Needs Assessment:
When patients present with a major depressive episode, one of the challenges inherent to current pharmacotherapy options is that medications often take several weeks to exert their antidepressant effects. A well-known anesthetic and analgesic medication, ketamine, has shown potential for providing a much more rapid relief of symptoms.

Learning Objectives:
• Summarize the evidence for a role of the glutamate system in major depressive disorder.
• List the most common acute adverse effects of intravenous ketamine infusion.
• Identify the main reasons why the antidepressant efficacy of ketamine is still considered preliminary.

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. aan het Rot is postdoctoral fellow in the Department of Psychiatry; Dr. Charney is dean and Anne and Joel Ehrenkranz Professor in the Departments of Psychiatry, Neuroscience, and Pharmacology and Systems Therapeutics; and Dr. Mathew is assistant professor in the Department of Psychiatry, all at the Mount Sinai School of Medicine in New York City.

Disclosure: Dr. aan het Rot reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Drs. Charney and Mathew receive grant support from the General Clinical Research Center, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health. Drs. Charney and Mathew have been named as inventors on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Drs. Charney and Mathew could benefit financially.

Acknowledgments: The authors acknowledge the valuable contributions of David L. Reich, MD, Andrew M. Perez, MD, Richard M. Lewis, MD, James W. Murrough, MD, Katherine A. Collins, MSW, and the New York Mood Disorders Support Group.

Please direct all correspondence to: Sanjay J. Mathew, MD, Mount Sinai School of Medicine, 1468 Madison Ave, Annenberg 21, Room 90, One Gustave L. Levy Place, Box 1217, New York, NY 10029; Tel: 212-241-4480; Fax: 212-241-7973; E-mail:; Website:




Conventional pharmacologic treatments for major depressive disorder (MDD) generally take several weeks to several months to have a clinically meaningful effect. This time lag to response constitutes a major burden for patients and contributes to increased morbidity and mortality. Two published studies in patients with MDD have now provided evidence for rapid and robust antidepressant efficacy of a single intravenous (IV) infusion with a sub-anesthetic dose of ketamine hydrochloride compared with an infusion of saline. In the approximately 60% of patients who responded, ketamine’s acute antidepressant effects were maintained for at least several days and up to 2 weeks. This article reviews the pathophysiologic rationale underlying this approach, the clinical evidence for the use of IV ketamine for treatment of MDD, ketamine’s safety profile, and areas of uncertainty to be explored in future studies.



The United States National Comorbidity Survey Replication recently estimated the lifetime prevalence of major depressive disorder (MDD) to be approximately 17%.1 The occurrence of a major depressive episode (MDE) is often associated with significant impairment in multiple areas, including functioning in school or at work and interaction with family and friends. This may negatively impact patient outcomes long after the MDE has been resolved and may increase risk of recurrence or relapse.2 The clinical availability of therapeutic interventions with rapid onset of action may help reduce or even prevent the long-term effects of an MDE.

However, most existing pharmacologic treatments for MDD take several weeks to months to achieve their full clinical effects. This constitutes a major burden for patients, contributes to significant morbidity, and increases risk for suicide. The delay in onset of action that is typical of currently available antidepressants may exist because these medications exert their pharmacologic effects on systems upstream from the core pathophysiology of MDD.3 Thus, the interaction of these medications with their corresponding binding molecules (eg, receptors, transporters) activates intracellular signaling cascades that only in turn lead to changes in the expression and sensitivity of downstream neurotransmission molecules that are part of MDD pathophysiology. Most notable in this respect has been the recent accumulation of data indicating that antidepressants impact pathways that regulate cellular plasticity and survival in brain regions involved in mood regulation.4 In keeping with this are studies demonstrating atrophy and cell death in subgroups of patients with MDD.5-7

Plasticity and survival of brain cells involve multiple actions of the excitatory amino acid neurotransmitter glutamate.4 It is not surprising that there is an increasing interest in the use of glutamate system modulators for treatment of MDD.8,9 The potential efficacy of the high-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, in particular, has received attention both in the scientific community and from the general public.10 This article reviews two published placebo-controlled studies in which ketamine was given intravenously to patients with MDD. A single dose of ketamine (0.5 mg/kg) infused over 40 minutes had robust antidepressant effects that appeared after only a few hours.11,12 In light of these two promising initial reports, ketamine may have potential as a novel antidepressant with rapid onset of action, which is essential for minimizing the long-term effects of an MDE.


