning from combat operations.
 
  • Recognize the relative contributions of pre-deployment behavior, warzone experiences, and posttraumatic stress disorder to the emergence of violence and antisocial behavior.
 


Target Audience:
Primary care physicians and psychiatrists.

 

Accreditation Statement: Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

 

Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.

 

It is the policy of 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.

 

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 quiz. To obtain credits, you should score 70% or better. Termination date: March 31, 2008. The estimated time to complete all three articles and the quiz is 3 hours.

Return

Primary Psychiatry. 2006;13(3):51-56

 

Drs. Benedek and Grieger are associate professors and assistant chairmen in the Department of Psychiatry at the Uniformed Services University in Bethesda, Maryland.

 

Disclosure: Drs. Benedek and Grieger report no affiliation with or financial interest in any organization that may pose a conflict of interest.

 

Please direct all correspondence to: David M. Benedek, MD, DFAPA, Department of Psychiatry, Uniformed Services University, 4301 Jones Bridge Rd, Bethesda, MD 20814; Tel: 301-319-4944; Fax: 301-295-1536; E-mail: Dbenedek@usuhs.mil.


 

 
 

Abstract

 

The United States has historically been concerned with successful reintegration of returning combat veterans into civilian society. Apprehensions are based on the recognition that traumatic warzone exposures may have negative emotional and behavioral consequences, and that violent and aggressive behavior demonstrated in the combat zone may persist upon homecoming. The majority of clinical and empirical data on post-deployment violence and antisocial behavior in US combat veterans comes from studies of returnees from the Vietnam War. These studies have demonstrated correlations between warzone exposures, posttraumatic stress disorder, and post-deployment violence in subpopulations of Vietnam veterans; however, there are methodologic limitations to the generalizability of these findings. Study results regarding post-deployment violence and antisocial behavior in Vietnam veterans can inform efforts to mitigate violence and antisocial behavior in service members returning from combat related to the global war on terrorism as well as future research.

 

Introduction

 

The United States has long held concerns about its military service members returning from war.1,2 Apprehension surrounding the prospects for soldiers’ successful reintegration into society has stemmed from concerns about the persistence of aggressive behavior (that may be adaptive on the battlefield) and from concerns related to the potential behavioral and emotional consequences of traumatic battlefield exposures. A variety of clinical and empirical studies have examined the relationships between battlefield exposures and the development of mental disorders such as posttraumatic stress disorder (PTSD) and depression. Other studies have examined the effects of warzone experience on the development of post-deployment violence, aggression, and other antisocial behavior. Recent statistical analyses have attempted to model the extent to which PTSD itself may mediate the development of post-deployment antisocial behavior in the aftermath of deployment.

 

The prevalence and management considerations for combat-related PTSD have been described elsewhere in this issue.3 This article reviews the literature surrounding efforts to identify predictors of violence and antisocial behavior in returning war veterans with and without PTSD. Literature describing the relationship between PTSD and post-deployment violence, aggression, and antisocial behavior is summarized as well. Finally, studies attempting to delineate the effects of pre-deployment behavior, combat exposure, and PTSD as mediators of post-deployment antisocial behavior are reviewed.

 

Antisocial Behavior in Veteran Populations

Studies of postwar adjustment of Vietnam veterans have provided the vast majority of information concerning violence and antisocial behavior in returning soldiers. Yesavage4 collected data on 70 consecutive Vietnam era schizophrenic male patients admitted to the psychiatric intensive care unit of the Veterans Administration (VA) Medical Center in Palo Alto, California. Nineteen of the 27 subjects in Vietnam saw combat. Measuring incidents of assault and assault-related behavior during admission, the study made correlations to self-report of combat exposure and criminal behavior before and after military service. When examined independently as a risk for inpatient assaultive behavior, significant correlations were found between pre-service criminal behavior, combat experience, and post-service criminal behavior. Multiple regression analyses demonstrated that while pre-military antisocial behavior predicted post-military antisocial behavior, violent tendencies in Vietnam era veterans were better explained by their war experience than by premorbid criminal behavior. The study suggested that anger and violence was better viewed as “reaction stress rather than as simply another outburst of a notoriously sociopathic population.”4 The generalizability of these conclusions is limited because the sample size was small, all study participants had schizophrenia, and substance abuse was not controlled for in the analysis.

 

Resnick and colleagues5 reviewed assessment data from 118 Vietnam era veterans seeking services at two Los Angeles VA hospitals to examine the relationships between the number of pre-adult and adult antisocial behaviors (as defined by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition [DSM-III]6 criteria for antisocial personality disorder), level of combat exposure, and development of combat-related PTSD symptoms. The Structured Diagnostic Interview for Vietnam Veterans was used to obtain a thorough pre-military, military, and post-military history and to determine objective scores of pre-adult antisocial behavior, adult antisocial behavior, combat exposure, and PTSD symptom intensity.7 Hierarchical regression analyses indicated that combat exposure was significantly associated with PTSD severity (P<.005), and that the number of adult antisocial behaviors was predicted by the number of pre-adult antisocial behaviors (P<.05) and by combat exposure (P<.005). No interaction effect was observed for the pre-adult behavior and combat exposure. Resnick and colleagues5 concluded that the degree of combat exposure exerts independent effects on the development of PTSD symptoms as well as on post-combat antisocial behavior. The authors noted limitations based on data derived from retrospective interviews. Antisocial behavior scores were determined by behavior that included interpersonal violence, but this was only one of four determinants of overall score. Since other studies demonstrated an association between combat exposure and antisocial behavior, including non-violent arrests,8,9 the extent to which this study demonstrates combat exposure as a predictor of violence is less clear. Finally, the fact that subjects were drawn from clinical populations limits the generalizability to non-clinical populations. In a sample of 114 Vietnam veterans, Wilson and Zigelbaum10 noted a relationship between interpersonal assault, combat experience, and PTSD symptoms as well, but also failed to control for other variables associated with violent behavior.

 

PSTD as a Predictor of Post-Military Violence and Aggression

 

While the aformentioned studies examined combat exposure, violence, and antisocial behavior, they did not specifically explore the diagnosis of PTSD as a risk factor for these outcomes. Other studies of Vietnam veterans have examined this association in depth.

 

In the National Vietnam Veterans Readjustment Study (NVVRS), Kulka and colleagues11 found that male Vietnam veterans with PTSD reported an average of 13.3 acts of violence in the preceding year, in contrast to 3.5 acts of violence reported by Vietnam veterans who did not receive a PTSD diagnosis. However, in the original sample, veterans with PTSD had been exposed to greater levels of combat and had higher levels of post-Vietnam substance abuse. These variables were associated with increased violence and were not controlled for in the analysis, thus confounding interpretation of the association between PTSD per se, and violent acts.

 

Lasko and colleagues12 measured self-reported aggression using a number of previously validated instruments. Their sample included 27 male Vietnam veterans who met DSM-III-R13 Structural Clinical Interview criteria for PTSD,14 and 15 non-PTSD Vietnam veteran controls. Significant differences on nearly all psychometric measures of aggression were found with higher levels observed in the PTSD group. These differences were not explained by either level of combat exposure or history of substance abuse.

 

Mcfall and colleagues15 compared male Vietnam veterans seeking inpatient treatment for PTSD (N=228), to male psychiatric inpatients without PTSD (N=64), and to a community sample of Vietnam veterans with PTSD not undergoing inpatient treatment for violent behavior (N=273). Violent behavior included property destruction, physical fighting, and threats with and without weapons. After controlling for warzone variables, patients seeking inpatient treatment for PTSD were significantly more likely than psychiatric inpatients without PTSD to have engaged in one or more violent acts in the 4 months preceding hospitalization (P<.001). The PTSD inpatient group was more likely to endorse physical fighting (P<.01), threats of violence without a weapon (P<.01), or threats of violence with a weapon (P<.001), than the community sample. However, the small number of subjects without PTSD in the community sample precluded drawing distinctions between those patients with PTSD compared to those without PTSD. When considered in conjunction with the findings of Lasko and colleagues,12 the study provides supporting evidence of a relationship between PTSD and violent aggression independent of level of combat exposure. However, as in previously cited studies, the findings were essentially limited to males with combat-related PTSD.

 

Collins and Bailey16 examined a sample of 1,327 incarcerated male felons in the North Carolina prison system. No patients in the study developed PTSD from combat-related experience. Information from the Diagnostic Interview Schedule, Version III, was added to specific questions about demographics and criminal history in individual interviews and through a comprehensive review of State Department of Corrections and Bureau of Investigations records on each participant. Presence or absence of PTSD was recorded, as well as the temporal relationship between first PTSD symptom and six indicators of violence. The indicators of violence included history of multiple fights since 18 years of age, current incarceration or former arrests for rape or assault, and current incarceration or lifetime arrest for robbery. Of 1,140 subjects who agreed to participate and on whom sufficient data was available for analysis, 2.3% satisfied DSM-III criteria for PTSD. After controlling for demographic factors, race, antisocial personality, and problem drinking, the authors found that those who received a diagnosis of PTSD were significantly more likely to be currently incarcerated for homicide, rape, or assault (P<.001), or to have an arrest history for a violent offense in the year before incarceration (P<.001). The authors noted that among subjects who reported at least one PTSD symptom and at least one arrest for homicide, rape, or assault, 85% reported that their first PTSD symptom occurred in the same year of, or in the previous year to, their arrest. Despite the limited number of subjects who met criteria for PTSD, the authors noted that the stability of model results and the level of statistical significance suggested that PTSD—even when antisocial personality disorder was controlled for and when symptoms were unrelated to combat experience—was associated with subsequent violence.

 

A number of studies have sought to define the relationship of pre-military experience to warzone abusive violence (eg, participation in atrocities) and to subsequent development of PTSD. Laufer and colleagues17 examined data on 336 Vietnam combat veterans and found that combatants that participated in abusive violence or atrocities during the war were more likely to have enlisted rather than have been drafted, had higher rates of juvenile delinquency, and had dropped out of high school more frequently. In another NVVRS study, Kulka and colleagues18 examined childhood abuse, childhood problem behaviors, and antisocial personality before 18 years of age as potential predictors of later warzone violence. Self-report of pre-military difficulties were recorded on a Lichert scale and compared to six types of warzone abusive violence, which included torturing, wounding, or killing prisoners of war; terrorizing, wounding, or killing civilians; and mutilating of bodies. These types of violence were ultimately combined into a single magnitude variable. No significant correlations were found.

 

When Fontana and Rosenheck19 re-examined the NVVRS data for a relationship between being a prior victim of sexual abuse and warzone violence, no correlation was found. However, sexual abuse criteria were defined very broadly as “physical assault, torture, rape, mugging, or similar assault (not war related).” This diminished any understanding of the potential contribution of each component in the study (eg, individuals with a history of being mugged but not raped may have endorsed this abuse item). However, a second study of outpatient Vietnam veterans using the same database more carefully discriminated between childhood physical and sexual abuse items.19 When either was affirmed, frequency was measured on a Lichert scale. As in the first study, no correlations were found between abuse and violence in the warzone.

 

Finally, Hiley-Young and colleagues20 examined data on 207 consecutively admitted Vietnam veterans and assessed pre-military, warzone, and post-military experience. Complete data were available on 177 participants. High rates of childhood victimization, warzone violence, and post-military violence were found in the PTSD sample, as measured by the Minnesota Multiphasic Personality Inventory for PTSD subscale scores.21 Here, level of combat exposure predicted PTSD severity. Rates of childhood abuse were similar to those reported in previous epidemiologic studies of veterans with PTSD, but neither childhood abuse nor other childhood factors predicted warzone violence. Of the six measures of warzone abusive violence, only participation in mutilation was related to the development of PTSD (P<.01), and only participation in killing prisoners of war or civilians predicted post-military violence toward a spouse (P<.05) or others (P<.001). Participation in abusive violence did not predict post-military drug abuse, alcohol abuse, or criminality. The authors noted methodologic limitations due to the inadequacy of instruments available for measurement of PTSD, the use of single items to measure complex childhood variables, and ambiguities associated with subjective historical reports of violence related to enemy combatants versus civilians. Again, the fact that study subjects were all adult, male psychiatric inpatients with extensive combat exposure limits the generalizability to larger or mixed gender veteran populations.

 

Taken as a whole, these studies suggest that both pre-military antisocial behavior and, to some extent, combat exposure during wartime contribute to post-military antisocial behavior. The studies suggest that pre-military childhood experiences are not strong predictors of wartime abusive violence. However, small and selective samples, absence of control for substance abuse or previous antisocial behavior, and overly inclusive definitions of both causal factors and outcome measures limit both the generalizability of conclusions and the definitiveness with which they may be drawn.

 

Warzone Experience and Intimate Partner Violence

 

More recently, several studies have looked specifically at the relationship between battlefield deployment and subsequent spousal aggression and violence. Using structural equation modeling, Orcutt and colleagues22 examined the effects of warzone stressors and PTSD symptom severity on partner reports of male-perpetrated intimate partner violence in 376 Vietnam veteran couples. Investigators noted that perceived battlefield threat (not actual combat exposure), severity of PTSD symptoms, and a number of premilitary adverse experiences demonstrated direct relationships with subsequent intimate partner violence. Interestingly, after controlling for PTSD, a direct negative correlation between combat exposure and partner violence was demonstrated. This result suggested that battlefield exposures themselves may not contribute to interpersonal violence, absent the mediating effect of PTSD. However, certain warzone experiences (eg, participation in battlefield atrocities and killing) have been demonstrated to predict post-deployment spousal violence.20,23 McCarroll and colleagues24 compared deployed to non-deployed male soldiers and found that when age, race, and previous violence were controlled for, deployment to a non-combat environment did not predict domestic violence upon return home. As with the more general studies of post-deployment violence and antisocial behaviors, these studies suggest a considerable contribution of pre-military variables, direct effects of certain specific (but not all) warzone combat experiences, and an indirect contribution of these and other variables mediated through the development of PTSD.25

 

Relationship Between Warzone Trauma, PTSD, and Antisocial Behavior

An analysis of the extensive literature demonstrating that adverse childhood experiences predict subsequent development of PTSD (in military and civilian populations) and that these experiences correlate with a wide variety of antisocial and violent behavior is beyond the scope of this article. However, a recent examination of the potential mediating role that battlefield-specific PTSD (and not childhood experience) plays in the subsequent development of post-military antisocial behavior should be noted.

 

In an effort to examine the question of the etiology of post-military antisocial behavior through structural equation modeling, Fontana and Rosenheck26 recently reanalyzed data from the NVVRS in a manner that addresses several of the methodologic limitations of previous studies. With this approach, the total effects can be partitioned into those that are direct or unmediated by another variable, and those that are indirect or mediated by one or more other variables. All causal interpretations to be made of data are specified in advance and evaluated as a set. Such modeling cannot alter limitations of the associational data, but can provide an indication of how well a set of causal propositions fits the empirical associations within the data.27

 

In this study,26 a sample of 1,198 male Vietnam veterans were divided into two random subsamples of 599 patients each. The subsamples did not differ on demographics or on pre-determined causal variables, which included premilitary risk factors, traumatic exposure and disciplinary actions in the military, homecoming reception, PTSD and post-military substance abuse, and antisocial behavior. Each of the postulated causal variables was measured using summations of a variety of indicators within the NVVRS database. For example, substance abuse was derived from the Diagnostic Interview Schedule of alcohol abuse/dependence and drug abuse/dependence during the preceding 6 months, and homecoming reception was measured using the sum of three questions concerning the extent to which the American people made the veteran feel “at home again, respected . . . and proud,” and two scales of family support developed for the study.

 

By ordering the five causal variables according to their historic occurrence, pathways leading to antisocial behavior were generated in the two subsamples using an initial model (omitting PTSD and substance abuse) and an expanded model (including PTSD and substance abuse with the other causal variables). Amount of variance in antisocial behavior accounted for in the initial and expanded models differed by only 1%, but in the expanded model 55% of the total effects were attributed to the causal variables, and 30% of the total effect was attributed to PTSD and substance abuse. Both warzone exposure and homecoming reception contributed significantly to the development of PTSD in the causal model analysis. The investigators concluded that post-military antisocial behavior represented manifestations of a lifetime history of antisocial behavior far more than it reflected the after-effect of warzone experience. However, warzone trauma and homecoming reception, which contributed to the development of PTSD, contributed significantly to the variance in antisocial behavior observed. The authors acknowledged the limitations of the retrospective nature of historic data and reporting bias, particularly as they may affect models based on temporal occurrence and symptom self-reports of symptom severity and frequency.27 Although concerns related to overly inclusive definitions of variables are applicable here, the significant contribution of homecoming reception on the development of PTSD has also been replicated in other studies.28-30 The explanation of a mediating role for PTSD on antisocial behavior was consistent with the findings of Orcutt and colleagues22 in their study of PTSD and intimate partner violence.

 

Conclusion

 

Differences in the nature of deployment, combat, and warzone experiences of military service members currently deploying to Southwest Asia and eventually returning home may contribute to differences in the incidence and prevalence of PTSD and the course and progression of illness. Preliminary studies of the prevalence, severity, and natural history of PTSD in these veterans appear to support this observation.3 One such study of soldiers engaged in heavy combat in Iraq suggests that the rate of severe intimate partner violence reported 1 year after homecoming is considerably higher than the baseline rate of such violence in the non-deployed military population.31 As deployments and homecomings are ongoing, any analyses of the extent to which this generation of returning members of the armed forces engage in violent or otherwise antisocial behavior are now only preliminary. Anecdotal reports of interpersonal violence and substance abuse have garnered considerable media attention, but systemic analyses have been limited to comparisons of pre- and post-war rates of mood, anxiety disorders, suicide, and substance abuse. The extent to which the studies of post-deployment violence can be generalized to the current population of returning volunteer force veterans (including larger percentages of women, reservists, and national guardsman) is unclear. However, these studies suggest that, particularly in the population of veterans either actively seeking treatment or otherwise coming to clinical attention, antisocial behavior (including aggression, hostility, and interpersonal violence) will be an issue of concern. Interventions directed at identifying and treating individuals at risk should include treatment for PTSD. However, existing models of the relationship between combat experience, PTSD, and post-deployment antisocial behavior suggest that successful identification and treatment of veterans with PTSD from their battlefield experiences will not effectively engage the larger veteran population for whom post-deployment violence or antisocial behavior may also be a difficulty. PP

 

References

 

1. Leventman S. Epilogue: Social and Historical Perspectives on the Vietnam Veteran. In: Figley CR, ed. Stress Disorders Among Vietnam Veterans: Theory, Research and Treatment. New York, NY: Brunner/Mazel; 1978:291-295.

 

2. Wecter D. When Johnny Comes Marching Home. Cambridge, MA: Houghton Mifflin; 1944.

 

3. Grieger A, Benedek DM. Psychiatric disorders following return from combat duty during the twenty-first century. Primary Psychiatry. 2006;13(3):45-50.

 

4. Yesavage JA. Differential effects of Vietnam combat experiences vs. criminality on dangerous behavior by Vietnam veterans with schizophrenia. J Nerv Ment Dis. 1983;171(6):382-384.

 

5. Resnick HS, Foy DW, Donahoe CP, Miller EN. Antisocial behavior and post-traumatic stress disorder in Vietnam veterans. J Clin Psychol. 1989;45(6):860-866.

 

6. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.

 

7. Foy DW, Sipprelle RC, Rueger DB, Carroll EM. Etiology of posttraumatic stress disorder in veterans: analysis of premilitary, military, and combat exposure influences. J Consult Clin Psychol. 1984;52(1):79-87.

 

8. Wilson JP, Zigelbaum SD. Post-traumatic stress disorder and the disposition to criminal behavior. In: Figley CR, ed. Trauma and Its Wake: Traumatic Stress Theory, Research, and Intervention. Volume II. New York, NY: Brunner/Mazel; 1986:305-321.

 

9. Beckham JC, Feldman ME, Kirby AC, Hertzberg MA, Moore SD. Interpersonal violence and its correlates in Vietnam veterans with chronic posttraumatic stress disorder. J Clin Psychol. 1997;53(8):859-869.

 

10. Wilson JP, Zigelbaum SD. The Vietnam veteran on trial: the relation of post-traumatic stress disorder to criminal behavior. Behav Sci Law. 1983;(3):69-83.

 

11. Kulka RA, Schlenger WE, Fairbank JA, et al. Trauma and the Vietnam War Generation: Report of Findings from the National Vietnam Readjustment Study. New York, NY: Brunner/Mazel; 1990.

 

12. Lasko NB, Gurvits TV, Kuhne AA, Orr SP, Pitman RK. Aggression and its correlates in Vietnam veterans with and without chronic posttraumatic stress disorder. Compr Psychiatry. 1994;35(5):373-381.

 

13. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington, DC: American Psychiatric Association; 1987.

 

14. Spitzer RL, Williams JB. Structured Clinical Interview for DSM-III-R Non-Patient Version (Modified for Vietnam Veterans Readjustment Study 4/1/87). New York, NY: Biometric Research Department, New York State Psychiatric Institute; 1986.

 

15. McFall M, Fontana A, Raskind M, Rosenheck R. Analysis of violent behavior in Vietnam combat veteran psychiatric inpatients with posttraumatic stress disorder. J Trauma Stress. 1999;12(3):501-517.

 

16. Collins JJ, Bailey SL. Traumatic stress disorder and violent behavior. J Trauma Stress. 1990;3(2):203-220.

 

17. Laufer RS, Gallops MS, Frey-Wouters E. War stress and trauma: the Vietnam experience. J Health Soc Behav. 1984;25(1):65-85.