Depression Pathophysiology and Effect of Treatment

Rational drug development for treatment of MDD should be guided by a solid pathophysiologic model derived from both preclinical data and clinical observations. One such model focuses on the role of stressful experiences on glutamate function.13 The behavioral stress response involves multiple brain systems including not only activation of the hypothalamic-pituitary-adrenocortical axis but also initiation of complex cascades of reactions mediated by several neurotransmitters, including release of the excitatory amino acid neurotransmitter glutamate.14 When a stressor is acute and mild, the stress response helps an organism adapt and cope. However, when the stressor is chronic and severe, and especially when it is considered uncontrollable and inescapable, it may have pathologic consequences, including MDD.15,16 Preclinical studies have found that chronic stress may lead to excessive extrasynaptic accumulation of glutamate.17 In addition, chronic stress induces changes at the level of the glutamatergic NMDA receptor.18 Over time, this persistent hyperactivity of the stress system may contribute to glutamate-mediated excitotoxicity leading ultimately to cell death in brain areas such as the hippocampus.19,20 In addition, accumulating evidence from post-mortem and brain imaging indicates that glutamate metabolism is altered in individuals who are depressed compared to those who are well.21-24

Preclinical data on the involvement of the glutamate system in the mechanism of action of conventional antidepressants go back many years.8 For example, monoaminergic antidepressants have multiple effects on glutamate receptor function.25-27 In addition, there is abundant evidence of the positive effects of glutamatergic drugs in animal models of depression.8 These include antagonists at the NMDA receptor.28-31 Most relevant for this review are animal studies of ketamine, which in glutamatergic pathways works as a high-affinity NMDA antagonist.32 In rats ketamine induces antidepressant-like effects in the forced swimming test and in the learned helplessness model of depression.33-35 These effects may be mediated by regulating the functional interplay between NMDA and non-NMDA ionotropic glutamate receptors, especially α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors.36


Clinical Evidence for Ketamine

Though compelling, it was not the preclinical data that sparked interest in the potential use of ketamine as an antidepressant treatment. Instead, it was an experimental study in patients with MDD that originally aimed to characterize the psychotomimetic effects of a subanesthetic intravenous (IV) dose of ketamine in this population. In 2000, Berman and colleagues11 at Yale University reported on the effects of ketamine 0.5 mg/kg and saline infusions on mood in nine drug-free symptomatic inpatients with recurrent MDD. Mood change following each of the two 40-minute infusions was measured using the 25-item Hamilton Rating Scale for Depression (HAM-D25) and the Beck Depression Inventory, both acutely (40–230 minutes after the start of the infusion) and sub-acutely (1–3 days post-infusion). Treatment order was randomized across patients. The two infusions were separated by ≥1 week. HAM-D25 scores were virtually unchanged in the saline condition. In contrast, a significant ketamine-induced reduction in HAM-D25 scores was first seen after 230 minutes and continued to develop over time. Three days post-ketamine, HAM-D25 scores were reduced by an average of 48%. In four of the eight patients who received ketamine, the HAM-D25 reduction was ≥50% (one patient dropped out after having received saline during the first infusion). Within 1–2 weeks post-ketamine, all patients but one (who started antidepressants after responding to ketamine and never completed the saline condition) had relapsed.

Zarate and colleagues12 replicated this study in a larger sample using an inpatient protocol at the National Institutes of Health which involved administration of IV ketamine (0.5 mg/kg) and IV saline in a randomized order 1 week apart. All 18 patients had a diagnosis of recurrent MDD and a HAM-D21 score ≥18 at baseline. They had responded insufficiently to ≥2 adequate antidepressant trials in their lifetime and were therefore considered to be treatment resistant. Participants were rated 40–230 minutes after the start of the infusion and 1–7 days post-infusion. A significant ketamine-induced reduction in HAM-D21 scores was first seen after 110 minutes. One day post-infusion, HAM-D21 scores were significantly reduced in the ketamine condition (-56%) but not in the saline condition (-10%). At this point, 71% of patients reported ≥50% decreases in HAM-D21 scores following ketamine, versus 0% following saline. After 1 week, these percentages were 34% and 0%, respectively. Notably, whereas 17 patients received the ketamine infusion, only 14 patients received the saline infusion, because four patients who received ketamine first maintained the antidepressant response for >1 week.