 

18. Kulka RA, Schlenger WE, Fairbank JA, et al. Contractual Report of Findings From the National Vietnam Veterans Readjustment Study. Research Triangle Park, NC: Research Triangle Institute; 1988.

 

19. Fontana A, Rosenheck R. Posttraumatic stress disorder among Vietnam Theater Veterans. A causal model of etiology in a community sample. J Nerv Ment Dis. 1994;182(12):677-684.

 

20. Hiley-Young B, Blake DD, Abueg FR, Rozynko V, Gusman FD. Warzone violence in Vietnam: an examination of premilitary, military, and postmilitary factors in PTSD in-patients. J Trauma Stress. 1995;8(1):125-141.

 

21. Hathaway SR. Minnesota Multiphasic Personality Inventory. San Antonio, TX: Psychological Corporation; 1967.

 

22. Orcutt HK, King LA, King DW. Male-perpetrated violence among Vietnam veteran couples: relationships with veteran’s early life characteristics, trauma history, and PTSD symptomatology. J Trauma Stress. 2003;16(4):381-390.

 

23. Taft CT, Pless AP, Stalans LJ, Koenen KC, King LA, King DW. Risk factors for partner violence among a national sample of combat veterans. J Consult Clin Psychol. 2005;73(1):151-159.

 

24. McCarroll JE, Ursano RJ, Liu X, et al. Deployment and the probability of spousal aggression by U.S. Army soldiers. Mil Med. 2000;165(1):41-44.

 

25. Marshall AD, Panuzio J, Taft CT. Intimate partner violence among military veterans and active duty servicemen. Clin Psychol Rev. 2005;25(7):862-876.

 

26. Fontana A, Rosenheck R. The role of war-zone trauma and PTSD in the etiology of antisocial behavior. J Nerv Ment Dis. 2005;193(9):203-209.

 

27. James LR, Mulaik SA, Brett J. Causal Analysis: Assumptions, Models, and Data. Beverly Hills, CA: Sage Publications; 1982.

 

28. Bolton EE, Litz BT, Glenn DM, Orsillo SM, Roemer L. The impact of homecoming reception on the adaptation of peacekeepers following deployment. Mil Psychol. 2002;14(3): 241-251.

 

29. Johnson DR, Lubin H, Rosenheck R, Fontana A, Southwick S, Charney D. The impact of homecoming reception on the development of posttraumatic stress disorder. The West Haven Homecoming Stress Scale (WHHSS). J Trauma Stress. 1997;10(2):269-277.

 

30. Solomon Z, Oppenheimer B. Social network variables and stress reaction lessons from the 1973 Yom-Kippur War. Mil Med. 1986;151(1):12-15.

 

31. Hoge C. The psychological aftermath of war: the land combat study at one year. Symposium presentation at: Annual Meeting of the International Society for Traumatic Stress Studies; November 3, 2005; Toronto, Ontario, Canada.

 

Return

Journal CMEs

Print Friendly 

Virtual Reality and Other Experiential Therapies for Combat-Related Posttraumatic Stress Disorder

James L. Spira, PhD, MPH, Jeffrey M. Pyne, MD, Brenda Wiederhold, PhD, Mark Wiederhold, MD, Ken Graap, MEd, and Albert Rizzo, PhD

Needs Assessment: Posttraumatic stress disorder (PTSD) is a common mental health problem among combat veterans. Given the current conflicts in Iraq and Afghanistan, the prevalence of combat-related PTSD is expected to increase. Various psychotherapies have been used to treat PTSD. The most effect psychotherapies appear to be cognitive behavioral and exposure therapies. Virtual-reality–assisted exposure therapy for combat-related PTSD is a new method for delivering exposure therapy and is currently being tested by the Department of Defense.

 

Learning Objectives:

 
  • List the three core symptom clusters of PTSD.
 
  • Identify the most effective psychotherapies for PTSD treatment.
 
  • Describe the use of virtual reality as an exposure therapy for PTSD.
 


Target Audience:
Primary care physicians and psychiatrists.

 

Accreditation Statement: Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

 

Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.

 

It is the policy of 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.

 

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 quiz. To obtain credits, you should score 70% or better. Termination date: March 31, 2008. The estimated time to complete all three articles and the quiz is 3 hours.

 

Return

Primary Psychiatry. 2006;13(3):58-64

 

Dr. Spira is clinical professor in the Department of Psychiatry at the University of California in San Diego and clinical director of the Casa Palmera Residential Treatment Program in Del Mar, California. Dr. Pyne is research health scientist at the Central Arkansas Veterans Healthcare System in North Little Rock. Dr. B. Wiederhold is executive director and Dr. M. Wiederhold is president of the Virtual Reality Medical Center in San Diego. Mr. Graap is president and CEO of Virtually Better, Inc., in Decatur, Georgia. Dr. Rizzo is research scientist and research assistant professor at the University of Southern California in Los Angeles.

 

Disclosure: Drs. Spira and Rizzo report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Pyne has received research support from the Department of Veterans Affairs Health Services Research and Development Service. Drs. B. and M. Wiederhold, and Dr. Graap have received research support from the Office of Naval Research.

 

Please direct all correspondence to: James L. Spira, PhD, MPH, 817 Mola Vista Way, Solana Beach, CA 92075; Tel: 619-807-4953; Fax: 858-792-7356; E-mail: JimSpira@aol.com.


 

 

Abstract

 

Numerous experiences can lead to acute stress disorder or posttraumatic stress disorder (PTSD) in military personnel. Unfortunately, PTSD is a relatively common outcome of combat exposure. The primary focus of this article is the role of experiential psychotherapy treatments which teach skill development to better cope with combat-related PTSD. The article focuses largely on virtual-reality–assisted exposure therapies.

 

Introduction

 

Numerous experiences can lead to acute stress disorder or posttraumatic stress disorder (PTSD) in military personnel. Combat-related experiences that can lead to PTSD include witnessing another service member being killed or wounded, feeling responsible for the death of a military member, being ambushed, a near death experience, and witnessing the death or wounding of civilians, including children. Each of these experiences is outside the range of what is considered normal human experience. In addition, PTSD appears to be more severe and longer lasting when the event is caused by human means and design, such as warfare.1

 

Combat-related PTSD may be a condition that existed from the start of humankind. The written history of PTSD dates back to the account of Achilles in The Iliad by Homer (800 B.C.). More recently in the United States, symptoms of PTSD have been described as “soldier’s heart” during the Civil War, “shell shock” during World War I, “combat fatigue” or “war neurosis” during World War II, and PTSD after the Vietnam War. The Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III),2 published the first diagnostic criteria for PTSD.

 

In a study of Vietnam veterans, 31% of men and 27% of women suffered from PTSD at some point since their return from the war.3 A few months after returning from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), 12.2% to 19.9% of Marine Corps personnel and 6.2% to 11.5% of Army personnel met diagnostic criteria for PTSD.4 The numbers of OIF and OEF service members with PTSD is expected to increase over time because delayed PTSD symptom onset has been shown in connection with other recent military conflict.5 This heightened rate of PTSD ia also due to the duration of conflict, the repeated and longer deployments, the unknown duration of deployment, the unconventional type of warfare, the increased use of reservists, and the increased risks for all military occupations.

 

According to the Veterans Healthcare Administration, the British National Health Service National Institute for Clinical Excellence, the American Psychiatric Association (APA), and recent expert panels,6-9 the current treatment recommendations for PTSD include the use of medication and psychotherapy. Each of these sources recommends selective serotonin reuptake inhibitors (SSRIs) as the first-line medication treatment for PTSD. However, the remission rates for combat-related PTSD remain low (20% to 30%) with the use of SSRIs.10 Despite the commonality of combination therapy in clinical practice, there are no published controlled trials comparing the efficacy of combination medication and psychotherapy to medication or psychotherapy alone.

 

This article briefly reviews the PTSD symptom clusters and medication treatments for PTSD. The primary focus is a review of psychotherapies for PTSD. The use of virtual reality (VR)-assisted exposure therapy for the treatment of combat-related PTSD will also be discussed.

 

PTSD Symptom Clusters

 

After experiencing a traumatic event, the three core PTSD symptom clusters include re-experiencing, avoidance/numbing, and hyperarousal. The re-experiencing symptoms include recurrent and intrusive distressing recollections of the event, recurrent distressing dreams of the event, flashbacks, intense psychologic distress when reminded of the event, and physiologic reactivity when reminded of the event. The avoidance/numbing symptoms include efforts to avoid thoughts, feelings, or conversations associated with the event; efforts to avoid activities, places, or people that are reminders of the event; inability to recall important aspects of the event; decreased interest in significant activities; feeling detachment from others; decreased range of affect; and sense of foreshortened future. The hyperarousal symptoms include problems sleeping, increased irritability, difficulty concentrating, hypervigilance, and exaggerated startle response.

 

Medication Treatments for PTSD by Symptom Cluster

 

The APA recommends SSRIs as the first-line medication treatment for all three PTSD symptom clusters.9 The evidence supporting the use of other classes of medications by PTSD symptom cluster was also summarized in a recent article.11 For example, tricyclic antidepressants were found generally effective except in relieving symptoms in the avoidance/numbing cluster. While monoamine oxidase inhibitors (MAOIs) were found generally effective, there is limited evidence about the effectiveness of the more tolerable reversible MAOIs. Benzodiazepines were generally ineffective for core PTSD symptom clusters, but may improve sleep. Anticonvulsants appeared more helpful for re-experiencing symptoms. Second-generation antipsychotics appeared helpful for all core PTSD symptom clusters. Adrenergic inhibitors may be useful as an early intervention to prevent the development of PTSD following a traumatic event, to decrease re-experiencing symptoms, or as an adjunctive treatment. However, in a recent meta-analysis, the overall effectiveness of medication management was found to be half as effective as psychotherapy and had twice the drop-out rate.12

 

Psychotherapy Treatments for PTSD

 

The psychotherapy options include preventive and treatment strategies. The psychotherapeutic preventive strategies following traumatic exposure include one-session critical incident stress debriefing (CISD) and cognitive-behavioral therapy (CBT). Two recent meta-analyses found no evidence to support the use of CISD to decrease psychologic distress or prevent the onset of PTSD.13,14 A limited number of well-designed studies demonstrate some success in preventing PTSD using a few sessions of CBT starting 2–3 weeks after the traumatic event.15,16

 

Psychotherapeutic treatment strategies extend along the continuum from therapies where the focus is more reflective, to therapies where the focus is more experiential and skill-based. Each of the therapies outlined below include reflective and experiential elements. More reflective therapies include interpersonal and psychodynamic therapies. Combination reflective and experiential therapies include CBT and dialectical behavioral therapy. More experiential and skill-based therapies include somatic (relaxation training and biofeedback), attentional (meditation), and exposure (flooding, graded exposure, eye movement desensitization reprocessing [EMDR], and hypnosis) therapies.

 

Reflective Psychotherapies

 

The well-structured interpersonal psychotherapy (IPT) was developed to address the interpersonal and social problems stemming from the development of a patient’s personality and is influenced by social interactions.17 Interpersonal and social problems often lead a patient with PTSD to seek treatment, and they often influence the symptom course. A pilot study of group-based IPT demonstrated improvement in social functioning but had limited effect on more PTSD-specific symptoms.18 Therefore, there is minimal evidence to support the use of IPT for the treatment of PTSD.19

 

Psychodynamic psychotherapy is less structured and has a long tradition in mental health treatment. A broad exploration of a patient’s underlying personality structure offers clarity to his or her response to life events, particularly to traumatic events. Psychodynamic formulations enhance understanding of the traumatic stress associated with PTSD, and are often incorporated into other treatment strategies used for the treatment of PTSD. In one controlled trial comparing brief psychodynamic psychotherapy, hypnotherapy, desensitization, and a wait-list control, all active treatment groups resulted in significant symptom improvement.20 Therefore, minimal evidence supports the use of psychodynamic psychotherapy in the treatment of PTSD.19

 

Combination Reflective and Experiential Psychotherapies

 

CBT targets the patient’s distorted threat appraisal assumptions in order to reverse dysfunctional thinking patterns that are associated with and perpetuate the PTSD symptom clusters. Through reflective dialogue, therapists help patients identify distorted automatic cognitive, affective, physiologic, and behavioral responses to current events, and focus instead on more rational responses appropriate to a given situation. Experiential homework is given to assist the patient in implementing what was discussed in therapy sessions. Proponents of CBT sometimes incorporate other therapeutic modalities, including aspects of the more experientially oriented therapies discussed below. Similar to psychodynamic and interpersonal approaches, therapists using a CBT approach often examine underlying factors that may influence current responses to traumatic events, such as core beliefs about oneself or the world. In the case of PTSD, many CBT therapists also have the patient describe the traumatizing event while utilizing relaxation techniques; this can be considered a mild form of exposure therapy. CBT can be conducted in group or individual formats. However, there are fewer group CBT studies than individual ones, and no studies comparing group and individual CBT.21 The evidence base for PTSD CBT is supported by a number of controlled studies.19

 

Dialectical behavioral therapy (DBT) is a structured psychotherapy specifically developed for the treatment of borderline personality disorder. The combination of borderline personality disorder and PTSD is referred to as complex PTSD. Borderline personality disorder often develops within the context of childhood abuse or neglect and is a known risk factor for developing PTSD related to a traumatizing event later in life. DBT combines reflective cognitive and experientially-based skill development by focusing on affect regulation, distress tolerance, and principles of mindfulness meditation to address distressing symptoms and behavior. While DBT has been used clinically in PTSD patients, the evidence base is limited to only case reports at this time.19

 

Experiential Psychotherapies

 

Experiential psychotherapies use non-reflective methods within a reflective psychotherapeutic context (usually CBT-based). These therapies focus on developing attentional control and autonomic regulation, in an attempt to gain mastery over troublesome symptoms. The more experiential therapies can be divided into somatic (eg, autonomic regulation through relaxation training and biofeedback), attentional (eg, meditation, developing control over cognitive processing), and exposure (eg, flooding, graded exposure, EMDR, hypnosis). As is true of all the psychotherapies, there is considerable overlap across the reflective-to-experiential continuum, and there is also considerable overlap among the components of the more experientially oriented therapies.

 

Many popular treatments for PTSD include a skill-based somatic component. Relaxation exercises have a physical (autonomic) emphasis. Typically, patients are trained to reduce the sympathetic arousal associated with PTSD symptoms and enhance parasympathetic recuperation using progressive muscle relaxation and slow abdominal breathing with or without biofeedback. There is no evidence to support relaxation training as an independent intervention, but it is often incorporated as an aspect of CBT, exposure therapy, or attentional interventions.

 

Biofeedback can be useful as a method of self-regulation. Practiced for more than 40 years, there are a variety of approaches to biofeedback. Using the oldest forms, the patient watches a monitor or listens to a tone that reflects autonomic arousal as measured by skin temperature, skin conductance, muscle tension, respiratory rate, and/or heart rate. Patients are told to manipulate the monitor (sound or graphic) by any means they can (eg, recall or imagining a pleasant scene or slow abdominal breathing). Rather than simply instructing the patient to “make the tone go up” any way possible, modern-day biofeedback practitioners continually monitor the physiologic data and suggest attentional and somatic exercises for the patient’s use. In this way, the relaxation approach is tailored to each patient. Such physiologic monitoring and feedback is a useful tool in conjunction with other interventions (including VR-graded exposure therapy, described below) to continually monitor objective arousal in patients with PTSD and assist patients in regaining a sense of mastery over their symptoms.22 No evidence supports the use of biofeedback interventions alone in the treatment of PTSD.

 

Attentional therapies employ various meditative traditions, which emphasize different aspects of attention. For example, Zen meditation emphasizes signal enhancement, ie, attending to and becoming absorbed in what one sees, hears, feels, and smells at each moment. When thoughts arise, practitioners note that “noise,” let it go, and returns to the sensations (“signal”) at hand. Vipassana (mindfulness) meditation emphasizes noise reduction. In other words, a person should notice what thoughts and feelings arise, but should not react to it or judge it. A person should simply notice what arises, passively attend to it until it dissipates, and then return to the moment at hand (such as feeling the breath flow in and out, or continuing with one’s work activity). These practices are complementary, merely emphasizing different aspects of the same principle.

 

Meditative traditions share with CBT the belief that cognitive processes drive affective, physiologic, and behavioral reactivity. However, while CBT focuses on underlying belief systems as the cause of current dysfunction, meditative traditions emphasize mastery over fundamental cognitive processes or attentional retraining (eg, whatever one attends to, one enhances). Indeed, when patients attend to a distressing thought or feeling, their sympathetic arousal is significantly increased. By contrast, when engaged in Zen meditation (attending to what they see, hear, and feel), patients significantly reduce their sympathetic arousal, even without controlling their breathing or otherwise consciously manipulating their physiology.23,24 While research on the effectiveness of meditation alone for PTSD is lacking, clinically it appears to be helpful when used in combination with other approaches.

 

Exposure-based therapy helps patients decrease fear response to internal and external cues that would otherwise cause symptom intensification. Exposure therapy is based on emotional processing theory (EMT). Applying EMT to PTSD, fear memories are stored as a “fear structure” and include psychologic and physiologic information about stimuli, meaning, and responses.25 Once accessed and emotionally engaged, the fear structure is then open to modification and, if treated appropriately, over time will result in habituation and extinction of the fear response. Common approaches to exposure therapy include flooding, graded exposure, EMDR, tolerating narrative report of the traumatic event, and hypnosis.

 

Flooding exposure therapies present the patient with as much stimulation as possible, and have the patient sustain attention to that stimulation until it begins to extinguish, (usually in approximately 20 minutes). Several theories support the use of flooding-type exposure. Classical conditioning is the original theoretical basis of this approach, where the conditioned stimulus (loud sound, internal memory) is no longer paired with a conditioned response (fear arousal), and therefore the conditioned response extinguishes over time. Case studies using flooding exposure therapy have reported mixed results.26-28 Therefore, the evidence base for flooding therapy lacks strength at this time.

 

Graded exposure therapy attempts to elicit arousal at the level the patient can tolerate and then increase exposure gradually over time as the patient learns skills to modulate arousal. This approach is most often coupled with a skill-based de-arousal method, such as relaxation training (progressive muscle relaxation, biofeedback), distancing (hypnosis, visual imagery), and/or attentional retraining (Zen or Vipassana meditation). Graded exposure can include imaginal, in vivo, or VR exposure techniques. To date, the most commonly used graded exposure technique used for PTSD treatment is imaginal exposure. VR-graded exposure is discussed in more detail below.

 

EMDR most typically involves the patient focusing on a disturbing memory while the therapist initiates saccadic eye movements by asking the patient to track the horizontal motion of the therapist’s rapidly moving finger. Following the therapist’s finger movement is thought to disassociate memories from associated emotions. In studies with and without the saccadic eye movements, it is unclear that the eye movements are necessary for treatment efficacy.29 A meta-analysis of EMDR and other exposure techniques found no significant differences in outcomes.30 At this time, the evidence base for EMDR treatment of PTSD shows it to be at least equivalent to CBT and in some cases to other exposure therapies.19

 

Hypnotherapy using light or deep trance techniques has been used clinically for decades to treat combat-related stress disorders.31 Typically, the patient is induced into a comfortable, relaxed mental and physical state while simultaneously reviewing and distancing from the traumatic episode. Thus, the patient learns to dissociate the traumatic event from arousing sequelae. However, results from controlled studies are unavailable at this time.32 Therefore, there is minimal evidence to support the use of hypnotherapy for the treatment of PTSD.

 

In summary, exposure-based therapies (including CBT with exposure) have been found to be the most effective form of treating PTSD.33 van Etten and Taylor12 analyzed 61 treatment trials that included pharmacotherapy and modalities such as behavior therapy (particularly exposure therapy), EMDR, relaxation training, hypnotherapy, and dynamic psychotherapy. Specifically, the effect size for all types of psychotherapy interventions was 1.17 compared with 0.69 for medication, and the mean dropout rate in medication trials was 32% compared with 14% in psychotherapy trials. Additionally, this meta-analysis found that exposure therapy was more efficacious than any other type of treatment for PTSD according to clinician-rated measures.

 

Virtual Reality-Assisted Exposure Therapy

 

VR can be used to deliver graded exposure or flooding exposure therapies. Graded exposure therapy has been used clinically for a variety of anxiety disorders.34,35 There are advantages of VR exposure over imaginal exposure. Therapist control over the exposure presented and VR exposure does not rely upon individual imagery ability or even the ability of the patient to verbalize his or her experiences (although the ability to talk about the traumatic event(s) can be utilized within a VR environment to increase personal relevancy and increase arousal). Many patients are unwilling or unable to effectively visualize the traumatic event. In fact, avoidance of reminders of the trauma is inherent in PTSD and is one of the defining symptoms of the disorder.36 One disadvantage of the use of VR exposure for PTSD is that the VR environment is content specific and must be developed for a particular context. The evidence base for use in combat-related PTSD treatment at this time is limited to case studies,37,38 but will be expanding with treatment trials described below that are currently underway and supported by the Department of Defense.

 

A VR environment can be used to present both general and specific stimuli to patients in order to assist them in reducing reactivity to the traumatic event. A general VR environment (eg, Iraqi village) is often sufficient to elicit a general reminder of the arousal experienced during deployment. Additionally, if the VR environment allows for operator control over a repertoire of various optional stimuli, then a graded exposure of relevant arousing stimuli can be individually tailored to allow for an arousal hierarchy to be developed and presented to each patient. For example, a Marine who conducted night operations may not get sufficiently aroused in a daytime environment. Similarly, a Navy Construction Battalion (Sea Bee) driver may require a convoy scenario to elicit arousal. Since the goal is to teach mastery over cognitive, affective, and physiologic arousal, the ability to generate arousal is critical for successful treatment. An optimal VR environment would therefore contain a general reminder of the deployment and have a range of options that the therapist can employ to bring out an arousal more specific to each patient’s unique experience.

 

Other aspects of VR environments important to treatment include realism, immersion, and interaction. Although technology has been steadily improving with regard to video graphics and VR in particular, it is unnecessary that the environment be completely “realistic.” Various VR studies have shown that exact reproductions are unnecessary to elicit anxiety.39 If the VR environments are similar enough to the index traumatic events, then it should be possible to trigger emotional responses similar to those which may have occurred originally, thereby providing access to the memories of the trauma. In the future, degree of realism (eg, the addition of vibration, scent, and other stimuli to the VR) will likely enhance the options available to clinicians and provide greater coverage of traumatic situations.

 

Immersion appears to be related to the degree of arousal that can be achieved with a given exposure. Using a head mount with the greatest clarity, viewing range, and comfort, along with the patient’s ability to see the environment move along with head or body movements, allows the patient greater immersion and perhaps greater arousal. Sounds presented through headphones are also a critical element for improved immersion. It is also possible to enhance immersion by placing a vibration platform underneath the patient (eg, to vibrate with helicopters going overhead, rockets exploding), matching climate (eg, dry heat blowing on the patient), or even using a machine to present smells to the patient (eg, burning rubber, gun powder). In theory, the more sensory modalities stimulated, the greater the immersion.

 

Another factor that effects immersion is the degree to which a patient can interact with the VR environment. Usually, the patient will use a joystick or computer mouse to navigate through the environment and move his or her head to change the visual field. The level of patient interaction with the VR environment is another aspect of exposure that the therapist can utilize to influence arousal.

 

Two Department of Defense-funded studies are underway to examine the use of VR therapies for combat-related PTSD. One study will utilize a graded exposure approach in a randomized controlled design, and the other will utilize a flooding approach in a case series design. In both studies (as described below), the primary outcomes will be symptom severity, physiologic reactivity to a test VR environment, and health-related quality of life.

 

Eighteen marine and navy personnel recently diagnosed with combat-related PTSD and receiving outpatient mental health treatment were interviewed by the authors of this article in order to develop the general and specific content for the VR environments. Specifically, patients were asked about the precise sights, sounds, smells, and feelings associated with the recurring intrusive thoughts they experienced upon returning from their combat tours. This information was then used to create VR environments for use with medical and Marine Corps personnel. Some relevant specific stimuli that can be turned on or off as needed include voices of Iraqi civilians, Arabic prayer, sounds of gunfire, rocket’s fired and exploding, helicopters flying overhead or landing, terrorists running and firing guns, comrades being wounded by gunfire, buildings and vehicles burning, and driving through dangerous areas.

 

In the flooding VR exposure study, the therapist will ask the patient to relate his or her narrative of the sentinel traumatic event or sequence of events and then presents the patient with VR stimuli sufficient to maintain a high level of arousal for at least 20 minutes. All patients will also be treated with an SSRI prescribed by their mental health provider. It is critical to not over-arouse the patient to the extent of cognitive dissociation, emotional shutdown, or being overwhelmed during or after the session. The therapist will also record the patient narrative and the sounds of the VR environment during the VR session so that the patient can continue to listen to the recording daily in between sessions, in order to facilitate the extinguishing of arousal. In a small, single-group design study of Vietnam veterans with chronic combat-related PTSD, the use of a similar protocol twice a week for 6 weeks proved beneficial in reducing PTSD symptoms.38

 

In the graded exposure VR study, the authors of this article will determine the relative value of 10 weekly sessions of VR graded exposure plus SSRI treatment compared to 10 weekly group CBT sessions plus SSRI treatment. The VR graded exposure therapy will incorporate Zen absorption techniques to focus comfortably into the moment (attentional retraining) and Vipassana internal noise reduction techniques to distance arousing thoughts and feelings. The graded exposure VR intervention will also incorporate biofeedback to monitor physiologic response so that the therapist can both better determine when a patient is becoming aroused, and train the patient to modulate these responses. Over the past 5 years, heart rate variability (HRV) has become the indicator of choice for many biofeedback therapists and those who wish to monitor physiologic reactivity in their patients or research subjects.24 In particular, the very low frequency (VLF)/low frequency (LF) ratio (part of the HRV spectral analysis) is the best single indicator of when a patient is focused comfortably in the moment without significant cognitive/affective/physiologic arousal. Simply, when VLF is >50% the LF, the therapist should instruct the patient to relax and focus in the moment. If this is impossible for the patient, the therapist should reduce the intensity of the VR stimulus. When the VLF is <50% the LF, the patient is calmer and more relaxed, and the VR stimuli can be increased so that the patient has more opportunity to practice experiential methods of self-regulation. As the patient becomes more skilled at modulating physiologic response to the VR environment, the patient will gain a sense of mastery over arousal, develop confidence to be able to handle even more arousal, and re-establish the calm and relaxed state as his or her natural baseline. As with other exposure therapies, the goal is to generalize these skills into everyday activities. At this time, it is unknown which patients will be more likely to benefit from VR-assisted exposure therapies or how best to integrate VR therapies with other existing treatments for PTSD.

 

Conclusion

 

Existing medications and psychotherapies are helpful in the treatment of PTSD. However, there is still a need to improve the outcomes for patients with PTSD, including combat-related PTSD. Experiential psychotherapies utilized within a therapeutic framework are promising additions to existing approaches. Ongoing studies testing VR-assisted interventions will help define the role of novel VR interventions in the treatment of combat-related PTSD. PP

 

References

 

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

 

2. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.

 

3. Schlenger WE, Kulka RA, Fairbank JA, Hough RL, Jordan BK, Marmar CR. The prevalence of post-traumatic stress disorder in the Vietnam generation: A multimethod, multisource assessment of psychiatric disorder. J Trauma Stress. 1992;5(3):333-363.

 

4. Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Eng J Med. 2004;351(1):13-22.

 

5. Gray MJ, Bolton EE, Litz BT. A longitudinal analysis of PTSD symptom course: delayed-onset PTSD in Somalia peacekeepers. J Consult Clin Psychol. 2004; 72(5):909-913.

 

6. VHA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder in Adults. Available at: www.oqp.med.va.gov/cpg/MDD/MDD_GOL.htm. Accessed January 30, 2006.

 

7. The expert consensus guideline series. Treatment of posttraumatic stress disorder. The expert consensus panels for PTSD. J Clin Psychiatry. 1999;60(suppl 16):3-76.

 

8. Foa EB, Keane TM, Friedman MJ. Effective Treatments for PTSD: Practice Guidelines from the International Society for Traumatic Stress Studies. New York, NY: The Guilford Press; 2000.

 

9. Ursano RJ, Bell C, Eth S, et al. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Am J Psychiatry. 2004;161(11 suppl):3-31.

 

10. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry. 2002;159(10):1777-1779.

 

11. Schoenfeld FB, Marmar CR, Neylan TC. Current concepts in pharmacotherapy for posttraumatic stress disorder. Psychiatr Serv. 2004;55(5):519-531.

 

12. van Etten ML, Taylor S. Comparative efficacy of treatments for posttraumatic stress disorder: a meta-analysis. Clin Psych and Psychotherapy. 1998;5:126-144.

 

13. van Emmerik AA, Kamphuis JH, Hulsbosch AM, Emmelkamp PM. Single session debriefing after psychological trauma: a meta-analysis. Lancet. 2002;360(9335):766-771.

 

14. Rose S, Bisson J, Churchill R, Wessely S. Psychological debriefing for preventing post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2001;(3):CD000560.

 

15. Bryant RA, Sackville T, Dang ST, Moulds M, Guthrie R. Treating acute stress disorder: an evaluation of cognitive behavior therapy and supportive counseling techniques. Am J Psychiatry. 1999;156(11):1780-1786.

 

16. Bryant RA, Moulds ML, Nixon RV. Cognitive behaviour therapy of acute stress disorder: a four-year follow-up. Behav Res Ther. 2003;41(4):489-494.

 

17. Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES. The interpersonal approach to understanding depression. In: Klerman GL, Rounsaville BJ, eds. Interpersonal Psychotherapy of Depression. New York, NY: Basic Books; 1984:51-69.

 

18. Robertson M, Rushton PJ, Bartrum D, Ray R. Group-based interpersonal psychotherapy for posttraumatic stress disorder: theoretical and clinical aspects. Int J Group Psychother. 2004;54(2):145-175.

 

19. Robertson M, Humphreys L, Ray R. Psychological treatments for posttraumatic stress disorder: recommendations for the clinician based on a review of the literature. J Psychiatr Pract. 2004;10(2):106-118.

 

20. Brom D, Kleber RJ, Defares PB. Brief psychotherapy for posttraumatic stress disorders. J Consult Clin Psychol. 1989;57(5):607-612.

 

21. Ruzek JI, Young BH, Walser RD. Group treatment of posttraumatic stress disorder and other trauma-related problems. Primary Psychiatry. 2003;10(8):53-57.

 

22. Wiederhold BK, Jang DP, Kim SI, Wiederhold MD. Physiological monitoring as an objective tool in virtual reality therapy. Cyberpsychol Behav. 2002;5(1):77-82.

 

23. Spira J. Using meditation and hypnosis to modify eeg and heart rate variability. Paper presented at: 35th Annual Meeting of the American Association of Biofeedback and Psychophysiology; April 1-4, 2004; Colorado Springs, CO.

 

24. Spira J, Kotay A. Influence of relaxation and stress on very low frequency heart rate variability. Paper presented at: 35th Annual Meeting of the American Association of Biofeedback and Psychophysiology; April 1-4, 2004; Colorado Springs, CO.

 

25. Foa EB, Kozak MJ. Emotional processing of fear: exposure to corrective information. Psychol Bull. 1986;99(1):20-35.

 

26. Keane TM, Kaloupek DG. Imaginal flooding in the treatment of a posttraumatic stress disorder. J Consult Clin Psychol. 1982;50(1):138-140.

 

27. Keane TM, Fairbank JA, Caddell JM, Zimering RT. Implosive (flooding) therapy reduced symptoms of PTSD in Vietnam combat veterans. Behav Therapy. 1989;20(2):245-260.

 

28. Pitman RK, Orr SP, Altman B, et al. Emotional processing and outcome of imaginal flooding therapy in Vietnam veterans with chronic posttraumatic stress disorder. Compr Psychiatry. 1996;37(6):409-418.

 

29. Cahill SP, Carrigan MH, Frueh BC. Does EMDR work? And if so, why?: a critical review of controlled outcome and dismantling research. J Anxiety Disord. 1999;13(1-2):5-33.

 

30. Davidson PR, Parker KC. Eye movement desensitization and reprocessing (EMDR): a meta-analysis. J Consult Clin Psychol. 2001;69(2):305-316.

 

31. Watkins JG. The psychodynamic treatment of combat neuroses (PTSD) with hypnosis during World War II. Int J Clin Exp Hypn. 2000;48(3):324-335.

 

32. Cardena E. Hypnosis in the treatment of trauma: a promising, but not fully supported, efficacious intervention. Int J Clin Exp Hypn. 2000;48(2):225-238.

 

33. Foa EB. Psychosocial treatment of posttraumatic stress disorder. J Clin Psychiatry. 2000;61(suppl 5):43-48.

 

34. Wiederhold BK, Gevirtz R, Spira J. Virtual reality exposure therapy vs. imagery desensitization therapy in the treatment of flying phobia. In: Riva G, Galimberti C, eds. Towards CyberPsychology: Mind, Cognition, and Society in the Internet Age. Amsterdam: IOS Press; 2001:254-272.

 

35. Moore K, Wiederhold BK, Wiederhold MD, Riva G. Panic and agoraphobia in a virtual world. Cyberpsychol Behav. 2002;5(3):197-202.

 

36. Difede J, Hoffman HG. Virtual reality exposure therapy for World Trade Center post-traumatic stress disorder: a case report. Cyberpsychol Behav. 2002;5(6):529-535.

 

37. Rothbaum BO, Foa EB. Exposure Therapy for PTSD. National Center for PTSD Newsletter. 1999;10(2).

 

38. Rothbaum BO, Hodges LF, Ready D, Graap K, Alarcon RD. Virtual reality exposure therapy for Vietnam veterans with posttraumatic stress disorder. J Clin Psychiatry. 2001;62(8):617-622.

 

39. Hodges LF, Rothbaum BO, Alarcon RD, et al. A virtual environment for the treatment of chronic combat-related post-traumatic stress disorder. Cyberpsychol Behav. 1999;2(1):7-14.

 

Return

Column

Print Friendly 

Computer Physician Order Entry: To Implement or Not?

John S. Luo, MD

Return

Primary Psychiatry. 2006;13(3):19-21

 

Dr. Luo is assistant clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California in Los Angeles; past president of the American Association for Technology in Psychiatry (AATP) in New York City; and Gores Informatics Advocacy chair at the AATP.


 

 

An Institute of Medicine report1 in 2000 cited two large studies indicating an average of 3% medical error incidences in New York, Utah, and Colorado. In Utah and Colorado, 6.6% of these adverse events led to death, compared to 13.6% of adverse events in New York. The economics of preventable medical errors is staggering, ranging from $17–$29 billion due to loss of income and household production, disability, and healthcare costs. The Leapfrog Group,2 which includes organizations that leverage their healthcare purchasing power to encourage patient safety, quality, and customer value, uses computer physician order entry (CPOE) as an important measure toward patient safety in hospitals. Given that illegible handwriting might be open to misinterpretation, hospital systems see CPOE as a viable solution to reduce errors in prescriptions and medical orders. However, implementation of CPOE is not necessarily quick or easy. Cedars Sinai Hospital in Los Angeles abandoned their CPOE program in January 2003 when 400 physicians complained that it was difficult, time-consuming, and posed risks to patient safety. The hospital has no plans to try to implement a new CPOE program until sometime after 2006.3 CPOE is a conceptually good idea, but it is difficult to implement. A more than cursory assessment of CPOE will clarify whether your organization is ready.

 

What is CPOE?

 

CPOE is difficult to implement. Although most healthcare systems utilize computerized medication or laboratory orders in some form, the goal of using physicians for order entry is not to add to their administrative burden, nor is it to reduce costs by decreasing the number of inpatient ward clerks. Basic CPOE ensures standardized, legible, and complete orders by only accepting typed orders in a standard format. CPOE systems are implemented with varying degrees of an integrated clinical decision support system (CDSS) that alerts the physician of a medication dosing error or potential drug interaction.4 Basic clinical decision support may include suggestions or default values for drug doses, routes, and frequencies. A more sophisticated CDSS can perform drug allergy checks, drug-laboratory value checks, and drug-drug interaction checks, and can provide reminders about corollary orders such as prompting the user to order lithium levels after ordering lithium.5 Traditional inpatient wards also utilize nursing staff who often scrutinize medication and laboratory orders for clarification when their clinical judgment and experience tells them that something appears amiss. In teaching hospitals, this role to check and validate orders is often crucial when resident physicians are clinically inexperienced with medication dosing strategies.

 

Benefits and Limitations of CPOE

 

CPOE systems are challenging to implement, but the projected benefits are real. CPOE has been demonstrably effective in improving both efficiency and accuracy of orders.6

 

Bates and colleagues,7 and Cullen and colleagues,8 in their reviews of CPOE and CDSS on medication errors, established that these systems can reduce serious medication errors by 55%. Additionally, there was a 17% decrease in adverse drug events, and as the study progressed, the frequency decreased. Jha and colleagues,9 in 1998 reported that CPOE identified more adverse drug events, but not at a statistically significant difference. Ozdas and colleagues10 demonstrated that CPOE-based initial order sets which implement standardized acute coronary syndrome recommendations for acute myocardial infraction significantly increased the number of patients who received aspirin.

 

In contrast to the popular opinion that CPOE has benefits for reduction of adverse drug events, Berger and Kichak11 challenge the Institute of Medicine1 report on rates of adverse events, as well as the conclusions of the Bates studies.6,7 The authors11 indicate that the rates of adverse events based on studies in the 1980s was flawed due to lack of control groups, and that there were other methodologic flaws. King and colleagues12 demonstrated that CPOE generated a 40% decrease in medication error rates, but no actual difference in morbidity or mortality was shown. Berger and Kichak11 also highlighted conflict of interest in the Leapfrog Group, where 10% of the companies are involved in sales of software or hardware to healthcare organizations. In a review of the literature in 2003, Oren and colleagues13 noted that despite the published evidence on the effects of CPOE and other technologies such as automated dispensing machines, bar coding, and computerized medication administration records, the literature supporting the impact of these technologies in the reduction of medication errors and adverse drug events was limited because many of these systems could not be generalized to other systems. King and colleagues,12 in a cohort retrospective study of CPOE use on a pediatric inpatient ward, found a 40% reduction in medication error rate, but not in improved adverse drug events.

 

Significant Barriers

 

Implementation of a CPOE system evokes strong emotion, as identified in a qualitative study by Sittig and colleagues.14 In this study, a secondary analysis was done on previously collected qualitative data sets from interviews and observations of individuals where CPOE was implemented. The authors note that negative emotional responses were the most prevalent of the observations, and the number of positive emotions was quite small. An interesting conclusion from this study was that most of the negative emotions were based on how the system provided negative feedback, such as a failure to complete a task or erroneous actions. The authors surmise that a positive feedback system, which provides education and congratulatory messages, may help physicians react differently to the system by recognizing how CPOE helps them to achieve their own objectives of quality care. In a survey of 143 Johns Hopkins School of Medicine students, Knight and colleagues15 demonstrated that 95% of medical students thought that CPOE would help them learn what types of tests and treatments their patients needed. However, limitations were due to housestaff and faculty not wanting students to enter orders, because it would require extra time spent training and reviewing the orders.

 

A more distressing issue is how new errors arise with information technology in healthcare. Based on qualitative study of CPOE in four hospital systems, Ash and colleagues16 highlight two types of errors—those which occur in the process of entering and retrieving information, and errors in the communication and coordination process. The authors note that many computer systems are not well designed. Thus, providers are required to direct and isolate their attention in order to avoid juxtaposition errors. Such errors are often due to choosing a selection on the screen that is close to the correct, desired selection. In addition, the highly structured data needs of CPOE systems do not fit into the “flow” of human thinking, which is geared more toward free text. Therefore, such shifts to check all of the boxes on the screen may create a loss of perspective on the patient and fragment the focus on care. In terms of communication and coordination, some problems are inherent in the way that a CPOE system is often inflexible, forcing physicians to work in a linear and structured fashion. Urgency in such a structured system could prevent nurses from executing stat orders to be charted later. Feedback via communication with other healthcare professionals is often critical, and a CPOE may falsely limit the discussion among professionals because it was assumed that everyone saw it in the system. These new errors are not the result of poor computer programming, but are rather due to poor design or poor implementation of a CPOE system (Table).

 

Implementation Issues

 

The decision to implement a CPOE system is not simply a matter of deciding that it is a good idea for improving quality of care and patient safety. Ash and colleagues,17 members of the Oregon Health & Science University’s Physician Order Entry Team, interviewed thirteen experts from around the globe for the purpose of developing recommendations for CPOE implementation.

 

Clearly, successful implementation requires more than administration approval, as evidenced by Cedar Sinai’s experience of CPOE termination without physician buy-in. Multiple factors, including workflow, cost, change-management principles, vendor readiness, long-term support, continued evaluation and education, and integration into work flow must be addressed and constantly monitored.18

 

Conclusion

 

CPOE, using computers to enter orders directly, appears to be a simple solution for reducing errors. However, converting from paper to computer is not a simple matter. An underlying system of checks and balances exists with other care providers such as nursing and pharmacists who play a significant role in the oversight process. Clinical decision support systems are necessary to make CPOE more successful in catching errors and changing behavior to implement guidelines. Addressing human factors and emotional response to change are crucial in the successful adoption of the CPOE system. Seamless integration into the workflow process is necessary to reduce resistance. CPOE at the present time appears to be a great idea, but it is a complex process. With improved mobile computer technology, secure wireless communication, and standardized information exchange between various healthcare computer systems, CPOE may find its way into medical practice on a standard basis. PP

 

References

 

1. Corrigan JM, Kohn LT, Donaldson MS. To Err Is Human: Building a Safer Health System. Washington, DC: National Academies Press; 2000.

 

2. The Leapfrog Group. Available at: http://www.leapfroggroup.org. Accessed February 9, 2006.

 

3. Morrissey J. Harmonic divergence. Cedars-Sinai joins others in holding off on CPOE. Mod Healthc. 2004;34(8):16.

 

4. Osheroff JA, Pifer EA, Teich JM, Sittig DF, Jenders RA. Improving Outcomes with Clinical Decision Support: An Implementer’s Guide. Chicago, IL: Health Information Management and Systems Society; 2005.

 

5. Kaushal R, Bates DW. Computerized physician order entry (CPOE) with clinical decision support systems (CDSSs). In: Wachter RM. Making Health Care Safer: A Critical Analysis of Patient Safety Practices. Evidence Report/Technology Assessment no. 43l. Agency for Healthcare Research and Quality. Contract No. 290-97-0013; 2001. Available at: http://www.ahrq.gov/clinic/ptsafety/chap6.htm. Accessed February 9, 2006.

 

6. Bates DW, Leape LL, Cullen DJ, et al. Effect of a computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA. 1998;280(15):1311-1316.

 

7. Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA. 1995;274(1):29-34.