These two studies11,12 suggest that IV ketamine can have a robust (large effect size) and rapid (within 2 hours) antidepressant effect in patients with MDD. A recent third study,37 also conducted at Yale University and presented in abstract form at the 2007 Society for Biological Psychiatry Annual Meeting, again replicated the acute response to ketamine in an additional 10 patients (Table 1).11,12,37,38


Importantly, although neither study included patients who were actively suicidal, both Berman and colleagues11 and Zarate and colleagues12 observed meaningful reductions in suicidal ideation. Patients who responded acutely subsequently remained well for several days. The authors of this article and several other groups are currently conducting follow-up studies in order to develop adequate continuation treatment, with the goal of sustaining the acute ketamine response for longer time periods. For example, a recent report of two patients with treatment-resistant depression (TRD) who received one or more continuous ketamine infusions of approximately 0.3 mg/kg/h for 5 days found that the patients remained well for >1 year.39 However, another case study in a patient with TRD and comorbid alcohol and benzodiazepine dependence found that the antidepressant effect of a second 0.5 mg/kg ketamine infusion was reduced compared to the first infusion.40 Berman and colleagues11 and Zarate and colleagues12 excluded patients with recent alcohol and drug use disorders. It remains to be seen if including such patients will alter the antidepressant efficacy of IV ketamine in a placebo-controlled study.


Clinical Use

While the interest in ketamine as an antidepressant developed fairly recently, its use in anesthesia and sedation in both adults and children goes back many years.41,42 Surgical anesthesia is typically produced by IV doses of approximately 1–3 mg/kg.43,44 The efficacy of ketamine as an analgesic agent is also well documented and may outlast that of anesthesia.41,42 Treatment at sub-anesthetic doses may in fact be sufficient for long-term therapeutic benefit in patients with chronic pain.45,46 Notably, a 2005 study in 40 patients with complex regional pain syndrome (CRPS) who had previously insufficiently responded to conventional treatments found that the effects of 10 open-label ketamine infusions (of up to 20 mg/hour infused over 4-hour periods, or 40–80 mg per infusion) included not only a decrease in subjective pain intensity scores and an increase in mobility, but also a reduced need for antidepressants.47 These benefits lasted for periods lasting from 2 weeks to 15 months.


Adverse Effects

Based on an extensive anesthesia literature, ketamine may be considered a very safe drug. Its sympathomimetic effects generally include mild-to-moderate increases in heart rate, blood pressure, and cardiac output.41-43,48 Ketamine produces no or only a mild respiratory depression.41,42 Unless patients present with cardiovascular disease and/or uncontrolled hypertension, acute risks associated with IV ketamine administration are therefore regarded as minimal.48 Other adverse effects may include perceptual disturbances, which usually manifest as floating-in-space sensations and/or out-of-body experiences, but in rare events might also include visual or auditory hallucinations.41 While some patients describe these dissociative experiences as pleasurable, joyful, and fascinating (in 1999 ketamine was placed in Schedule 3 of the Controlled Substance Act), others find them bizarre or frightening.48 The perceptual disturbances are usually mild and do not last long beyond ketamine administration.42 Several studies have addressed the question of prolonged psychological effects of ketamine in the general population, secondary to its anesthetic use, and concluded that ketamine does not place patients at a greater risk than do other anesthetics.49,50 Perceptual disturbances following ketamine may be more common and last longer in individuals with preexisting psychosis.48,49,51 However, an investigation of patients with schizophrenia who received a sub-anesthetic dose of IV ketamine in experimental studies found no evidence of enduring adverse effects and distress at follow-up 8 months later.52

Consistent with ketamine’s acute effects on perception, both Berman and colleagues11 and Zarate and colleagues12 found that, 40–45 minutes after the start of the ketamine infusion, patients reported more positive symptoms on the Brief Psychiatric Rating Scale (BPRS) than at baseline. Ketamine administration was also associated with a significant increase in subjective “high” and in scores on item 1 of the Young Mania Rating Scale (elevated mood).11,12 However, none of these effects were seen beyond 80 minutes. The authors of this article are currently investigating methods to attenuate the acute psychotomimetic and dissociative effects of ketamine. They are also carefully characterizing ketamine’s acute side effect profile in patients with TRD using validated measures for adverse event reporting. A report on data from 295 healthy volunteers who were repeatedly administered ketamine (at the dose found to have antidepressant effects in patients with MDD) revealed no increase in positive symptoms, subjective “high,” and perceptual alterations between the first and subsequent exposures.53