 

8. Cullen DJ, Sweitzer BJ, Bates DW, Burdick E, Edmondson A, Leape LL. Preventable adverse drug events in hospitalized patients: a comparative study of intensive care and general care units. Crit Care Med. 1997;25(8):1289-1297.

 

9. Jha AK, Kuperman GJ, Teich JM, et al. Identifying adverse drug events: development of a computer-based monitor and comparison with chart review and stimulated voluntary report. J Am Med Inform Assoc. 1998;5(3):305-314.

 

10. Ozdas A, Speroff T, Waitman LR, Ozbolt J, Butler J, Miller RA. Integrating best of care protocols into clinicians’ workflow via care provider order entry: impact on quality of care indicators for acute myocardial infarction. J Am Med Inform Assoc. 2005. Available at: http://www.jamia.org/cgi/reprint/M1656v1. Accessed February 9, 2006.

 

11. Berger RG, Kichak JP. Computerized physician order entry: helpful or harmful? J Am Med Inform Assoc. 2004;11(2):100-103.

 

12. King WJ, Paice N, Rangrej J, Forestell GJ, Swartz R. The effect of computerized physician order entry on medication errors and adverse drug events in pediatric inpatients. Pediatrics. 2003;112(3 Pt 1):506-509.

 

13. Oren E, Shaffer ER, Guglielmo BJ. Impact of emerging technologies on medication errors and adverse drug events. Am J Health Syst Pharm. 2003;60(14):1447-1458.

 

14. Sittig DF, Krall M, Kaalaas-Sittig J, Ash JS. Emotional aspects of computer-based provider order entry: a qualitative study. J Am Med Inform Assoc. 2005;12(5):561-567.

 

15. Knight AM, Kravet SJ, Harper GM, Leff B. The effect of computerized provider order entry on medical student clerkship experiences. J Am Med Inform Assoc. 2005;12(5):554-560.

 

16. Ash JS, Berg M, Coiera E. Some unintended consequences of information technology in health care: the nature of patient care information system-related errors. J Am Med Inform Assoc. 2004;11(2):104-112.

 

17. Computerized Physician/Provider Order Entry Team. Available at: http://www.ohsu.edu/dmice/research/cpoe/index.shtml. Accessed February 9, 2006.

 

18. Ash J. Considerations concerning computerized physician order entry implementation: The 2001 menucha conference list. Available at: http://www.ohsu.edu/dmice/research/cpoe/research/menucha_2001.pdf. Accessed February 9, 2006.

Return

Dr. McMeekin is a psychiatrist in private practice at Piedmont Psychiatric Associates in Rock Hill, SC.

Acknowledgments: Dr. McMeekin is a regional speaker for Novartis Pharmaceuticals. The author reports no financial, academic, or other support of this particular work.


 

Abstract

A case of bipolar illness is presented demonstrating the varied presentations of the illness longitudinally, the effects that hormonal events and therapy can produce in bipolar patients, and how adequate mood stabilization can modify those events.

Introduction

Most gender-related studies and those that examine the impact of hormones on the onset of emotional illness have focused on major and minor depression. It is only recently that the effects of hormones and reproductive-related events have been studied in larger bipolar populations. The results have shown significant hormonal sensitivity in bipolar women.1 The more subtle and comorbid presentations of bipolar illness are often difficult to diagnose. This can delay accurate treatment and lead to significant psychosocial morbidity. Treatment based solely on current symptoms can be misleading, and a detailed longitudinal history accompanied by input from family members is often necessary for accurate diagnosis.2 Described here is a longitudinal case history illustrating the variability of symptoms and hormonal sensitivity in a female bipolar patient.
 

Case

A 45-year-old white woman was referred for treatment of chronic depression not responsive to, or even worsened by, most antidepressant medications.
 

During her initial interview she presented as poised and organized. However, this changed as she spoke; she became more disorganized in her thinking and speech, as she would become distracted by a thought or an outside diversion (such as a noise or a movement) and “block,” forgetting her line of thought. When questioned about this, she replied that she had often wondered if she had attention-deficit/hyperactivity disorder. Her main symptoms were compatible with mixed bipolar depression and included racing thoughts, insomnia, blunting of emotions with decreased ability to feel pleasure and intimacy, and marked anxiety with periods of panic, depressed mood, irritability, decreased energy, and a sense of boredom. There was a marked obsessive quality to her depression, as she was constantly ruminating about her “mistakes” and whether she should change jobs or marry her current boyfriend. She denied suicidal thoughts or psychotic thinking. Her memory was good. She sat rigidly and appeared tense, with little spontaneous movement other than her leg, which shook constantly. When she did move, her gestures were quick and hesitant.
 

In retrospect, she had first noted mild depression at the age of 9 years. She experienced her first hypomanic period at age 18 years, where she enjoyed an elevated mood, decreased need for sleep, increased energy, increased sexual drive, and an increased sense of well-being. This lasted for several months before she returned to her usual mildly depressed state. This pattern continued throughout her life, worsening with time. By age 35 years, her illness had progressed so that she felt “addicted to men.” She would “fall in love” and engage in “whirlwind romances,” which often involved activities such as sky diving, jaunts to foreign countries, and other exotic and sometimes dangerous activities. Her mood would then shift to an anxious, agitated depression and she would begin to worry about whether “she was making the wrong choice.” She broke numerous engagements while depressed and would ruminate about her career and lifestyle choices until her mood shifted into mania, after which she would begin the process anew. Some years she experienced four complete cycles. She would make impulsive decisions during her excited manic periods, changing jobs and residences often. This pattern shifted after she was diagnosed with Crohn’s disease at age 39 years and began treatment with prednisone.
 

With prednisone her mood shifted into a sustained period of mild mania that continued as long as she was given the medication. When the medication was stopped, she would shift into a chronic mixed depression. This pattern repeated each time prednisone was used to control an exacerbation of her Crohn’s disease. Control of her emotional state was complicated by her becoming perimenopausal and requiring hormonal replacement with 0.2 mg estrogen patches and 5 mg of progesterone for 10 days every 3 months to induce menses. She reported that the estrogen had no effect on her mood, but that she became “depressed” during and for a time following the progesterone therapy. She had not responded to or become irritable and hyperactive on clomipramine, sertraline, paroxetine, and bupropion. She reportedly had not responded to a trial of lithium or valproate, but tolerated and had a partial response to venlafaxine 225 mg/day that decreased with time. Her medications, when first evaluated, included venlafaxine 37.5 mg sustained release tablets, alprazolam 0.125–0.25 mg three to four times per day as needed for anxiety, and zolpidem 5–10 mg for sleep. Her other medications included the previously mentioned estrogen and progesterone, and mercaptopurine 25–50 mg/day for her Crohn’s disease.
 

Family, Medical, and Social History

There was a family history of depression and bipolar disorder. Her birth and early development were without difficulties. She had her menarche at age 9 years and gradually developed severe premenstrual symptoms, including racing thoughts, irritability, sensory hypersensitivity, and difficulty sleeping prior to each menstrual period. She had no allergies, accidents, or severe reactions to medications.
 

She was a high school and college graduate. She never married and had never been pregnant. She was extremely successful in her chosen profession. She had no police record, had never been in serious financial problems, and had never used illegal drugs or abused alcohol.
 

Treatment

The patient’s treatment was typified by disappointing responses to medications. She was continued on venlafaxine, alprazolam, and zolpidem. To this regimen was first added quetiapine 25 mg/day (discontinued due to sedation) and then lamotrigine 25 mg/day (discontinued due to agitation). She  responded to 7.5 mg of olanzapine with less anxiety and a stabilization of her mood cycles. Topiramate 50 mg was added for further mood stabilization and to prevent weight gain. Her mood improved and stabilized, her concentration improved, and she became less obsessive. She then decompensated, with her thoughts becoming disjointed and speeded, her sleep becoming broken, and her irritability and depression worsening. Her symptoms then began to decrease and she restabilized on olanzapine and topiramate.

After several months of increased stability and decreasing need for the olanzapine, she decompensated again. This time it was noted that it occurred after she had taken progesterone 5 mg for 10 days. Further discussions confirmed this pattern of deterioration coinciding with her course of progesterone. Her gynecologist prescribed norethindrone 0.35 mg in place of the progesterone, with the same increase in symptoms resulting. Her gynecologist then stopped her hormones and prescribed an injection of 3.75 mg leuprolide. The patient gradually began to feel more agitated and pressured, her anxiety and depression worsened, and her sleep deteriorated. This state lasted approximately 6 weeks. The leuprolide was determined to be the cause and no further injections were given. Hysterectomy was discussed and rejected by the patient.
 

The patient was able to tolerate a maximum of olanzapine 10 mg/day due to sedation, and topiramate 50 mg/day due to agitation. Neither was sufficient to fully control her symptoms while using the progesterone and norethindrone, or after taking the leuprolide. When taking estrogen alone she stabilized with olanzapine 1.25 mg, topiramate 25 mg, and venlafaxine 25 mg/day. She continued taking mercaptopurine 25 mg/day and promethazine 12.5 mg as needed for nausea caused by the mercaptopurine.
 

In an attempt to find a medication that the patient could tolerate at higher doses, she was given a trial of oxcarbazepine, and topiramate was stopped. The result was a complete remission of symptoms at 1,200 mg/day. The patient was able to concentrate and her distractibility ceased. Her movements were smoother and her facial expressions became more fluid, better following and reflecting her inner emotions and thoughts. Her obsessions stopped and she was able to make decisions without difficulty.
 

Unfortunately, side effects of nausea and stomach pain caused by the oxcarbazepine forced a decrease in the dose to 150 mg BID. Her side effects stopped, but her baseline depression, obsessions, and racing thoughts returned. When she returned 1 month later, she had gone through a course of progesterone and had an exacerbation of her symptoms. She decided to increase her oxcarbazepine by adding “micro” doses as tolerated. By her return she was taking 1,200 mg/day and was back in remission.
 

When she returned in 3 months she was taking olanzapine 1.25 mg, venlafaxine 25 mg, and oxcarbazepine 600 mg BID. Several events had occurred: First, she had gone through a progesterone-induced period with minimal effect. She also reported that she became irritable “the last 4 days,” but that this irritability remitted shortly after the progesterone was stopped. There was no evidence of bipolar illness on her return. She appeared confident; spoke clearly and to the point; and her movements, affect, and speech reflected the emotional stability she now felt.
 

One year later, her symptoms remain in remission except for some mild anxiety following her use of progesterone. Her Crohn’s disease is also in remission and she has stopped the mercaptopurine.
 

Discussion

This case demonstrates the overlapping and sometimes confusing effects of steroids and neuropeptides on mood and behavior in many patients with bipolar disorder. The suspected reason for variability is the probability that no single gene is responsible for the disease, but rather multiple genes interact to determine severity, symptoms produced, and treatment response.3
 

One area of increasing interest in mood disorders is the hypothalamic-pituitary-adrenal (HPA) axis. Patients with major depression have been shown to have enlargement of the pituitary and adrenal glands. This is believed to reflect an increased production of corticotropin-releasing hormone (CRH), which has been shown, in animals, to produce behavior resembling depression, increased vigilance, anxiety, and dysregulation of sleep. Normally, glucocorticoid receptors regulate the activity of the HPA axis and the production of CRH, adrenocorticotrophic hormone, and, ultimately, cortisol. Inability of a standard test dose of the steroid dexamethasone to suppress HPA axis overactivity is the basis of the dexamethasone suppression test (DST).
 

Evidence of continued HPA axis hyperactivity, even with symptomatic improvement with treatment, is a predictor of relapse. DST nonsuppression has been a consistent finding in major depression and a frequent (but not consistent) finding in mixed bipolar states (a combination of irritable-anxious mania and depression), but has not been found in euphoric mania.4,5
 

Regulation of female reproductive hormones is controlled by the hypothalamic-pituitary-ovarian (HPO) axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile fashion that stimulates follicle stimulating hormone (FSH) and luteinizing hormone (LH). Of these, the matching LH pulse frequency is most critical. LH pulse frequencies that are too rapid (as in polycystic ovary disease) or too slow (as in hypothalamic amenorrhea) lead to anovulation.6 Leuprolide is a potent GnRH agonist which initially overstimulates and then “down regulates” the receptor, causing an initial rise then a reversible suppression of the synthesis and release of LH and FSH.
 

The GnRH agonists have been used effectively in premenstrual dysphoric disorder, precocious puberty, carcinoma of the prostate, endometriosis, uterine fibroids, and polycystic ovarian disease. The frequency of psychiatric symptoms incurred by the use of GnRH agonists appears to be underappreciated. These symptoms include anxiety states, delirium, mania, depression, and psychosis associated with paranoia and auditory hallucinations. Sertraline has been reported to correct these symptoms even when the leuprolide injections are continued.7
 

Stress activates the HPA axis and may inhibit the HPO axis and reproductive functioning in women with depression. There have been findings of mean plasma estradiol levels being 30% less in women with major depression compared to matched controls. Estradiol has effects on brain levels of serotonin and norepinephrine. Estradiol also has anxiolytic effects6 and, when used with a transdermal delivery system, 17-β-estradiol has been shown to have antidepressant effects in perimenopausal women.8 Bipolar patients report a 20% increase in psychiatric problems during the perimenopausal/ menopausal phase of life. Seventy percent report depressive syndromes, 20% report anxiety and agitation, and 20% have manic episodes (some for the first time).1
 

Progesterone’s role in producing psychiatric symptoms in the general population has been studied by examining users of depot-medroxyprogesterone acetate in a health maintenance organization. Depressive symptoms were found in 40% of users and 60% of those discontinuing its use.9 The effects of estrogen or estrogen plus progesterone have been studied in postmenopausal women without psychiatric histories. No change in mood was found with estrogen alone; a slight but statistically significant increase in daily anxiety was noted when progesterone was added.10 There is more evidence for exacerbation if a prior psychiatric illness is present. If women with a prior history of postpartum depression are first given leuprolide to induce a hypogonadal state for 1 month, are then given supraphysiologic levels of estradiol and progesterone for 8 weeks to mimic pregnancy, and are then abruptly withdrawn from those hormones to mimic delivery, 62.5% will develop significant mood symptoms, with some showing mania.11
 

There is evidence of a hormonal effect in bipolar I women. In a survey, 45.3% reported severe psychiatric symptoms either during pregnancy or within 1 month after childbirth, with 86% of these women reporting depression as their major symptom. A small percentage reported “increased mood cycling or shifts from manic to depressed mood after delivery.” Also, 66% reported mood changes either prior to or during their menstrual cycles, with the majority (75%) reporting anger and mood lability as their primary symptoms. As noted previously, approximately 20% of bipolar women describe an increase in psychiatric symptoms during the perimenopausal and postmenopausal phase of their reproductive life.1
 

Leuprolide-induced sustained mania and mania followed by depression have been reported previously.12,13 The patient noted here had a prior history of documented bipolar disorder with a moderate but stable response to treatment that was destabilized by leuprolide, norethindrone, and progesterone. With the use of these drugs, a mixed anxious and depressed state resulted that was similar to that seen during her depressive episodes, but with greater intensity. To my knowledge, this is the first evidence of leuprolide-exacerbated mixed bipolar disorder to be reported in the literature.
 

In reporting her symptoms during an initial evaluation, she emphasized their depressive and anxious qualities. It was only on direct questioning that she recounted her racing thoughts, her nonstop intrusive and obsessive negative thinking, and her marked distractibility and sensory hypersensitivity to repetitive noises and noxious stimuli, suggesting a dysphoric manic diagnosis. It was only after some improvement that she was able to recount earlier euphoric manic episodes. No evidence of euphoric mania was seen during her period of treatment.
 

Conclusion

The patient’s symptoms show the myriad ways that steroids affect patients with bipolar spectrum disorder, and the beneficial effects that adequate mood stabilization can produce. Problematically, most of these patients present in a depressed or anxious and irritable state, and are often treated with antidepressants. While antidepressants as monotherapy in bipolar patients may be helpful,14 they may (as occurred in this patient) have no effect or have an initial response with decay. Antidepressants remain an important and effective therapeutic tool, but there is increasing awareness of their limitations in controlling symptoms and preventing suicide in bipolar patients,15 and of the need for adequate mood stabilization with drugs such as lithium or anticonvulsants as the cornerstone of therapy.16   PP
 

References

1.    Blehar MC, Depaulo JR Jr, Gershon ES, Reicht T, Simpson SG, Nurnberger J. Women with bipolar disorder: findings from the NIMH genetics initiative sample. Psychopharmacol Bull. 1998;34(3):239-243.
2.    Bowden CL. Update on bipolar disorder: epidemiology, etiology, diagnosis, and prognosis. Medscape Mental Health. 1997;2:1-9.
3.    Souery D, Rivelli SK, Mendlewicz J. Molecular genetic and family studies in affective disorders: state of the art. J Affect Disord. 2001: 62:45-55.
4.    Pariante CM, Miller AH. Glucocortcoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry. 2001;49(5):391-404.
5.    Risby E, Hartline K, Owens MJ, Nemeroff CB. Neuropeptides in bipolar disorder. In: Young T, Joffe R, eds. Bipolar Disorder: Neurobiology and Clinical Applications. New York, NY: Marcelle Decker; 1996.
6.    Young E, Midgley A, Carlson N, Brown M. Alteration in the hypothalamic-pituitary-ovarian axis in depressed women. Arch Gen Psychiatry. 2000;57:1157-1162.
7.    Warnock JK, Bundren JC. Anxiety and mood disorders associated with gonadotropin-releasing hormone agonist therapy. Psychopharmacol Bull. 1997;33(2):311-316.
8.    Soares C, Almedida Op, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women. Arch Gen Psychiatry. 2001;58:529-534.
9.    Civic D, Scholes D, Ichikawa L, LaCroix AZ, Yoshida CK. Depressive symptoms in users and non users of depo-medroxyprogesterone acetate. Contraception. 2000;61(6):385-390.
10.    Girder SS, O’Briant C, Steege J, Grewen K, Light KC. A comparison of the effect of estrogen with or without progesterone on mood and physical symptoms in postmenopausal women. J Womens Health Gend Based Med. 1999;8(5):637-646.
11.    Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000;157(6):924-930.
12.    Rachman M, Garfield DA, Rachman I, Cohen R. Lupron-induced mania. Biol Psychiatry. 1999;45(2):243-244.
13.    Sussman N. Leuprolide-induced mania: gonadotropin-releasing hormone agonist-associated mood disorder. Primary Psychiatry. 2000;7(4):26-31.
14.    Haykal RF, Akiskal HS. The long-term outcome of dysthymia in private practice: clinical features, temperament, and the art of management. J Clin Psychiatry. 1999;60(8):508-518.
15.    Baldessarini RJ, Tondo L, Hennen J. Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic depressive disorders. J Clin Psychiatry. 1999;60(suppl 2):77-84.
16.    Frye MA, Ketter TA, Leverich GS, et al. The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study. J Clin Psychiatry. 2000;61(1)9-15.

Return

 

Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy is a consultant to Myriad; is on the speaker’s bureaus of Forest and Pfizer; and has received grant support from Forest, Myriad, Novartis, Pfizer, and Takeda.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.


 

Parkinson’s disease affects as many as 1 million Americans and with advanced age is complicated by dementia in a majority of cases. However, the recognition of cognitive impairment in Parkinson’s disease is made complicated by the predominance of motor symptoms and a neuropsychiatric profile that differs from the more common dementia of the Alzheimer’s type. Differentiating the decline in personal and social activities due to cognitive impairment rather than preexisting movement disorder is difficult. Several expert bodies have addressed the use of cholinesterase inhibitors for the dementia of Parkinson’s disease, but the evidence base is far less substantial than that which exists for Alzheimer’s disease. Although most patients with Parkinson’s disease dementia should be offered a trial of anti-cholinesterase therapy, particularly those experiencing hallucinations, dramatic benefits are not common. Temporary symptomatic relief rather than disease modification is the most that can be expected. As a result, treatment should be presented as an option rather than an imperative.

Introduction

Parkinson’s disease has a mean age of onset of 57 years and a prevalence of 1% to 2% among adults ≥60 years of age. There may be as many as 1 million Americans with the illness.1 It is manifested by bradykinesia, rigidity, resting tremor, postural instability, frozen gait disorder, and flexed posture. The progression and severity of Parkinson’s disease varies widely and the associated motor disability may be substantially reduced by numerous medications singly or in combination. The goal is an increase in brain dopamine through either enhanced production or reduced breakdown of the molecule.2 The disease begins as a movement disorder, but with advancing age is complicated by dementia in as many as 80% of patients. The characteristic frozen facial expression, slowed cognition (bradyphrenia), fluctuation in attention, and motor impairment compounded by depression and hallucinations make the assessment of possible dementia challenging. In addition, dopaminergic medications precipitate hallucinations with recognized frequency. Although medication to treat the dementia of Parkinson’s disease is most often modestly effective for patients in aggregate, failure to recognize dementia means that the minority of individuals who might receive substantial benefit will not be offered a therapeutic trial. As a result, practitioners need guidance to efficiently assess cognitive decline among people with Parkinson’s disease as well as realistic expectations for the benefits of dementia treatment. 

      
Similarities and Differences with Other Dementias

Loss of dopaminergic neurons in the substantia nigra is the hallmark of Parkinson’s disease and the basis for the use of dopamine agonists. In contrast, neuronal dropout in the entorhinal cortex and hippocampus are seen in Alzheimer’s disease. Yet, similar to Alzheimer’s disease, cholinergic deficits are common in Parkinson’s disease and parallel the decline in cognition. Hematoxilyn and eosin staining neuronal inclusions known as Lewy bodies occur in both Parkinson’s and Lewy body dementia but not in Alzheimer’s disease. However, amyloid plaques and neurofibrillary tangles thought to be the signature pathology of Alzheimer’s disease commonly occur in both Parkinson’s disease and Lewy body dementia as well, though less extensively. Differences between Alzheimer’s disease and the dementia of Parkinson’s and Lewy body disease detected by imaging studies, whether structural (magnetic resonance imaging [MRI], computerized axial tomography) or metabolic (positron emission tomography, single photon emission computed tomography, functional MRI), are too subtle for use in clinical diagnosis.   

Clinical features of Alzheimer’s, Parkinson’s, and Lewy body dementia overlap as severity progresses but significant differences are apparent in the early stages (Table 1).3-5 In Alzheimer’s disease, memory impairment is prominent with executive dysfunction, aphasia, apraxia, and anomia often present but less obvious. Apathy is more common than depression, but one or the other will be present in ~25% of affected individuals. Hallucinations occur in 10% of cases most often at the mid- to later stage of the disease.6 Severe motor impairments in gait, balance, muscle strength, and swallowing occur in the later stages. In Parkinson’s dementia, the movement disorder precedes the onset of cognitive impairment. Inattention, executive dysfunction, bradyphrenia, and visuospatial deficits may be more noticeable than impaired memory. Hallucinations are four times more frequent and depressive symptoms somewhat less so than in Alzheimer’s disease. Irritability, anger, aggression, and delusions may be more prominent in Alzheimer’s disease. More severe postural instability and gait disorder predict the onset of dementia among people with Parkinson’s disease. Incident hallucinations also predict the subsequent emergence of dementia.3

 

Hallucinations are also a distinguishing feature of Lewy body dementia. Marked fluctuations in attentiveness and mild impairment in memory—both of which precede the appearance of rigidity, tremor, postural instability and gait disorder—distinguish Lewy body dementia from that of Parkinson’s disease. Unanticipated sensitivity to neuroleptic-induced extrapyramidal symptoms also indicates that Lewy body dementia, rather than Alzheimer’s disease with hallucinations, is the correct diagnosis.

Efficient Screening Procedures 

Not every older adult should be screened for cognitive impairment. Screening in clinical practice is predicated on the recognition of cognitive decline interfering with personal or social activities by the patient, family, or clinician. However, Parkinson’s disease often impacts social and personal activities as a result of motor impairment. Thus, personal responsibilities may already have been abandoned before impaired cognition could have made noticeable contribution. Given the elevated frequency with which dementia emerges in Parkinson’s disease, the practitioner’s concern for impairment should be heightened. When hallucinations, apathy, or excessive daytime drowsiness appear after a period of stable treatment, dementia should be suspected.

In a 2007 review7 on the diagnosis and treatment of Parkinson’s disease dementia, the Movement Disorders Society’s taskforce recommended the Mini-Mental State Examination (MMSE) as a global measure of cognitive performance in which a score <26 indicates impairment. They also suggested a number of screening procedures to detect impairments in specific cognitive domains. These included domains of attention, visuo-constructive ability, executive function, and memory. Parkinson’s disease patients with impairments in more than one domain associated with deterioration in personal care or social activities would meet the criteria for dementia. Attention would be assessed with the serial seven subtraction task from the MMSE or by asking the patient to list months of the year in reverse order. In either test, two errors or omissions is considered evidence of impairment. For executive dysfunction, impairment is defined as failure to recite nine examples from the lexical category of words starting with the letter “S” in one minute or inability to draw a clock with the time set at 10 past 2. Visuo-constructional impairment is defined by inability to copy two intersecting pentagons from the MMSE. Impairment in memory is defined by failure to recall all three words from the MMSE’s registration and recall task. The review also provides a comprehensive listing of neuropsychological instruments that have been used to assess cognition among people with Parkinson’s disease.

However, busy practitioners may find the copyrighted MMSE and clock drawing cumbersome. As an alternative, the Memory Impairment Screen and the oral version of the Trail Making Test for executive function do not require paper and pencil, may be administered by phone, and are quite brief. Both have been validated as screening measures for use in population assessments of dementia.8 For the Memory Impairment Screen, the subject is tasked to repeat and remember four words (eg, apple, table, penny, spoon) given in sequence at 1-second intervals and then asked to recall each when prompted with a category cue (eg, fruit, furniture, money, utensil). The registration phase may be repeated up to five times before moving to the next test. Next, the subject is asked to recite the alphabet from “A to Z” and then to count from 1–25. The person is then asked to continue the sequence, which the examiner starts with “One A, Two B, Three C, Four ?” Subjects making two errors as they reach “M 13” are considered to exhibit executive impairment. Following the Trail Making test, the examiner returns to the Memory Impairment Screen by asking the subject to recall the four words that were previously rehearsed. Allowing 1 minute for free recall the examiner then provides the category cue for each word not remembered spontaneously. Words recalled freely receive a score of 2; those that required the cue for recall receive a score of 1. A total score of 4 is predictive of dementia. A free demonstration of the Trail Making Test, clock-drawing test, and other measures of executive dysfunction can be accessed on the Internet.6 Baseline assessment of cognition with simple screening procedures following the diagnosis of Parkinson’s disease will set the stage for detection of genuine impairment should warning signs of dementia emerge.

Responsiveness to Cholinesterase Inhibitors

The evidence base regarding the efficacy of pharmacotherapy for Parkinson’s disease dementia is limited9 but more extensive if one considers the illness to be part of a spectrum including dementia with Lewy bodies.10 In the largest randomized controlled trial to date, Emre and colleagues11 conducted a pivotal study of 541 people whose Parkinson’s disease was accompanied by mild-to-moderate dementia defined by MMSE score of 10–24. Patients were allocated to rivastigmine or placebo in a 2:1 ratio. Rivastigmine 1.5 mg was introduced and titrated to a maximum tolerated dose or 12 mg over 16 weeks. Exclusion criteria included a history of major depressive disorder, use of cholinesterase inhibitor or anticholinergic drug, or change in Parkinson’s disease medication within 4 weeks of enrollment. The initiation of a psychotropic medication during the study with the exception of an antipsychotic for an acute episode of psychosis was forbidden. The mean age of study participants was slightly >72 years and 66% were men. Forty percent were diagnosed with a mental disorder in addition to dementia.

Greater than 25% of participants were taking an antipsychotic at baseline, 25% were on an antidepressant, 20% were on a benzodiazepine or sedative hypnotic, and 95% were taking levodopa. The two primary efficacy measures were the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change (ADCS-CGIC). Each were separately assessed by trained raters blind to the assessment outcome. The ADAS-cog is a 70-point measure of cognitive performance. The ADCS-CGIC is a 7-point categorical scale anchored at baseline where “1” equals marked improvement, “7” equals marked worsening, and “4” denotes no change. Detectable changes that were not clinically meaningful were defined as minimal; changes associated with obvious clinical improvement were defined as moderate. Secondary efficacy measures included the ADCS measure of activities of daily living, the Neuropsychiatric Inventory, the MMSE, tests of attention and reaction time, and tests of executive function as measured by letter-category verbal fluency and clock-drawing.

At the end of dose titration, >50% of treated participants were taking rivastigmine 9–12 mg/day. Of those completing the study, 72% were in the rivastigmine group and 82% in placebo. Adverse events accounted for most of the premature withdrawals in both groups. Nausea (29%), vomiting (16.6%), and worsening tremor (10.2%) were significantly more frequent among the rivastigmine group. Of the efficacy measures comparing rivastigmine to placebo, at 24 weeks all were statistically significant. There was an 11.7% difference in cognitive performance (ADAS-cog) between drug and placebo groups. Clinically meaningful (marked to moderate) improvement was seen in 14.5% of placebo and 19.8% of the rivastigmine group. Clinically meaningful deterioration was seen in 23.1% of placebo and 13.0% of the rivastigmine group. Among the secondary measures of disability, neuropsychiatric symptoms, cognition, and executive functions all showed improvement with rivastigmine and decline with placebo with the differences being statistically significant. Of note, 34.6% of placebo and 45.4% of the rivastigmine group exhibited a ≥30% improvement in neuropsychiatric symptoms. Hallucinations disruptive enough to be considered adverse events occurred in 9.5% of placebo and 4.7% of rivastigmine participants, and the difference was significant.

Emre and colleagues11 conclude that their findings among patients with Parkinson’s disease and dementia are similar to those seen in studies of cholinesterase inhibitors for Alzheimer’s disease. Benefits are modest, representing a 6-month reprieve in the course of symptoms without genuine disease modification. However, close to one in five patients will show dramatic benefit obvious to the family and the clinician alike. Indeed, Press12 advocates the family’s impression of benefit over formal neuropsychological measures to assess the effectiveness of treatment. Given that benefits if apparent at all emerge within the first weeks of treatment, the most realistic expectation for patient and family is a 60–90-day trial of therapy rather than an open-ended course. Also noteworthy were the relatively more substantial benefits of rivastigmine for neuropsychiatric symptoms, including hallucinations, a finding similar to McKeith and colleagues’10 rivastigmine study of 120 patients with Lewy body dementia. The number of study participants receiving a neuroleptic during the Emre and colleagues11 study was considerable. Low doses of atypical antipsychotics such as olanzapine, quetiapine, and clozapine were initially used to control levodopa-induced hallucinations because they were less likely than typical antipsychotics to induce extrapyramidal symptoms.12

However, the 2005 Food and Drug Administration warning of increased mortality when prescribed to patients with dementia11 amplified by more recent reports14,15 raise the threshold at which these agents may be considered for psychosis in dementia nearly out of reach. Clearly, a trial of cholinesterase therapy should be recommended to reduce hallucinations of dementia in Parkinson’s disease before a neuroleptic is offered. The transdermal rivastigmine patch with less frequent gastrointestinal effects, not available at the time of Emre’s11 study, is an added advantage.16 It should be added that other cholinesterase inhibitors may be efficacious for the dementia of Parkinson’s disease but have not been subjected to large-scale trials. Nonetheless, the Cochrane Review and other sources17-20 find at least minimal evidence to support the use of donepezil as well (Table 2).

 

 

Conclusion

Dementia is such a frequent complication that every older patient with Parkinson’s disease should be screened for memory impairment and executive dysfunction, particularly if hallucinations emerge in the context of stable dopaminergic treatment. The impact of cholinesterase inhibitor therapy on cognition and activities of daily living will be obvious in only one patient in five. However, the reduction in hallucinations may be more robust. Consistent reports of elevated mortality associated with antipsychotics prescribed to people with dementia make cholinesterase inhibitor therapy preferable when hallucinations emerge. A 60–90-day trial of a cholinesterase inhibitor should be adequate to give the patient, family, and practitioner sufficient evidence on which to base a decision for ongoing treatment. In equivocal cases, the medication can be reinstituted if visible decline is observed following discontinuation.8 With adverse reactions and lack of efficacy taken into account, 40% to 60% of treated patients would withdraw from cholinesterase inhibitor therapy. However, lacking predictors of treatment responsiveness and balancing in the safety of cholinesterase inhibitor therapy, most patients with Parkinson’s disease dementia should be offered a trial of treatment. Practitioners’ zeal for treatment must be tempered by the realization that temporary symptomatic relief rather than disease modification is the most that can be expected. As a result, treatment should be presented as an option rather than an imperative. PP

References

1. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson’s disease. Mov Disord. 2002;18(1):19-31.
2. LeWitt PA. Levodopa for the treatment of Parkinson’s disease. N Engl J Med. 2008;359(23):2468-2476.
3. Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with parkinson’s disease movement disorders. Mov Disord. 2007;22(12):1689-1707.
4. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
5. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65(12):1863-1872. Erratum in: Neurology. 2005 ;65(12):1992.
6. Lyketsos CG, Sheppard JM, Steinberg M, et al. Neuropychiatric disturbance in Alzheimer’s disease clusters into three groups: the Cache County study. Int J Geriat Psychiatry. 2001;16(11):1043-1053.
7. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the Movement Disorder Society Task Force. Mov Disord. 2007;22(16);2314-2324.
8. Kennedy GJ, Smyth CA. Screening older adults for executive dysfunction: an essential refinement in the assessment of cognitive impairment. American Journal of Nursing. 2008;108(12):60-69.
9. Poewe W, Gauthier S, Aarsland, et al. Diagnosis and management of Parkinson’s disease dementia. Int J Clin Pract. 2008;62(10);1581-1587.
10. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double blind, placebo controlled international study. Lancet. 2000;356(9247):2031-2036.
11. Emre M, Aarsland, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Eng J Med. 2004;351(24):2509-2518.
12. Press DZ. Parkinson’s disease dementia–A first step? N Engl J Med. 2004;351:(24)2547-2549.
13. Kennedy GJ. Caution vs. closure: the use of atypical antipsychotics for the treatment of behavioral disturbances in dementia. Primary Psychiatry. 2005;12(9):16-19.
14. Ballard C,  Hanney ML, Theodoulou M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol.  2009;8(2):151-157.
15. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Eng J Med. 2009;360(3):225-235.
16. Lefèvre G, Pommier F, Sedek G, et al. Pharmacokinetics and bioavailability of the novel rivastigmine transdermal patch versus rivastigmine oral solution in healthy elderly subjects. J Clin Pharmacol. 2008;48(2):246-252.
17. Maidment I, Fox C, Boustani M. Cholinesterase inhibitors for Parkinson’s disease dementia. Cochrane Database Syst Rev. 2006;(1):CD004747.
18. Ravina B, Putt M, Siderowf A, et al. Donepezil for dementia in Parkinson’s disease: a randomised, double blind, placebo controlled crossover study. J Neurol Neurosurg Psychiatry. 2005;76(7):934-939.
19. Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil for cognitive impairment in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry. 2002;72(6):708-712.
20. Leroi I, Brandt J, Reich SG, et al. Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson’s disease. Int J Geriatr Psychiatry. 2004;19(1):1-8.

Return

 

Dr. Raby is assistant clinical professor of psychiatry at Columbia University in New York City.

Disclosure: Dr. Raby reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Off-label disclosure: This article includes discussion of the following unapproved medications for co-occurring marijuana abuse or dependence and psychotic disorders: bupropion, dronabinol, and nefazodone.

Please direct all correspondence to: Wilfrid Noël Raby, MD, PhD, Division on Substance Abuse, Unit 66, New York State Psychiatric Institute, 1051 Riverside Dr, New York, NY, 10032;
Tel: 212-923-3031; Fax: 212-568-3832; E-mail: rabywil@pi.cpmc.columbia.edu.


 

Focus Points

• Cannabis use before 15 years of age increases the risk of serious mental illness, especially psychotic illness later in life.
• A family history of psychiatric illness may increase the risk of cannabis-induced psychosis.
• Clinicians need to investigate not only the use of cannabis by patients, but also its effect, in order to determine vulnerability to mental illness from its ongoing use.
 

Abstract

Marijuana abuse can lead to transient psychosis, but can it cause or worsen psychotic disorders like schizophrenia? This article reviews the evidence from key research reports, leading to the conclusion that marijuana use, especially in early adolescence, can lead to psychotic disorders in adulthood, such as schizophrenia. There is a want of treatment approaches for marijuana use in individuals with schizophrenia, or for emerging psychosis in patients dependent on marijuana. Second-generation antipsychotics, especially clozapine, appear to be the best approach to treatment for psychosis co-occurring with—and often secondary to—marijuana abuse. More research is needed to develop appropriate and effective treatments for marijuana dependence, both alone as well as in conjunction with psychosis and psychotic disorders.

Introduction

Is marijuana dangerous? With an estimated 150 million people worldwide smoking or eating marijuana leaves annually,1 the question is pertinent. Marijuana is perceived as an innocuous drug in many circles due to its association with cultural and religious rituals, and with the fact that unlike alcohol, cocaine, or heroin, it rarely brings individuals to the brink of destitution. However, this perception is changing. In 1997, Tanda and colleagues2 reported that marijuana, like most drugs of abuse, increases dopamine release in the nucleus accumbens. Moreover, the increasing potency of available marijuana has led to the recognition of a withdrawal syndrome, characterized by irritability, restlessness, insomnia, anorexia, and aggressivity, which may last up to several weeks after stopping marijuana.3 Marijuana, like tobacco smoking, also increases the risk of lung cancer in young adults.4 With respect to mental health, marijuana smoking is reported to elicit psychotic disorders in individuals at risk5 as well as worsen psychotic symptoms in patients with psychotic disorders. This last point will be the focus of this article, which will review of the evidence, discuss clinical symptoms that may indicate an enhanced risk of psychosis stemming from marijuana, and present available treatment options.

Review of the Evidence Linking Marijuana to Psychosis

Marijuana use appears to be beginning at an increasingly early age. Based on the Substance Abuse and Mental Health Service Administration (SAMHSA) 2002–2003 survey, 90.8 million adults in the United States (42.9%) ≥18 years of age had used marijuana at least once in their lifetime. Among them, 2.1% had reported a first use before12 years of age, 52.7% between 12–17 years of age, and 45.2% at ≥18 years of age.6 In the same survey, 12.5% of individuals >18 years of age who reported lifetime use of marijuana were classified as having a serious mental illness in the past year. Furthermore, 21% of adults who first used marijuana before 12 years of age were classified as having a serious mental illness in the past year, as opposed to 10.5% of adults who had first used at ≥18 years of age. Strictly with respect to psychosis, results from the US National Epidemiological Catchment Area Study7 highlight that daily marijuana smokers were 2.4 times more likely to report psychotic symptoms than non-daily users, even after adjusting for psychiatric conditions and sociodemographic factors.8 Data like these have created the suspicion that marijuana may not be as innocuous as it has been previously thought.

Before inquiring about psychotic disorders, this article evaluates how prone marijuana users are to experience some form of psychosis. As early as 1972, marijuana use was stated to possibly cause acute psychosis.9 Usually, the effects of marijuana are dose related. Mild intoxication causes drowsiness, euphoria, and heightened sensory perception, while severe intoxication leads to motor incoordination, lethargy, and postural hypotension.10 Psychosis is not considered a usual manifestation of marijuana use. Cross-sectional studies have attempted to look at the types of symptoms that might be elicited by marijuana: positive (perceptual anomalies, magical or paranoid ideation), and negative (asociality, anhedonia) in non-clinical samples. While methodologic differences abound in these studies, these studies11-14 imply that marijuana users are more prone to transient positive symptoms of psychosis; one study15 found an association with negative symptoms as well. It is unclear whether these negative symptoms represent true negative symptoms or the so-called “amotivational syndrome” (loss of interests, motivation, impaired occupational performance and achievement), which is described as a subacute, reversible encephalopathy caused by chronic marijuana use.16 A review17 of randomized trials unrelated to mental health assessing the antiemetic effects of cannabis found that 6% of patients receiving cannabis experienced hallucinations and 5% paranoia, effects not seen with the other antiemetic drugs tested. Using a method called Experience Sampling Method, which is a structured daily diary method to investigate subjective experience during daily life in which subjects a prompted every three hours to complete the diary, Verdoux and colleagues18 found that in a given 3-hour period the likelihood of reporting unusual perceptions was increased if marijuana was used in the same 3-hour period, and not if used in the previous three hour period. This finding is consistent with the estimated duration of the pharmacologic effects of marijuana.19 With heavy marijuana use, symptoms of hypomania, agitation, auditory hallucinations, and thought disorder have been reported, which have tended to improve substantially after 5–7 days.20 However, one may ask if the association between marijuana use and psychotic experiences extends to psychotic disorders. National surveys support this association, such as the data from the US National Epidemiological Catchment Area study7 presented earlier. Two other national surveys also concur. The Australian National Survey of Mental Health and Well Being revealed that 12% of those diagnosed with schizophrenia also met International Classification of Diseases and Health Related Problems, Tenth Edition21 criteria for cannabis dependence. After adjusting for other disorders and sociodemographic factors, individuals with cannabis dependence were found to be nearly three times as likely to be diagnosed with schizophrenia as those not diagnosed with cannabis dependence.22 In the Netherlands, marijuana use was more prevalent among individuals with psychosis (15.3%) than those without (7.7%).23 Taken together, these findings support the association of marijuana use not only with transient psychosis, but also with the development of psychotic disorder. However, they cannot answer the question: do we need to worry that marijuana use can cause a psychotic illness?

The issue of causality is a difficult one to answer when it comes to conditions such as psychosis which can have multiple etiologies. To establish causality, three factors must be established: association (presented above), a temporal priority, and a direction of effect.24 The latter two factors can only be scrutinized in prospective studies, where a group is selected for assessment of a risk (marijuana use) and followed over time to evaluate how potent the risk is in causing a particular condition (psychotic disorders).