Several experimental studies in healthy volunteers have found acute effects of ketamine on neuropsychological test performance. Ketamine impairs performance on tests of attention (eg, trail making, Stroop color-word test, continuous performance), memory (eg, immediate and delayed, verbal and non-verbal recall) and executive function (eg, word list generation fluency, Wisconsin card sorting).54-57 It has been argued that these acute impairments in cognition may have a long-term impact.10 However, studies investigating cognition in recreational ketamine users are confounded by several factors, including comorbid substance abuse.58 Very few prospective controlled studies have addressed this critical issue, but a recent study in patients with treatment-resistant CRPS found no adverse neuropsychological effects of extended ketamine treatment at relatively high doses of 3–7 mg/(kg*h).59

The absence of enduring adverse effects and behavioral sensitization following administration of a subanesthetic dose of IV ketamine also argues against the idea that its antidepressant effects may be offset by possible glutamate-mediated toxicity and cell death.10 This is corroborated by recent findings from preclinical studies36 of increases in glutamatergic AMPA throughput in response to a subanesthetic dose of IV ketamine. It is likely that any toxicity precipitated by ketamine is dose dependent. Thus, the authors of this article hypothesize that, at the relatively low single dose required to achieve a therapeutic effect on mood, ketamine does not cause the cell death that may result from higher doses and more prolonged courses of treatment. Medications with similar pharmacologic properties, the glutamate receptor modulators riluzole and memantine, have been found to have neuroprotective effects in neurodegenerative disorders (amyotrophic lateral sclerosis and Alzheimer’s disease, respectively).9,60-62


Areas of Uncertainty

Despite evidence from two published studies,11,12 ketamine’s effectiveness in relief of MDD symptoms must still be considered a preliminary finding. Drawing conclusions on the effectiveness of ketamine is hindered by the fact that both studies used saline as the placebo control. The acute effects of ketamine and the acute effects (or lack thereof) of saline were likely to be readily distinguishable, which means it was impossible to maintain the integrity of the blind (in both patients and clinicians). The problem is illustrated by the fact that not all study participants received both IV ketamine and IV saline. In the study by Zarate and colleagues,12 crossing participants over from one treatment to another after 1 week was problematic in patients who were administered ketamine on the first infusion day and showed an antidepressant response that lasted longer than 1 week. These patients never received the subsequent saline infusion. A longer inter-treatment interval might be one possible solution for future studies employing a within-group crossover design. Berman and colleagues11 separated the two infusions by up to 2 weeks such that patients who had received ketamine on the first infusion day and showed an antidepressant response had relapsed, except for one patient who initiated continuation treatment following ketamine-induced mood improvement and never completed the saline infusion. A between-groups study may be preferable to ensure that patients complete the placebo condition.

The lack of a placebo control that maintains integrity of the blind in both patients and clinicians during the infusions may also explain why in one of the studies12 the magnitude of psychotomimetic effects during ketamine infusion (ie, increase in BPRS positive symptoms) was correlated with the mood improvement at day 1 (ie, decrease in HAM-D scores). Neither study has reported if the elevated mood reported by patients 40–80 minutes after the start of the ketamine infusion was associated with the observed change in HAM-D scores at later time points.10 Such an association would call into question to what extent ketamine’s antidepressant effects may have been based on patients’ expectations derived from its acute effects. This issue of unmasking participants would remain even if ketamine was compared with saline in a between-groups study. To circumvent this, future studies should therefore consider the use of an active placebo control instead of, or in addition to, saline. The active control should have subjective effects similar to those of ketamine during the infusion but not have any known antidepressant effects after the infusion. A 2002 study63 in medicated depressed patients undergoing surgery has found that those induced with propofol, fentanyl, and ketamine reported improved mood and reduced subjective pain 2–4 days post-surgery, whereas no such changes were seen in patients induced with propofol and fentanyl alone. It is unlikely that patients were unblinded to the different treatments during the procedure, given that post-surgery confusion scores were similar across the two groups. This study provides some evidence that IV ketamine can have an antidepressant effect even when patients are masked to the treatment they are receiving.