Two landmark prospective studies will be reviewed: the Swedish Conscript Cohort25,26 and the Dunedin study from New Zealand.27 The Swedish study examined a cohort of 50,087 conscripts and found a dose-response relationship between marijuana use at 18 years of age and a schizophrenia diagnosis. Self-described “heavy marijuana users” (>50 lifetime use) were 2.3 times more likely than non-users to have a schizophrenia diagnosis 15 year later (after controlling for pre-existing psychosis).25 When the analysis was extended to 27 years, heavy users were 6.7 times more likely than non-users to carry a schizophrenia diagnosis, after controlling for drug use other than marijuana, low intelligence quotient, and antisocial personality, among other factors.26 Restricting the analysis to a 5-year window past 18 years of age to examine whether cannabis use might be a result of prodromal psychosis did not change those risks, leading the authors to state that their results were “consistent with a causal relationship between cannabis use and schizophrenia.”26

The prodromal phase of schizophrenia is marked by gradual but profound changes in behavior, perception, and cognition, raising the question as to whether marijuana use may be a consequence of emerging psychosis rather than a cause of it. Although small in contrast to the Swedish study, the Dunedin study27 provided unique insights in this regard, studying a birth cohort of 1,037 individuals born in Dunedin, New Zealand between 1972–1973, with a 96% follow-up rate at 26 years of age. It gathered information on self-reported psychotic experiences at 11 years of age, before the onset of marijuana use, and on self-reported use of marijuana at 15 and 18 years of age. All individuals were assessed to yield Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition28 diagnoses if present at 26 years of age, allowing the investigators to note the presence of psychotic symptoms along a continuum or the presence of a formally diagnosed psychotic disorder. Psychotic symptoms stemming from alcohol or other drugs were ruled out. Cannabis use by 15 and 18 years of age, respectively, led to higher rates of psychosis at age 26 compared to non-users, even after controlling for psychotic experiences preceding marijuana use. Age of first marijuana use was a significant factor: 10.3% of individuals who had used marijuana by 15 years of age were diagnosed with schizophreniform disorder at 26 years of age, compared to 3% of controls. The risk for adult schizophreniform disorder remained elevated after controlling for psychotic experiences at 11 years of age, with an odds ratio of 3.1. Marijuana use by 15 years of age did not predict depression at 26 years of age, and other drug use did not pose a risk for schizophreniform disorder above the one posed by marijuana. Marijuana use begun between ages 15 and 18 was associated with a heightened risk for schizophreniform disorder, but only if preceded by psychotic experiences at 11 years of age. This study corroborated the notion that marijuana use in adolescence is a risk factor for schizophrenia in later life, especially if used at an early age, suggesting both a temporal priority and direction between early marijuana use and schizophrenia. The issue of age may be especially important because at  ≤15 years of age, the developing brain may be especially susceptible to suspected trophic and neurobiologic effects of marijuana exposure, for which there is accumulating evidence.29-31

Since the Dunedin study, other studies and reviews have lent support to its findings. Semple and colleagues32 conducted a meta-analysis in which odds ratio from 2–9 were found between early exposure to marijuana and psychosis, leading them to conclude that early marijuana is an independent risk factor for psychosis and psychotic disorders. Arendt and colleagues33 reported on a cohort of 535 patients who had been diagnosed with marijuana-induced psychotic disorder and found that 47% of the patients received a diagnosis of schizophrenia 1 year later. Ferdinand and colleagues34 concluded, after a 14-year follow-up study of 1,580 individuals 4–16 years of age at study entry, that there was a specific link between marijuana use and psychosis, independent of other forms of psychopathology. In a nationwide population-based sample of 2 million individuals, the authors concluded that marijuana-induced psychosis could be an early sign of schizophrenia rather than a distinct form of psychosis.35 In individuals with prodromal symptoms of schizophrenia, marijuana increased the intensity and frequency of psychotic symptoms, especially hallucinations, and did so during and shortly after marijuana use.36 This lead the authors to ponder whether marijuana could worsen prodromal symptoms and increase the likelihood of developing schizophrenia  in young adolescents at risk. Genetic predisposition may further enhance this risk. In a study of the Dunedin cohort, Caspi and colleagues37 reported that individuals with a functional polymorphism in the catechol-O-methyltransferase (COMT) gene were at increased risk of schizophreniform disorder after use of marijuana during adolescence as compared with those who did not carry this polymorphism. Similar evidence is being found for polymorphisms at the cannabinoid receptor (CB1).38 These genetic factors may influence future risk of schizophrenia by interacting with other potential risk factors. For example, accumulating evidence points to dysregulation of the endogenous cannabinoid anandamide in patients with schizophrenia, with elevation of anandamide levels in blood and cerebrospinal fluid during acute exacerbations of psychosis and resolution after treatment (Figure).10,39-41 Hence, exogenous cannabinoids may worsen preexisting states that could make some individuals more at risk to develop schizophrenia from consuming marijuana.

 

 

 

Faced with this mounting evidence that marijuana use, particularly at an early age, can increase the risk of schizophrenia in adults, what is a clinician to do? The next section will describe an approach that may help in advising patients on the risk inherent to marijuana use and on the risk of developing a psychotic disorder.

Clinical Approaches to Advising Patients

Given the prevalence of marijuana use, psychiatrists and clinicians will encounter patients who smoke marijuana. As a starting point, not only is it important to know which substances have been and are being used (marijuana in this instance), but it is useful to ask the patient about what they experienced when smoking marijuana. Usually, mild intoxication can be followed by drowsiness, euphoria, heightened sensory awareness, and altered time perception. Moderate intoxication may produce memory impairments, depersonalization, and mood alteration. Severe intoxication can lead to decreased motor coordination, lethargy, slurred speech, and postural hypotension. These are the usual symptoms of marijuana use. Individuals who consistently experience these symptoms may have smoked marijuana for many years, with perhaps an ensuing decline in motivation, mental acuity, and a stalling in their personal and professional achievements. These later symptoms are often those that bring these patients to seek treatment. For those other patients who may be unknowingly more at risk of psychosis from marijuana, the experience of consuming marijuana seems to be different.

Clinicians are encouraged to look for any symptoms that might differ from the usual effects of marijuana stated above. After first smoking marijuana, or after some time thereafter, some patients may experience dysphoria, restlessness, generalized anxiety, panic attacks, paranoia, and sometimes hallucinations (Table). In most cases, marijuana-induced psychiatric symptoms, such as panic attacks, agitation, or persecutory delusions, are transient.5,42 Although no literature appears to exist looking at how these early effects of marijuana may portend future risk of mental illness, they may represent a first warning. In this author’s experience, marijuana-smoking patients with these symptoms frequently have a family history of psychiatric illness as well, be it depression, bipolar disorder, anxiety disorders, or schizophrenia. How these familial risks enhance the probability of acquiring a psychotic disorder from marijuana is not yet elucidated. Nonetheless, this author has witnessed patients with these anomalous effects of marijuana go on to develop autonomous psychotic disorders from not stopping their marijuana use in time. In the face of current evidence, the most conservative stance would dictate that patients be told that symptoms contrary to the usual effects of marijuana may signal that continued use of marijuana may possibly and seriously jeopardize their future mental health, although no definite proof of this exists for now. Presently, the state of reimbursement for clinical care forbids ancillary testing that might substantiate this risk, such as genetic testing for polymorphisms in the COMT or CB1 receptor genes.

 

 

Treatment for Marijuana-related Psychosis

Compared to psychosis unrelated to marijuana, marijuana-associated psychosis is emerging as more challenging to treat. In established schizophrenia, marijuana or other drug abuse leads to decreased adherence to treatment43 as well as increases recurrence of symptoms,44 episodes of violence,45 victimization (such as being used as drug “mules” to carry drugs),46 hospitalizations,47 and suicide.48 This underlies the seriousness of the problem, and the importance of developing effective treatments. Before moving on to potential medication treatments, the context of treatment deserves special mention. Programs that integrate counseling for substance abuse, psychosocial support for mental illness, and medication treatment provide the continuity and comprehensiveness that is more likely to make such treatment a success with the severely mentally ill. The inclusion of cognitive-behavioral and motivational interviewing approaches enhances treatment success.44,49-51 Features such as contingency management, where abstinence is rewarded with small prizes, can further increase success.52 For the most recalcitrant patients, long-term residential programs must be considered.53 However, many clinics are not equipped to provide such comprehensive services, and much remains to be overcome to disseminate such services throughout the current mental health network and to a wider population.

There are few guidelines concerning the pharmacologic treatment of co-occurring marijuana abuse or dependence and psychotic disorders. With respect to marijuana dependence itself, the cannabinoid receptor antagonist rimonabant is showing promise in primate trials to alter marijuana-seeking behavior.54 Low dose naltrexone (12 mg) has been reported to reduce the effects of marijuana, an approach that may hold promise in schizophrenia patients.55 Nefazodone, buspirone, and dronabinol show some promise as well in attenuating the manifestations of marijuana withdrawal.56 However, this research is in the preliminary stages, and it is yet to be made clear how these various approaches can be implemented in schizophrenia patients with marijuana dependence. As psychosis must be addressed in any approach to treatment for these patients, antipsychotics have featured prominently in the attempts to treat psychosis and marijuana dependence.

The first-generation antipsychotics appear to have little role in the treatment of other cannabis use disorders, and indeed, there are reports that they may worsen substance abuse.57 Older antipsychotics, especially high-potency dopamine antagonists, may further disrupt an already dysregulated mesocorticolimbic dopamine pathway, a feature common to both schizophrenia58 and drug dependence.59 Marijuana or other drug use may very well transiently relieve core deficits in schizophrenia patients, even though it may worsen psychotic symptoms.60,61 Buckley and colleagues62 reported on a 6-month study with clozapine, showing equal response in individuals for schizophrenia who did and did not use recreational drugs. Outcomes from dual diagnosis programs are of interest as well; for the 36 out of 151 schizophrenia patients on clozapine, remission rates from marijuana and alcohol were reported at 67% to 79%, compared to 34% for the remaining patients on first-generation antipsychotics.63 A 10-year follow-up study of this group showed that schizophrenia patients on clozapine and in remission had an 8% relapse risk in the following year compared to 40% on typical antipsychotics.64 Results have been more equivocal for the other second-generation antipsychotics.65 These antipsychotics, most prominently clozapine, seem to offer the best approach to the treatment of marijuana-associated psychosis, based on the literature available and in the personal experience of the author who has treated many patients with emerging psychosis due to marijuana use. Few treatments for individuals with emerging psychosis from marijuana use can be sifted from the existing literature. This author has found clozapine, olanzapine, and aripiprazole to be most useful in treating such patients that do not yet meet criteria for schizophrenia or other psychotic disorders.

Conclusion

Despite the major public health problems posed by marijuana abuse, the weight of disability imposed by schizophrenia, and the emerging consensus that marijuana use—especially at an early age—can lead to psychotic disorders in adults, treatment approaches to schizophrenia patients with marijuana dependence or for emerging marijuana-related psychosis are still sorely lacking.66 Any medication approach will likely not deliver its promise without the proper supportive and psychotherapeutic environment. Although medications like naltrexone or rimonabant may be applicable to the treatment of marijuana dependence in patients with schizophrenia as these might be less likely to exacerbate psychosis, they remain to be tested. Clozapine offers the best promise thus far among antipsychotics to mitigate both psychosis and marijuana misuse, both in individuals with schizophrenia and in patients with incipient psychosis due to marijuana. The difficulties of using clozapine have reduced its acceptability to patients and still pose a major hurdle to its more widespread use. Alternatives to clozapine that preserve its benefits and shed its severe liabilities are being actively sought after. Much more work is necessary to address the issue of marijuana-related psychosis, especially in light of the risk of serious mental illness posed by marijuana use in adolescents. Intervening early to stop marijuana use, as with overall drug use in the US, must remain a public health priority and may represent a unique and significant preventative measure to preserve good mental health in individuals at risks. PP

References

1.    Global Illicit Drug Trends 2002. New York, NY: United Nations Office for Drug Control and Crime Prevention; 2002.
2.    Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu-1 opioid receptor mechanism. Science. 1997;276(5321):2048-2050.
3.    Budney AJ, Moore BA, Vandrey RG, Hughes JR. The time course and significance of cannabis withdrawal. J Abnorm Psychol. 2003;112(3):393-402.
4.    Aldington S, Harwood M, Cox B, et al. Cannabis use and risk of lung cancer: a case-controlled study. Eur Respir J. 2008;31(2):280-286.
5.    Arseneault L, Cannon M, Witton J, Murray RM. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry. 2004;84:110-117.
6.    SAMHSA. Office of Applied Studies. The NSDUH Report:  Age at First Use of Marijuana and Past Year Serious Mental Illness. Available at: http://oas.samhsa.gov/2k5/MJageSMI/MJageSMI.cfm. Accessed February 26, 2009.
7.    Robins LN, Regier DA. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York, NY: The Free Press; 1991.
8.    Tien AY, Anthony JC. Epidemiological analysis of alcohol and drug use as risk factors for psychotic experiences. J Nerv Ment Dis. 1990;178(8):473-480.
9.    Halikas JA, Goodwin DW, Guze SB. Marijuana use and psychiatric illness. Arch Gen Psychiatry. 1972;27(2):162-165.
10.    Emrich HM, Leweke FM, Schneider U. Towards a cannabinoid hypothesis of schizophrenia: cognitive impairment due to dysregulation of the endogenous cannabinoid system. Pharmacol Biochem Behav. 1997;56(4):803-807.
11.    Williams JH, Wellman NA, Rawlins JN. Cannabis use correlates with schizotypy in healthy people. Addiction. 1996;91(6):869-877.
12.    Kwapil TR. A longitudinal study of drug and alcohol use by psychosis-prone and impulsive-nonconforming individuals. J Abnorm Psychol. 1996;105(1):114-123.
13.    Skosnick PD, Spatz-Glen L, Parks S. Cannabis use is associated with schizotypy and attentional disinhibition. Schizophr Res. 2001;48(1):83-92.
14.    Nunn J, Rizza F, Peters ER. The incidence of schizotypy among cannabis and alcohol users. J Nerv Ment Dis. 2001;189(11):741-748.
15.    Verdoux H, Sorbara F, Gindre C, Swenden D, van Os J. Cannabis and dimensions of psychosis in a non-clinical population of female students. Schizophr Res. 2003;59(1):77-84.
16.    Johns A. Psychiatric effects of cannabis. Br J Psychiatry. 2001;178:116-122.
17.    Tramèr MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ. 2001;323(7303):16-21.
18.    Verdoux H, Gindre C, Sorbara F, Tournier M, Swendsen J. Effects of cannabis use and psychosis vulnerability in daily life: an experience sampling test study. Psychol Med. 2003;33(1):23-32.
19.    Ashton C. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry. 2001;178:101-106.
20.    Hall W, Degenhardt L. Is there a specific “cannabis psychosis”? In: Murray R, Castle D, eds. Marijuana and Madness. New York, NY: Cambrige University Press; 2004:89-100.
21.    International Statistical Classification of Diseases and Health Related Problems. 10th rev. 2nd ed. Geneva, Switzerland: World Health Organization; 2004.
22.    Hall W, Degenhardt L. Cannabis use and psychosis: a review of clinical and epidemiological evidence. Aust N Z J Psychiatry. 2000;34(1):26-34.
23.    Van Os J, Bak M, Bijl RV, De Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol. 2002;156(4):319-327.
24.    Susser M. What is a cause and how do we know one? A grammar for pragmatic epidemiology. Am J Epidemiol. 1991;133(7):635-648.
25.    Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and schizophrenia: a longitudinal study of Swedish conscripts. Lancet. 1987;2(8574):1483-1485.
26.    Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self-reported cannabis use as a risk factor for schizophrenia: further analysis of the 1969 Swedish conscript cohort. BMJ. 2002;325(7374):1199-1201.
27.    Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. 2002;325(7374):1212-1213.
28.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
29.    Pistis M, Perra S, Pillolla G, Melis M, Muntoni AL, Gessa GL. Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse in rat midbrain dopamine neurons. Biol Psychiatry. 2004;56(2):86-94.
30.    Schneider, M. Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure. Addict Biol. 2008;13(2):253-263.
31.    Psychoyos D, Hungund B, Cooper T, Finnell RH. A cannabinoid analogue of delta(9)-tetrahydrocannabinol disrupts neural development in chick. Birth Defects Res B Dev Reprod Toxicol. 2008;83(5):477-488.
32.    Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol. 2005;19(2):187-194.
33.    Arendt M, Rosenberg R, Foldager L, Perto G, Munk-Jorgensen P. Cannabis-induced psychosis and subsequent schizophrenia spectrum disorders: follow-up study of 535 incident cases. Br J Psychiatry. 2005;187:510-515.
34.    Ferdinand RF, van der Ende J, Bongers I, Selten JP, Huizink A, Verhulst FC. Cannabis-psychosis pathway independent of other types of psychopathology. Schizophr Res. 2005;79(2-3):289-295.
35.    Arendt M, Mortensen PB, Rosenberg R, Pedersen CB, Waltoft BL. Familial predisposition for psychiatric disorder: comparison of subjects treated for cannabis-induced psychosis and schizophrenia. Arch Gen Psychiatry. 2008;65(11):1269-1274.
36.    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.
37.    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.
38.    Agrawal A, Wetherill L, Dick DM, et al. Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence. Am J Med Genet B Neuropsychiatr Genet. 2008 Nov 14 [epub ahead of print].
39.    De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis. 2003;2:5.
40.    Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D. Elevated endogenous cannabinoid in schizophrenia. Neuroreport. 1999;10(8):1665-1669.
41.    Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology. 2004;29(11):2108-2114.
42.    Zvolensky MJ, Lewinsohn, P, Bernstein A, et al. Prospective association between cannabis use, abuse, and dependence and panic attacks and disorder. J Psychiatr Res. 2008;42(12):1017-1023.
43.    Owen RR, Fischer EP, Booth BM, Cuffel BJ. Medication noncompliance and substance abuse among patients with schizophrenia. Psychiatr Serv. 1996;47(8):853-858.
44.    Swartz MS, Wagner HR, Swanson JW, et al. Substance use in persons with schizophrenia: baseline prevalence and correlates from the NIMH CATIE study. J Nerv Mental Dis. 2006;194(3):164-172.
45.    Abram KM, Teplin LA. Co-occurring disorders among mentally ill jail detainees. Implications for public policy. Am Psychol. 1991;46(10):1036-1045.
46.    Goodman LA, Salyers MP, Mueser KT, et al. Recent victimization in women and men with severe mental illness: prevalence and correlates. J Trauma Stress. 2001;14(4):615-632.
47.    Drake RE, Mueser KT, Brunette MF, McHugo GJ. A review of treatments for people with severe mental illness and co-occurring substance use disorders. Psychiatr Rehabil J. 2004;27(4):360-374.
48.    Potvin S, Stip E, Roy JY. Clozapine, quetiapine, and olanzepine among addicted schizophrenic patients: towards testable hypotheses. Int Clin Psychopharmacol. 2003;18(3):121-132.
49.    Mueser KT, Noordsy D, Drake RE, Fox M. Integrated Treatment for Dual Disorders: A Guide to Effective Practice. New York, NY: Guilford Press; 2003.
50.    Bellack AS, Bennett ME, Gearon JS, Brown CH, Yang Y. A randomized clinical trial of a new behavioral treatment for drug abuse with people with severe and persistent mental illness. Arch Gen Psychiatry. 2006;63(4):426-432.
51.    Weiss RD, Griffin ML, Kolodziej ME, et al. A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence. Am J Psychiatry. 2007;164(1):100-1007.
52.    Drebing CE, Van Ormer EA, Krebs C, et al. The impact of enhanced incentives on vocational rehabilitation outcomes in dually diagnosed veterans. J Appl Behav Anal. 2005;38(3):359-372.
53.    Brunette MF, Mueser KT, Drake RE. A review of research on residential programs for people with severe mental illness and co-occurring substance use disorders. Drug Alcohol Rev. 2004;23(4):471-481.
54.    Justinova Z, Munzar P, Panlilio LV, et al. Blockade of THC-seeking behavior and relapse in monkeys by the cannabin oid CB(1)-receptor antagonist rimonabant. Neuropsychopharmacology. 2008;33(12):2870-2877.
55.    Haney M. Opioid antagonism of cannabinoid effects: differences between marijuana smokers and non-marijuana smokers. Neuropsychopharmacology. 2007;32(6):1391-1403.
56.    Elkashef A, Vocci F, Huestis M, et al. Marijuana neurobiology and treatment. Subst Abus. 2008;29(3):17-29.
57.    Brady K, Anton R, Ballenger JC, Lydiard RB, Adinoff B, Selander J. Cocaine abuse among schizophrenic patients. Am J Psychiatry. 1990;147(9):1164-1167.
58.    Svensson TH, Mathé JM, Andersson JL, Nomikos GG, Hildebrand BE, Marcus M. Mode of action of atypical neuroleptic in relation to the phencyclidine model of schizophrenia: role of 5-HT2 receptor and alpha-1 adrenoreceptor antagonism. J Clin Psychopharmacol. 2005;15(1 suppl 1):11S-18S. Erratum in: J Clin Psychopharmacol. 1995;15(2):154.
59.    Raby WN, Levin, FR, Nunes EV. Pharmacological treatment of substance abuse disorders. In: Tasman A, Kay J, Lieberman JA, First MB, Maj M, eds. Psychiatry. 3rd ed. West Sussex, UK: Wiley-Blackwell; 2008:2390-2412.
60.    Green AI, Zimmet SV, Strous RD, Schildkraut JJ. Clozapine for co morbid substance use disorder and schizophrenia: Do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine? Harvard Rev Psychiatry. 1999;6(6):287-296.
61.    Roth RM, Brunette MF, Green AI. Treatment of substance use disorders in schizophrenia: a unifying neurobiological mechanism? Curr Psychiatry Rep. 2005;7(4):283-291.
62.    Buckley P, Thompson P, Way L, Meltzer HY. Substance abuse among patients with treatment-resistant schizophrenia: characteristics and implications for clozapine therapy. Am J Psychiatry. 1994;151(3):385-389.
63.    Drake RE, Xie H, McHugo GJ, Green AI. The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull. 2000;26(2):441-449.
64.    Brunette M, Drake RE, Xie H, McHugo GJ, Green AI. Clozapine use and relapses of substance use disorder among patients with co-occurring schizophrenia and substance use disorders. Schizophr Bull. 2006;32(4):637-643.
65.    Green AI, Noordsy DL, Brunette MF, O’Keefe C. Substance abuse and schizophrenia: pharmacotherapeutic interventions. J Subst Abuse Treat. 2008;34(1):61-71.
66.    Bodkin LL, Singh A, Corcoran C. Cannabis as a risk factor for psychosis in vulnerable teens: implications for treatment. Primary Psychiatry. 2008;15(1):51-57.

Return

 

Dr. Compton is assistant professor in the Department of Psychiatry and Behavioral Sciences and Ms. Ramsay is research coordinator of the Atlanta Cohort on the Early Course of Schizophrenia Project, both at Emory University School of Medicine in Atlanta, Georgia.

Disclosures: Dr. Compton receives grant support from the Emory University Research Committee and the National Institute of Mental Health. Ms. Ramsay reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Michael T. Compton, MD, MPH, Assistant Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 49 Jesse Hill Jr. Drive, S.E., Room #333, Atlanta, GA 30303; Tel: 404-778-1486; Fax:  404-616-3241; E-mail: mcompto@emory.edu.


 

Focus Points

• Cannabis, or marijuana, is a drug that is commonly abused by adolescents and young adults; it is the most frequently abused illicit drug among people with schizophrenia or other psychotic disorders.
• Among people with comorbid substance abuse and schizophrenia or other psychotic disorders, substance use and abuse are typically initiated prior to the overt onset of the psychotic disorder.
• Some research suggests that cannabis use prior to onset may be associated with an earlier age at onset of psychosis, although it is difficult to establish whether this association is causal.
• Athough additional research is needed, preliminary research suggests that cannabis use prior to any psychiatric symptoms may be associated with an earlier age at onset of the prodromal symptoms that commonly precede the onset of schizophrenia.

 

Abstract

Schizophrenia is currently conceptualized as an illness that is caused by both genetic predispositions and exposure to stressors or environmental factors, particularly during early childhood and adolescence. This article focuses on one such environmental factor, cannabis use, especially use occurring prior to the onset of clinically evident psychiatric symptoms. Cannabis is commonly abused by adolescents and is the most abused illicit drug in the context of schizophrenia. Several first-episode studies document that the initiation of substance use and abuse typically precedes the onset of psychosis. This article highlights eight studies that characterize the impact of cannabis use on the age at onset of psychosis and three studies that provide early information on the impact of cannabis use on the age at onset of even earlier prodromal symptoms. Future research is needed to better characterize the impact of cannabis use on the onset of psychotic disorders and to determine if cannabis use increases the risk of developing a psychotic disorder, as several other studies suggest. Based on emerging evidence, preventing or reducing cannabis use among adolescents, particularly those at elevated risk of developing psychosis, may delay the onset of psychosis in some.

Introduction

Schizophrenia is currently conceptualized from the perspectives of the neurodevelopmental and diathesis-stress models.1-3 The neurodevelopmental model integrates altered pre- or perinatal brain development, adolescent developmental abnormalities, and potentially progressive processes that occur after illness onset.3 The diathesis-stress model suggests that symptomatic manifestations of the biologic vulnerability for schizophrenia are influenced by exposure to stressors or environmental factors.4 Based on these conceptualizations, the following points are fairly well accepted among schizophrenia researchers: First, the etiology of the disorder is most likely related to a number of genetic and early environmental risk factors. Second, later risk factors (during adolescence and young adulthood) and neurohormonal changes likely impact the manifestation of underlying vulnerability. Third, genes and environmental risk factors may interact to affect risk. Fourth, the sequential onset of symptoms usually occurs in a gradual  fashion from the premorbid phase to the prodrome to the onset of full psychosis. Fifth, symptom onset, phenomenology, and course are highly heterogeneous. Last, both genetic and environmental factors contribute to this heterogeneity.

This article focuses on one such environmental factor, cannabis use, especially that which occurs prior to the onset of clinically evident psychiatric symptoms. Although adolescent-onset cannabis use has been shown by epidemiologic research to be a risk factor (presumably a causal risk factor, or component cause) for schizophrenia,5-10 the present article examines this environmental factor in terms of its potential to adversely affect two key features of disease onset—age at onset of psychosis and age at onset of even earlier prodromal symptoms. This qualitative summary of the literature is not meant as a systematic review, but as a synthesis of select studies in this area.

The Crossroads of Schizophrenia and Cannabis Use

Cannabis is the most commonly used illicit drug in the United States. According to the 2006 National Survey on Drug Use and Health, 45.4% of Americans ≥12 years of age have tried cannabis at least once.11 Among those ≥18 years of age with lifetime cannabis use, >50% report first using it between 12 and 17 years of age.12,13 Earlier onset of drug use has consistently been associated with greater risk of developing abuse and dependence.12,14-17 Cannabis use disorders occur in approximately 4% of the general US population, with a peak in the 18–29-year age range.15,18,19 Some 56% of those seen in treatment for cannabis abuse/dependence began using by 14 years of age, and 92% began by 18 years of age.13,20 Cannabis use is now considered a substantial public health problem by many, due to several reasons, as noted previously.21 First, US adolescents and young adults have very high rates of cannabis use. Second, cannabis dependence in youths predicts increased risks of using other illicit drugs and underperforming in school.22 Third, the cannabinoid content of smoked cannabis has increased substantially during recent decades,23 potentially resulting in a larger “dose” of psychoactive cannabinoids during drug use.

Unsurprisingly, given the aforementioned high population prevalence of cannabis use, cannabis is the most abused illicit drug in the context of schizophrenia.24 The Epidemiologic Catchment Area study found the lifetime prevalence of a cannabis use disorder in people with schizophrenia to be 19.7%.25 Many studies confirm high rates (20% to 70%) of cannabis use in patients with schizophrenia.26-31 Data from 53 studies of schizophrenia revealed that 12-month prevalence estimates of use and misuse of cannabis were 29% and 19%, and lifetime use and misuse estimates were 42% and 23%, respectively.32 Researchers report rates of cannabis misuse ranging from 15% to 65% in first-episode samples.33-39

Several first-episode studies document that the initiation of substance use and abuse typically precedes the onset of psychosis, often by several years.31,38,40-42 When prodromal symptoms are taken into account, one German study37 of 232 patients with a first episode of psychosis found that 29.5% of those using drugs had a drug problem >1 year before the earliest sign of an emerging psychotic disorder. In an additional 34.6%, drug abuse emerged at the same time as the first symptoms. In a first-episode sample (n=133) from the Netherlands, among those patients who had used cannabis by the time of their first treatment contact, 64.3% reported initiating cannabis use before the onset of social and/or occupational dysfunction and 85.7% before the onset of psychosis.43 In a sample of 109 hospitalized patients with first-episode non-affective psychosis in the US, 79.8% had used cannabis at least once in the years prior to hospitalization (Compton MT, unpublished data, March 2009). While mean ages at the onset of prodromal symptoms and psychotic symptoms in that sample were 19.4±5.3 and 21.8±4.7 years, respectively, the mean age at first use of cannabis among the 87 who had used it was 15.8±4.0. These and other studies indicate a high prevalence of cannabis use occurring prior to the onset of psychiatric symptoms in people who develop a psychotic disorder.

Although numerous studies show that the initiation of substance use commonly precedes the onset of psychosis, this does not necessarily imply a directional or causal association.  It is not surprising that substance use often precedes psychosis given that initiation of substance use usually occurs during adolescence.  However, research establishing that early-course patients typically begin substance use prior to onset confirms temporality (ie, that exposure precedes outcome in a plausible way), which is one criterion in ultimately establishing a causal relationship. This article, which largely focuses on the possibility that pre-onset cannabis use may hasten onset of psychotic disorders, notes as important the substantial research showing that, among patients with comorbidity, substance use often precedes the manifestation of symptoms.

The biologic pathways linking cannabis use and psychosis are being actively studied. Numerous research findings, six of which are briefly described here, may demonstrate the biologic plausibility of pre-onset cannabis use impacting not only vulnerability for developing schizophrenia, but also the age at onset among those who do develop the disorder. First, exogenous cannabinoids (eg, marijuana) are extremely lipid soluble, accumulating in fatty tissues from which they are slowly released back into body compartments, including the brain,23 suggesting that even occasional cannabis use leads to long-term exposure of central receptors to cannabinoids. Second, exogenous and endogenous (eg, anandamide) cannabinoids exert their effects (such as modulating the release of neurotransmitters including glutamate, norepinephrine, and dopamine) by interactions with specific cannabinoid (CB1) receptors44,45 that are distributed in brain regions implicated in the pathophysiology of schizophrenia (including the cerebral cortex, limbic areas, basal ganglia, and thalamus).23 Third, cannabis increases mesolimbic dopaminergic transmission and inhibits glutamatergic release.46 Fourth, several studies have shown an increased CB1 receptor density in brain regions of interest in schizophrenia, including the dorsolateral prefrontal cortex and the anterior cingulate cortex,47-49 and elevated levels of endogenous cannabinoids in the blood and cerebrospinal fluid of patients with schizophrenia.50-52 Fifth, gene variants of the CB1 receptor may be associated with schizophrenia and risk of substance abuse in individuals with schizophrenia.48,53,54 However, other studies have not found an association with risk for schizophrenia,55 and a recent meta-analysis did not implicate these gene variants among 24 showing significant effects.56 Sixth, acute administration of cannabis causes both patients and controls to experience transient increases in cognitive impairments and schizophrenia-like positive and negative symptoms.57 It could be argued that these six points provide only a weak argument for a causal effect of cannabis on hastening onset. For example, the findings of increased CB1 receptor density in regions implicated in schizophrenia are not surprising given that CB1 receptors are relatively widely dispersed.  However, when taken together, these findings do suggest biologic plausibility, which, like temporality, is one criterion for eventually demonstrating causality. 

Having provided some evidence supporting potential biologic plausibility, the remainder of this article focuses on two themes—the potential impact of early-course cannabis use on both the age at onset of psychotic symptoms and the age at onset of even earlier prodromal symptoms. Age at onset of the prodrome and psychosis are critical variables to understand because they are important prognostic factors. An earlier age at onset is associated with a higher degree of cognitive impairment, increased severity of psychosocial and functional disability, more severe symptoms and behavioral deterioration, less responsiveness to antipsychotics, decreased ability to tolerate discontinuation of medication, and greater likelihood of rehospitalization.58-69 Given extensive literature connecting earlier onset with poorer course and outcomes, discovering potentially modifiable determinants of age at onset is crucial. Could pre-onset cannabis use in adolescence be one such determinant?

The Impact of Pre-psychotic Cannabis Use on the Age at Onset of Psychosis

At least eight studies, generally collecting cross-sectional or retrospective information from individuals with a recent onset of psychosis, have examined the potential impact of cannabis use on the age at onset of psychosis. These studies, discussed briefly here, are also summarized in the Table (Compton MT, unpublished data, March 2009).28,34,38,42,43,70,71 Although numerous older studies explored the relationship between substance abuse and psychosis, Hambrecht and Häfner28 were perhaps the first to study the exact timing of the onset of substance use and symptoms in first-episode psychosis. In the Age, Beginning, and Course (ABC) schizophrenia study,28 they found that the mean age at onset of the first negative symptom, first positive symptom, and first admission were lower in the 32% who had abused drugs prior to admission than in those who had not. The mean ages at first positive and negative symptoms were each 5.7 years younger for those with a history of drug abuse than for those with no substance abuse history (21.1 compared to 26.8, and 24.3 compared to 30.0, respectively). Among those who reported a history of drug abuse, the mean age at onset of drug abuse was 18.6 years, or 1.5 and 5.7 years before the mean age at onset of the first negative and first positive symptoms. However, the analysis of age at onset was not restricted to those who had initiated drug abuse specifically before, rather than during or after, the onset of illness. In addition, the independent effects of particular substances of abuse were not considered (although 90% of those abusing drugs in the sample had abused cannabis, 63% had used other drugs as well). Finally, the study did not examine the impact of drug use before it reached the threshold of drug abuse.
Among a sample of patients in New York State with a first episode of either affective or non-affective psychosis (n=541), symptom onset among men and women was examined by Rabinowitz and colleagues38 in three groups: those with no lifetime substance use disorder diagnosis, those in remission or with mild substance use, and those with current moderate-to-severe substance abuse at the time of admission. Females with current moderate-to-severe substance abuse were 6 years younger at the onset of first psychotic symptoms than their counterparts with no lifetime substance use. No significant impact on the age at onset was observed for males. However, the inclusion of patients with affective as well as non-affective psychoses introduces heterogeneity in the expected age at onset, disease mechanisms, gender distribution, and rates of comorbid substance abuse. Nonetheless, this study is notable for accounting for the severity of substance use.

 

In the Calgary Early Psychosis Program, which assesses and treats patients with a recent onset of psychosis, 44% of 357 consecutively admitted patients had substance abuse or dependence in the previous year.70 In this sample, Van Mastrigt and colleagues70 found that patients who had misused cannabis (or cannabis and alcohol) were younger and had an earlier age at onset of positive psychotic symptoms than non-users or those who misused alcohol only or alcohol and other drugs. These findings suggest that a link may exist between cannabis use and age at onset of psychosis, and that this effect may be related to the cannabis, per se, as opposed to personality traits or other vulnerabilities that lead to a substance use disorder, given that misuse of other substances did not carry the same association. However, without data on the age at first cannabis use or abuse, or on the onset of prodromal or negative symptoms, it is not possible to establish the directionality of the association between cannabis use and the age at onset of symptoms.

Veen and colleagues43 used an incidence cohort of patients in the Netherlands to examine the independent influences of gender and cannabis use on early course features. The sample (n=133) included natives of the Netherlands, first- and second-generation immigrants from Surinam and Morocco, and individuals from other racial/ethnic groups. Patients who used cannabis (n=70) had an earlier median age at onset compared to the 63 patients not using cannabis. In a multiple regression analysis, male cannabis users (n=55) were found to have had their first psychotic episode a mean of 6.9 years earlier than 37 male nonusers. Cannabis use was a stronger predictor of age at first psychotic episode than gender. However, the study did not control for the effects of family history or the use of other substances (eg, alcohol, cocaine). Furthermore, the study treated cannabis use as categoric/dichotomous variable (which is true of most studies conducted to date) and therefore could not examine potential dose-effect relationships.

Mauri and colleagues42 retrospectively studied 285 first-episode patients in Italy and found that patients abusing cannabis had an earlier age at onset compared with those who did not abuse cannabis, though it is unclear how onset was operationalized. Further, this comparison failed to control for the influence of gender, and only 18% of females had used substances compared to 44% of males. Additionally, much of the data were obtained by retrospectively reviewing medical records (which are presumably less thorough and accurate than formal research assessments), 56% of patients having used drugs were multi-drug abusers (and this apparently was not controlled for), and the amount and duration of substance use was not considered.

In London, Barnes and colleagues34 assessed 152 first-episode patients and found that those reporting past substance use were significantly younger at the onset of psychotic symptoms compared with those who had not used substances. In a linear regression, use of any substances other than cannabis was not significantly related to age at onset, though gender and cannabis use were. The age at onset of psychosis was on average 4.2 years older for women and 5.0 years younger for participants using cannabis, adjusting for the other variables. In this study, like most others, cannabis was the most prevalently used illicit substance, and, therefore, detecting an effect of cannabis may be easier than finding effects of other drugs, given issues of statistical power. Unfortunately, inquiries about past substance use did not include detailed assessment of the frequency and quantity of drugs taken, and it is unclear whether the initiation of cannabis use in fact preceded the onset of symptoms in the patients included in the analysis.

González-Pinto and colleagues71 found, among 131 first-episode patients in Spain, a significant, gradual reduction in age at onset as the level of use of cannabis increased—a decrement of 7, 8.5, and 12 years for patients with cannabis use, abuse, and dependence, respectively. The effect was not explained by the use of other drugs or gender. However, the study included patients with affective psychosis, who would be expected to have a later age at onset, and likely a lower prevalence of comorbid cannabis use. In addition, the study did not take into account the duration of cannabis use and it is not clear exactly how age at onset was operationalized.

Recently, Compton and colleagues (Compton MT, unpublished data, March 2009) examined the impact of prior cannabis use on the age at onset of psychosis in 109 patients hospitalized for a first episode of psychosis. This group found that both daily cannabis and daily tobacco use occurring before onset of psychosis had a significant effect on the risk of onset of psychosis (hazard ratios of 2.0 and 1.8, respectively, P<.05), when the level of frequency of use was treated as a time-dependent covariate in Cox regressions (ie, progression to daily use was associated with a higher risk of onset). Of note, cannabis and tobacco use were highly correlated (eg, having ever used nicotine was highly associated with having ever used cannabis, χ2=25.5, P<.001 [Compton MT, unpublished data, March 2009]) and therefore may not represent two independent risk factors. A gender by progression to daily cannabis use interaction was observed—progression to daily use was related to a much larger increased relative risk for onset of psychosis in females (hazard ratio=5.1) than in males (hazard ratio=3.4). Although this study took into account the frequency of cannabis use (ie, never, ever but not weekly use, weekly but not daily use, or daily use), it did not assess quantity of use and did not gather detailed information on patterns of use.

Impact of Pre-prodromal Cannabis Use on the Age at Onset of the Prodrome

While the previously reviewed studies suggest, through various analytic designs, that cannabis use may be associated with a younger age at onset of psychotic symptoms, only a few groups have attempted to determine if cannabis use is associated with a younger age at onset of prodromal symptoms. The prodrome is the syndromal period commonly comprised of non-specific psychiatric symptoms, emerging attenuated positive symptoms, negative symptoms, and psychosocial decline—commonly lasting several months to a few years—that precedes the emergence of frank psychosis in most patients. One critique of the literature is that the possible influence of cannabis use on prodromal symptoms has not been adequately explored.34 Doing so could shed light on the competing hypotheses that substance use precipitates or hastens onset of the illness versus that very early, subtle symptoms of the illness make patients vulnerable to substance use.

Hambrecht and Häfner28 conducted one of very few studies that included an analysis of prodromal symptoms in relation to substance use. In 232 first-episode patients from the ABC schizophrenia study, they found that the mean age at onset of the first sign was lower in the 32% who had abused drugs prior to admission than in those who had not. First signs included the first negative, positive, or non-specific psychiatric symptom if it occurred continuously until the onset of psychosis. In this way, the “first sign” represented the onset of the prodrome, if a prodrome had occurred, or psychosis, if there had been no prodrome. The age at first-sign onset was 7.2 years younger among those who had abused drugs than among those who had no history of drug or alcohol abuse (18.5 compared to 25.7 years).

In the report by Veen and colleagues,43 the relationship between prior cannabis use and the age at onset of the first sign of social or occupational dysfunction, which could be considered a proxy for the age at onset of the prodrome, was examined. In this cohort, the median age at onset was 18.1 years among patients using cannabis, as compared to 27.7 years in those not using cannabis. However, in a linear regression, gender was a more important predictor of age at onset, and after controlling for this variable, cannabis use was not a significant predictor. This study did not use a precise indicator of the onset of the prodrome, but it is noteworthy for its analysis of the effect of prior cannabis use on onset. Like their analysis of age at onset of psychosis, Veen and colleagues43 did not control for family history or other substance abuse, and they treated cannabis use as a categorical variable.

Similar to their findings pertaining to age at onset of psychosis, Compton and colleagues (Compton MT, unpublished data, March 2009) examined the impact of prior cannabis use on the age at onset of illness/prodromal symptoms in 109 hospitalized first-episode patients. When considering the level of frequency of use as a time-dependent covariate in Cox regressions, both daily cannabis and tobacco use had a significant effect on the risk of onset of the symptoms (which represented the onset of the prodrome in 70% of the sample), hastening onset (hazard ratios=2.1 and 1.8, respectively). As noted above, although this analysis accounted for the frequency of cannabis use, other methodologic limitations make the results preliminary, requiring further research.

Discussion and Unanswered Questions

In summary, several studies suggest that cannabis use among first-episode patients prior to onset may be associated with an earlier age at onset of positive psychotic symptoms. Much less is known about potential associations between pre-prodromal cannabis use and the onset of prodromal symptoms. The Figure depicts hypothesized symptom development and the accumulation of functional impairment in the early course of schizophrenia in patients with a history of cannabis use compared to those without a history of cannabis use. Further research is needed to show whether pre-onset cannabis use is in fact an independent risk factor for developing a psychotic disorder or for an earlier emergence of symptoms among those who do develop a disorder. Support for the psychotogenic properties of cannabis during a prodromal period comes from the finding that perceptual disturbances fluctuate over time with cannabis use in a clinical high-risk cohort.72

 

As stated above, an earlier age at onset of psychosis is a poor prognostic indicator. If further research proves a link between adolescent, pre-onset cannabis use and age at onset, then decreasing cannabis use among adolescents may delay the onset of psychosis among those destined to develop a psychotic disorder. Some have argued that there now exists sufficient evidence to inform the public that using cannabis could increase the risk of developing a psychotic illness73; this may be especially relevant for at-risk groups. Programs to decrease cannabis use may be particularly beneficial in adolescents identified as being at very high risk for psychosis, by virtue of a positive family history or by being identified as potentially prodromal or at “ultra-high risk” based on emerging psychiatric symptoms and functional decline. Just as decreasing cannabis use has been suggested as a potential preventive intervention to reduce the incidence of schizophrenia,74,75 reducing cannabis use also could delay onset among those who do, nonetheless, develop the disorder.76

Numerous unanswered questions should be the focus of ongoing research. First, given the high comorbidity between cannabis abuse and the abuse of other addictive substances, especially nicotine and alcohol,77,78 the independent effects of pre-onset cannabis use, as well as pre-onset nicotine, alcohol, and other drug use, should be examined. Although the neurobiologic feasibility of the cannabis/psychosis link was pointed out above, it must be recognized that alcohol and other drugs impact upon dopaminergic, glutamatergic, and other neurotransmitter systems affected by schizophrenia. Regarding potential effects of alcohol and cannabis, for example, on psychosis risk, the same neural structures are indeed affected by both substances, at least at a global level (mesolimbic dopamine pathways and the central reward system in general), though alcohol and cannabis exert their effects partly through different receptors (ie, g-aminobutyric acid-ergic/glutamatergic and cannabinoid receptors, respectively). Some evidence suggests that alcohol may exert modulatory actions in the endogenous cannabinoid system.79 In addition to cannabis and alcohol, nicotine use is also a critical variable to examine for a couple of reasons: Cigarette smoking is highly prevalent in individuals with schizophrenia80,81 (even in those with first-episode psychosis),82 and there is increasing interest in the literature in biologic links between the central nicotinic system and schizophrenia.83-85 However, though such elucidation of single-drug effects would be beneficial, it must be emphasized, as noted above, that the independent effects of each substance will be difficult to parse given the high degree of comorbidity across substances, especially cannabis, alcohol, and nicotine. Relatively large sample sizes likely will be necessary to examine independent effects.