The route of drug administration may have influenced the speed of ketamine’s antidepressant response. IV administration bypasses first-pass metabolism and results in higher plasma concentrations than oral administration. Some studies have demonstrated a rapid response to IV administration of conventional antidepressants.64,65 Other studies reported no difference between IV and oral administration in the speed of onset of action of these drugs.66,67 From the point of view of patient convenience, oral administration of antidepressants is usually the preferred route. It remains to be seen if ketamine will have rapid antidepressant properties when administered orally or in other formulations (eg, intramuscularly, intranasally, transdermally). The current data on the efficacy of other glutamate-modulating medications available for oral administration in patients with MDD are mixed. Oral administration of riluzole may improve mood in patients with TRD.68,69 Oral administration of memantine had no significant antidepressant effects in a recent study in patients with MDD.70 However, memantine has significantly lower affinity for the NMDA receptor than ketamine.71

Other areas of uncertainty include the relative effectiveness of the two optical enantiomers, S- and R-ketamine, and the role of neurotransmitters other than glutamate in ketamine’s antidepressant effects. Ketamine is approved by the US Food and Drug Administration only as a racemic mixture of both enantiomers. The more active enantiomer, S-ketamine, has approximately 4–5 times greater affinity for the NMDA receptor than R-ketamine.72 In healthy volunteers, S-ketamine was found to produce emotional disturbances, cognitive impairments, and dissociative experiences, whereas R-ketamine induced a state of relaxation.73 S-ketamine has been approved in some European countries based on evidence that it has more potent anesthetic and analgesic effects such that it can be used in smaller doses and therefore possibly decrease recovery time.74 There is also some indication that the psychotomimetic or unpleasant effects of S-ketamine may be less pronounced than those of the racemic mixture.75 S-ketamine–induced decreases in binding potential of the dopamine-2 receptor antagonist raclopride, measured using positron emission tomography in the striatum and surrounding brain areas, have been shown to correlate with subjective euphoria; this suggests that dopamine may play a role in its acute mood-elevating effects.76 Most experimental studies that administered single subanesthetic IV doses of racemic ketamine to humans have also found that ketamine has effects on dopamine receptors.77-80 These studies have also implicated a role for mu opioid receptors.81 In summary, ketamine has a complex pharmacologic profile, with its actions on the glutamate system and NMDA receptors being only one of multiple pathways that together are responsible for its diverse effects.

Other currently unresolved issues with ketamine include the following. First, the dose used thus far (0.5 mg/kg) may not be the optimal dose for induction and mainte­nance of the mood response. Second, it is unknown which medications are viable continuation treatment options in patients who show an initial favorable response (eg, repeated ketamine administration, use of another glutamatergic drug such as riluzole or memantine, or other more traditional approaches). Third, although there is no current evidence of addiction potential in controlled studies performed to date, the potential of ketamine abuse must continue to be consid­ered. Finally, future studies should more closely measure the acute and longer-term side effects of ketamine at multiple time points following its administration.


Comparison with Existing Rapid Antidepressant Treatments

Current treatments for MDD can be divided into “acute” interventions and continuation/maintenance strategies. However, besides ketamine only sleep deprivation produces antidepressant responses within 24 hours (Table 2). Sleep deprivation has a long-known rapid and robust efficacy in approximately 60% of patients with MDD.82 The magnitude of improvement is often equivalent to that observed after 6 weeks of antidepressant treatment. Hence, the acute therapeutic response to sleep deprivation must be mediated by mechanisms different from those mediating the gradual improvement obtained with antidepressants.83 Functional brain imaging studies are highly suggestive of an association between clinical improvement and increased activity in the ventral anterior cingulate cortex.84 Advantages of sleep deprivation include its noninvasive nature and safe use in pregnant and breastfeeding women. However, most patients relapse after one subsequent night of sleep regardless of medication status,82 which may explain why sleep deprivation is rarely administered by clinicians in the US. Nevertheless, sleep deprivation has been successfully used to hasten the onset of action of antidepressants.85 