A second direction for future research pertains to the issue of causality versus association. Like any observational study, the studies described here cannot rule out the possibility of reverse causality, in which the disease processes associated with the later development of psychosis render an individual more susceptible to the initiation of substance use and abuse earlier in life. Even if further research indicates that pre-onset cannabis use is associated with an earlier age at onset, sorting out whether the cannabis use causes an earlier onset or is a marker of a disease process or subtype associated with earlier onset will be challenging. Similar questions pertain to the link between cannabis use and risk of developing schizophrenia—causality remains difficult to prove, and a shared diathesis for both psychotic illnesses and substance abuse may be at play.

Third, regarding a potential impact of cannabis use on prodromal symptomatology, it is possible that cannabis use causes prodrome-like (but not definitively prodromal) symptoms in patients who later develop a psychotic disorder. That is, cannabis use in adolescence among patients who later develop a psychotic disorder may lead to apathy, academic problems, and other prodromal-appearing difficulties, though such problems may not necessarily be inherent to the schizophrenia process or they may not alter the course of the developing psychotic disorder in a way that conveys long-term course implications. A number of studies suggest that cannabis use is associated with schizotypal features in people who may or may not develop schizophrenia.21 Furthermore, in a recent study86 involving 6,330 adolescents (15–16 years of age) in a Finnish prospective birth cohort, the 356 (5.6%) participants who had used cannabis endorsed a higher mean number of “prodromal” symptoms, and a dose-response relationship was evident. However, actual prodromal symptoms can only be confirmed retrospectively; it remains to be determined through further longitudinal research whether or not the symptoms assessed in that study actually represented a prodrome.

A fourth important issue requiring further, more methodologically rigorous research, relates to the measurement of substance use in relation to ages at onset of prodromal and psychotic symptoms. As noted above, not all prior studies commented on (in fact, most did not) or restricted the analyses to those whose drug use/abuse preceded the onset of psychotic and/or prodromal symptoms,28,34,70,71 which is critical to the research question. To advance the field in this area, future research should carefully examine the timing of the initiation of cannabis use and the development of psychotic symptoms as well as earlier prodromal symptoms using well-defined operationalizations of onset. Such retrospective measurement is admittedly a difficult task. Comprehensive assessments of cannabis and other substance use with reliable and valid retrospective measures that incorporate calendars, timelines, and significant life events should be used to gather data on amount, duration, frequency, and patterns of use, thus allowing for the examination of temporal relationships and potential dose effects. Additionally, because the limited research in this area to date has generally consisted of cross-sectional and retrospective studies, other research designs, including case-control and longitudinal studies, would be beneficial.

Fifth, relevant covariates, including gender and family history, must be examined when studying age at onset. The fact that gender is a predictor of age at onset is one of the most consistent findings in schizophrenia research.87,88 For example, results from the ABC schizophrenia study indicate that women are 3–4 years older than men at illness onset, as defined by the onset of positive symptoms, negative symptoms, or psychosocial impairment.89,90 Family history of schizophrenia is also associated with an earlier age at onset,91-94 and should be assessed as a covariate. It should be noted, however, that even if future studies are more rigorous, it may still be difficult to establish with certainty that cannabis use hastens onset and that all relevant covariates have been taken into account. Confounding (the distortion of an apparent effect of cannabis use on risk brought about by an association with other significant risk factors), must be seriously considered.

These five issues, among others, suggest a need for further research to substantiate the early reports that pre-onset cannabis use, typically occurring in adolescence, may be associated with (and perhaps even causative of) an earlier age at onset. This line of research—in addition to ongoing research on the neurobiologic interface between cannabinoid systems and the neurocircuitry involved in schizophrenia, cannabis use as a potential component cause of schizophrenia, and the influence of cannabis use on symptom and neurocognitive profiles—may advance the field in terms of both further elucidating psychotic disorders and informing future preventive interventions.

Conclusion

Several first-episode studies document that the initiation of substance use and abuse typically precedes the onset of psychosis, often by several years. Studies reviewed also suggest that cannabis use among first-episode patients prior to onset may be associated with an earlier age at onset of positive psychotic symptoms. Much less is known about potential associations between pre-prodromal cannabis use and the onset of prodromal symptoms, though preliminary evidence suggests that an association may be present.  Future research should examine the effects of cannabis, independent of other substances used; establish the causal direction of these associations; clarify whether prodrome-like symptoms observed during concurrent cannabis abuse are, indeed, related to the subsequent psychosis; include more rigorous research design; and control for all significant covariates such as gender and family history. PP

References

1.    Keshavan MS, Gilbert AR, Diwadkar VA. Neurodevelopmental theories. In: Lieberman JA, Stroup TS, Perkins DO, eds. Textbook of Schizophrenia. Washington, DC: American Psychiatric Publishing, Inc.; 2006:69-83.
2.    Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363(9426):2063-2072.
3.    Walker EF. Developmentally moderated expressions of the neuropathology underlying schizophrenia. Schizophr Bull. 1994;20(3):453-480.
4.    Walker EF, Diforio D. Schizophrenia: a neural diathesis-stress model. Psychol Rev. 1997;104(4):667-685.
5.    Andréasson S, Allebeck P, Rydberg U. Schizophrenia in users and nonusers of cannabis. A longitudinal study in Stockholm County. Acta Psychiatr Scand. 1989;79(5):505-510.
6.    Arsenault L, Cannon M, Witton J, Murray R. Cannabis as a potential causal factor in schizophrenia. In: Castle DJ, Murray R, eds. Marijuana and Madness. Cambridge, MA: Cambridge University Press; 2004:101-118.
7.    Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol. 2005;19(2):187-194.
8.    Smit F, Boiler L, Cuijpers P. Cannabis use and the risk of later schizophrenia: a review. Addiction. 2004;99(4):425-430.
9.    Weiser M, Noy S. Interpreting the association between cannabis use and increased risk for schizophrenia. Dialogues Clin Neurosci. 2005;7(1):81-85.
10.    Zammit S, Allebeck P, Andréasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002;325(7374):1199-1203.
11.    Substance Abuse and Mental Health Services Administration (SAMHSA). Office of Applied Studies. 2006 National Survey on Drug Use and Health: Detailed Tables. Available at: http://oas.samhsa.gov/NSDUH/2k6NSDUH/tabs/Sect1peTabs1to46.htm#Tab1.19B. Accessed February 20, 2009.
12.    Substance Abuse and Mental Health Services Administration (SAMHSA). Results from the 2004 National Survey on Drug Use and Health: National Findings. NSDUH Series H-25. DHHS Pub. No. 04-3964. Rockville, MD: SAMHSA; 2005.
13.    National Institute on Drug Abuse (NIDA). InfoFacts. Marijuana. Available at: www.drugabuse.gov/PDF/InfoFacts/Marijuana06.pdf. Accessed February 20, 2009.
14.    Anthony JC, Petronis KR. Early-onset drug use and risk of later drug problems. Drug Alcohol Depend. 1995;40(1):9-15.
15.    Compton WT, Grant BF, Colliver JD, Glantz MD, Stinson FS. Prevalence of marijuana use disorders in the United States: 1991-1992 and 2001-2002. JAMA. 2004;291(17):2114-2121.
16.    Grant BF, Dawson DA. Age at onset of drug use and its association with DSM-IV drug abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse. 1998;10(2):163-173.
17.    Lynskey MT, Heath AC, Bucholz KK, et al. Escalation of drug use in early-onset cannabis users vs co-twin controls. JAMA. 2003;289(4):427-433.
18.    Robins LN, Regier DA. Psychiatric Disorders in America. New York, NY: Free Press; 1991.
19.    Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry. 1994;51(1):8-19.
20.    Substance Abuse and Mental Health Services Administration (SAMHSA). Treatment Episode Data Set (TEDS). Highlights – 2003. National Admissions to Substance Abuse Treatment Services. DASIS Series: S-27, DHHS Publication No. (SMA 05-4043). Rockville, MD: SAMHSA; 2005.
21.    Compton MT, Goulding SM, Walker EF. Cannabis use, first-episode psychosis, and schizotypy: a summary and synthesis of recent literature. Cur Psychiatry Rev. 2007;3(3):161-171.
22.    Hall WD. Cannabis use and the mental health of young people. Austr N Z J Psychiatry. 2006;40(2):105-113.
23.    Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry. 2001;178(2):101-106.
24.    Mueser KT, Yarnold PR, Levinson DF, et al. Prevalence of substance abuse in schizophrenia: demographic and clinical correlates. Schizophr Bull. 1990;16(1):31-56.
25.    Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiological Catchment Area (ECA) Study. JAMA. 1990;264(19):2511-2518.
26.    Bersani G, Orlandi V, Kotzalidis GD, Pancheri P. Cannabis and schizophrenia: impact on onset, course, psychopathology and outcomes. Eur Arch Psychiatry Clin Neurosci. 2002;252(2):86-92.
27.    Dubertret C, Bidard I, Adès J, Gorwood P. Lifetime positive symptoms in patients with schizophrenia and cannabis abuse are partially explained by co-morbid addiction. Schizophr Res. 2006;86(1-3):284-290.
28.    Hambrecht M, Häfner H. Substance abuse and the onset of schizophrenia. Biol Psychiatry. 1996;40(11):1155-1163.
29.    Hides L, Dawe S, Kavanagh DJ, Young RM. Psychotic symptom and cannabis relapse in recent-onset psychosis. Br J Psychiatry. 2006;189(2):137-143.
30.    Linszen DH, Dingemans PM, Lenior ME. Cannabis abuse and the course of recent onset schizophrenic disorders. Arch Gen Psychiatry. 1994;51(4):273-279.
31.    Sevy S, Robinson DG, Holloway S, et al. Correlates of substance abuse in patients with first-episode schizophrenia and schizoaffective disorder. Acta Psychiatr Scand. 2001;104(5):367-374.
32.    Green B, Young R, Kavanagh D. Cannabis use and misuse prevalence among people with psychosis. Br J Psychiatry. 2005;187(4):306-313.
33.    Addington J, Addington D. Impact of an early psychosis program on substance use. Psychiatr Rehab J. 2001;25(1):60-68.
34.    Barnes TR, Mutsatsa SH, Hutton SB, Watt HC, Joyce EM. Comorbid substance use and age at onset of schizophrenia. Br J Psychiatry. 2006;188(3):237-242.
35.    Compton MT, Furman AC, Kaslow NJ. Lower negative symptom scores among cannabis-dependent patients with schizophrenia-spectrum disorders: preliminary evidence from an African American first-episode sample. Schizophr Res. 2004;71(1):61-64.
36.    Cantwell R, Brewin J, Glazebrook C, et al. Prevalence of substance misuse in first-episode psychosis. Br J Psychiatry. 1999;174(2):150-153.
37.    Hambrecht M, Häfner, H. Cannabis, vulnerability, and the onset of schizophrenia: an epidemiological perspective. Austr N Z J Psychiatry. 2000;34(3):468-475.
38.    Rabinowitz J, Bromet EJ, Lavelle J, Carlson G, Kovasznay B, Schwartz JE. Prevalence and severity of substance use disorder and onset of psychosis in first-admission psychotic patients. Psychol Med. 1998;28(6):1411-1419.
39.    Wade D, Harrigan S, McGorry PD, Burgess PM, Whelan G. Impact of severity of substance use disorder on symptomatic and functional outcome in young individuals with first-episode psychosis. J Clin Psychiatry. 2007;68(5):767-774.
40.    Silver H, Abboud E. Drug abuse in schizophrenia: comparison of patients who began drug abuse before their first admission with those who began abusing drugs after their first admission. Schizophr Res. 1994;13(1):57-63.
41.    Bühler B, Hambrecht M, Löffler W, an der Heiden W, Häfner H. Precipitation and determination of the onset and course of schizophrenia by substance abuse—a retrospective and prospective study of 232 population-based first illness episodes. Schizophr Res. 2002;54(3):243-251.
42.    Mauri M, Volonteri L, De Gaspari I, Colasanti A, Brambilla M, Cerruti L. Substance abuse in first-episode schizophrenic patients: a retrospective study. Clin Pract Epidemiol Ment Health. 2006;2:4-12.
43.    Veen ND, Selten JP, van der Tweel I, Feller WG, Hoek HW, Kahn RS. Cannabis use and age at onset of schizophrenia. Am J Psychiatry. 2004;161(3):501-506.
44.    Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34(5):605-613.
45.    Iversen L. Cannabis and the brain. Brain. 2003;126(6):1252-1270.
46.    Zammit S, Lewis G. Exploring the relationship between cannabis use and psychosis. Addiction. 2004;98(11):1353-1355.
47.    Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neurosci. 2001;103(1): 9-15.
48.    Sundram S, Dean B, Copolov D. The endogenous cannabinoid system in schizophrenia. In: Castle DJ, Murray R, eds. Marijuana and Madness. Cambridge, MA: Cambridge University Press; 2004:127-141.
49.    Zavitsanou K, Garrick T, Huang XF. Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Progress Neuro-Psychopharmacol Biol Psychiatry. 2004;28(2):355-360.
50.    De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V. Endocannabinoid signaling in the blood of patients with schizophrenia. Lipids Health Dis. 2003;2(5):5-14.
51.    Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology. 2004;29(11):2108-2114.
52.    Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D. Elevated endogenous cannabinoids in schizophrenia. Neuroreport. 1999;10(8):1665-1669.
53.    Leroy S, Griffon N, Bourdel MC, Olié JP, Poirier MF, Krebs MO. Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Am J Med Genet (Neuropsychiatr Genet). 2001;105(8):749-752.
54.    Ujike H, Takaki M, Nakata K, et al. CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry. 2002;7(5):515-518.
55.    Zammit S, Spurlock G, Williams H, Norton N, Williams N, O’Donovan M, Owen MJ. Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. Br J Psychiatry. 2007;191(5):402-407.
56.    Allen NC, Bagade S, McQueen MB, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008;40(7):827-834.
57.    D’Souza DC, Abi-Saab WM, Madonick S, et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry. 2005;57(6):594-608.
58.    Johnstone EC, Owens DG, Bydder GM, Colter N, Crow TJ, Frith CD. The spectrum of structural brain changes in schizophrenia: age at onset as a predictor of cognitive and clinical impairments and their cerebral correlates. Psycholog Med. 1989;19(1):91-103.
59.    Mayer C, Kelterborn G, Naber D. Age at onset in schizophrenia: relations to psychopathology and gender. Br J Psychiatry. 1993;162(5):665-671.
60.    Häfner H, Nowotny B. Epidemiology of early-onset schizophrenia. Eur Arch Psychiatry Clin Neurosci. 1995;245(2):80-92.
61.    Sharma RP, Dowd SM, Davis JM, Janicak PG. Age of illness onset and schizophrenic symptomatology during an inpatient washout period. Schizophr Res. 1996;20(3):295-300.
62.    Jeste DV, McAdams LA, Palmer BW, et al. Relationship of neuropsychological and MRI measures to age at onset of schizophrenia. Acta Psychiatr Scand. 1998;98(2):156-164.
63.    Banaschewski T, Schulz E, Martin M, Remschmidt H. Cognitive functions and psychopathological symptoms in early-onset schizophrenia. Eur Child Adolesc Psychiatry. 2000;9(1):11-20.
64.    Lay B, Blanz B, Hartmann M, Schmidt MH. The psychosocial outcome of adolescent-onset schizophrenia: a 12-year followup. Schizophr Bull. 2000;26(4):801-816.
65.    Tuulio-Henriksson A, Partonen T, Suvisaari J, Haukka J, Lonnqvist J. Age at onset and cognitive functioning in schizophrenia. Br J Psychiatry. 2004;185(3):215-219.
66.    Rhinewine JP, Lencz T, Thaden EP, et al. Neurocognitive profile in adolescents with early-onset schizophrenia: clinical correlates. Biol Psychiatry. 2005;58(9):705-712.
67.    Ropcke B, Eggers C. Early-onset schizophrenia: a 15-year follow-up. Eur Child Adolesc Psychiatry. 2005;14(6):341-350.
68.    Amminger GP, Leicester S, Yung AR, et al. Early-onset of symptoms predicts conversion to non-affective psychosis in ultra-high risk individuals. Schizophr Res. 2006;84(1):67-76.
69.    Malla A, Norman R, Schmitz N, et al. Predictors of rate and time to remission in first-episode psychosis: a two-year outcome study. Psychol Med. 2006;36(5):649-658.
70.    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.
71.    González-Pinto A, Vega P, Ibáñez B, et al. Impact of cannabis and other drugs on age at onset of psychosis. J Clin Psychiatry. 2008;69(8):1210-1216.
72.    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.
73.    Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes. Lancet. 2007;370(9584):319-328.
74.    Ferdinand RF, Sondeijker F, van der Ende J, Selten JP, Huizink A, Verhulst FC. Cannabis use predicts future psychotic symptoms, and vice versa. Addiction. 2005;100(5):612-618.
75.    Verdoux H, Tournier M, Cougnard A. Impact of substance use on the onset and course of early psychosis. Schizophr Res. 2005;79(1):69-75.
76.    Bodkin L, Singh A, Corcoran C. Cannabis as a risk factor for psychosis in vulnerable teens: implications for treatment. Primary Psychiatry. 2008;15(6):51-57.
77.    Degenhardt L, Hall W, Lynskey M. The relationship between cannabis use and other substance use in the general population. Drug Alcohol Depend. 2001;64(3):319-327.
78.    Grant BF, Hansan DS, Chou SP, Stinson FS, Dawson DA. Nicotine dependence and psychiatric disorders in the United States. Arch Gen Psychiatry. 2004;61(11):1107-1115.
79.    Hunglund BL, Basavarajappa BS. Are anandamide and cannabinoid receptors involved in ethanol tolerance? A review of the evidence. Alcohol Alcohol. 2000;35(2):126-133.
80.    Poirier MF, Canceil O, Bayle F, et al. Prevalence of smoking in psychiatric patients. Progress Neuropsychopharmacol Biol Psychiatry. 2002;26(3):529-537.
81.    Üçok A, Polat A, Bozkurt O, Meteris H. Cigarette smoking among patients with schizophrenia and bipolar disorders. Psychiatry Clin Neurosci. 2004;58(4):434-437.
82.    Weiser M, Reichenberg A, Grotto I, et al. Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: a historical-prospective cohort study. Am J Psychiatry. 2004;161(7):1219-1223.
83.    Sacco KA, Termine A, Seyal A, et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry. 2005;62(6):649-659.
84.    Watkins SS, Koob GF, Markou A. Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine Tob Res. 2000;2(1):19-37.
85.    Ziedonis DM, George TP. Schizophrenia and nicotine use: Report of pilot smoking cessation programs and review of neurobiological and clinical issues. Schizophr Bull. 1997;23(2):247-254.
86.    Miettunen J, Törmänen S, Murray GK, et al. Association of cannabis use with prodromal symptoms of psychosis in adolescence. Br J Psychiatry. 2006;192(6):140-141.
87.    Angermeyer MC, Kühn L. Gender differences in age at onset of schizophrenia: an overview. Eur Arch Psychiatry Neurol Sci. 1988;237(6):351-364.
88.    DeLisi LE. The significance of age at onset for schizophrenia. Schizophr Bull. 1992;18(2):209-215.
89.    Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand Suppl. 2000;401:3-38.
90.    Häfner H, Maurer K, Löffler W, Reicher-Rossler A. The influence of age and sex on the onset and early course of schizophrenia. Br J Psychiatry. 1993;162(1):80-86.
91.    Häfner H, Maurer K, Löffler W, et al. The ABC Schizophrenia Study: a preliminary overview of the results. Soc Psychiatry Psychiatr Epidemiol. 1998;33(8):380-386.
92.    Shimizu A, Kurachi M, Yamaguchi N, Torii H, Isaki K. Does family history of schizophrenia influence age at onset of schizophrenia? Acta Psychiatr Scand. 1988;78(6):716-719.
93.    Gorwood P, Leboyer M, Jay M, Payan C, Feingold J. Gender and age at onset in schizophrenia: impact of family history. Am J Psychiatry. 1995;152(1):208-212.
94.    Stompe T, Ortwein-Swoboda G, Strobl R, Friedmann A. The age at onset of schizophrenia and the theory of anticipation. Psychiatry Res. 2000;93(2):125-134.

Return