Bright light therapy (BLT) can also be administered safely in pregnant and breastfeeding women. Like sleep deprivation, it is non-invasive. However, compliance may be difficult for some, as patients are usually required to self-administer bright light in the early morning.86 BLT reportedly has a response rate of approximately 60%. The effect size may be larger in patients with seasonal affective disorder (SAD) versus non-seasonal MDD.87 Like sleep deprivation, BLT has been successfully used as an adjunct to conventional antidepressant treatment in order to speed up its antidepressant effect.88 While BLT efficacy has mostly been studied over time periods in the range from weeks to months, at least two studies89,90 in patients with SAD are indicative that its onset of action may be faster than that of the commonly prescribed selective serotonin reuptake inhibitor, fluoxetine. Anecdotally, clinically meaningful mood changes have been found to occur even after time periods of 2–3 days.91,92 A 2004 Cochrane review of BLT studies in patients with non-seasonal MDD showed significant benefit in studies of up to a week, but no significant benefit in longer and better-controlled studies.93 However, a 2005 controlled trial reported significant benefit of BLT in approximately 50% of patients with non-seasonal chronic MDD.94

Electroconvulsive therapy (ECT) is usually administered to patients with TRD and generally involves three sessions per week, with most individuals requiring at least 6 treatments to achieve a response. ECT is considered the most effective antidepressant treatment, especially for patients with psychotic, melancholic, or bipolar depression.95 It is considered another rapid antidepressant treatment, although onset of action is rarely achieved during the first treatment session (Table 2). Interestingly, a recent case report in a patient with severe, recurrent MDD showed that intramuscular administration of 100 mg of ketamine in combination with a single session of ECT resulted in marked clinical improvement within 8 hours of treatment which continued at least until the next ECT session 3 days later.96 Disadvantages to ECT include its invasive nature, including the requirement of general anesthesia and the risk of significant retrograde amnesia, which in some patients may be irreversible.97 Without continuation treatment, the majority of patients will relapse within 6 months.98



The development of a rapid antidepressant strategy which is effective within 24 hours and can be sustained is an important therapeutic goal in psychiatry. Studies on the antidepressant effects of ketamine are a work in progress. This article has presented the currently available data, with the intention to stimulate future research.

As of yet, there are no established guidelines for ketamine administration in patients with MDD. Berman and colleagues11 and Zarate and colleagues12 have administered ketamine on an inpatient basis. Ongoing studies by the authors of this article and elsewhere also use this approach. Patients are monitored by an anesthesiologist during infusion, are continuously observed by nursing staff, and remain in the inpatient setting for 24 hours post-infusion to ensure safety. Acutely, ketamine’s potential side effects include respiratory or circulatory problems, especially in patients with lung disease and uncontrolled hypertension, respectively. Studies thus far have not encountered these problems; however, patient selection procedures actively excluded patients with known risk factors. At present, the use of ketamine for treatment of TRD in uncontrolled settings is discouraged by the authors of this article.

Nevertheless, in the future ketamine may offer the clinician a potentially efficacious and rapidly acting medication, especially for patients with TRD. As the therapeutic lag time inherent to currently available treatments for MDD is suboptimal, this and similar approaches are worthy of further investigation.



Ketamine is a well-known FDA-approved anesthetic and analgesic medication. In at least two placebo-controlled studies in patients with MDD,11,12 one of which included patients with TRD, ketamine has shown additional potential as a rapid and robust antidepressant. There was some evidence of a decrease in suicidality as part of the overall rapid clinical improvement. The acute antidepressant effects of a single ketamine infusion lasted up to 2 weeks. It remains to be seen if ketamine, in combination with existing or future continuation therapies, can be developed as a safe and effective treatment option for patients with an acute MDE. The development of a new pharmacologic intervention with acute and sustained antidepressant effects could have a significant impact on public health. PP



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33.    Garcia LS, Comim CM, Valvassori SS, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):140-144.
34.    Henn FA. Cells and circuits in learned helplessness: clues to making a rapidly acting antidepressant. Paper presented at: the 46th Annual Meeting of the American College of Neuropsychopharmacology; December 12, 2007; Boca Raton, FL.
35.    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.
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37.    Valentine G, Mason GF, Krystal JH, Sanacora G. The acute effects of ketamine on mood and occipital cortex amino acid neurotransmitter content. Biol Psychiatry. 2007;61(suppl 1):S233.
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41.    White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. 1982;56(2):119-136.
42.    Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989;36(2):186-197.
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44.    Green SM, Johnson NE. Ketamine sedation for pediatric procedures: part 2, review and implications. Ann Emerg Med. 1990;19(9):1033-1046.
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46.    Wood PB. A reconsideration of the relevance of systemic low-dose ketamine to the pathophysiology of fibromyalgia. J Pain. 2006;7(9):611-614.
47.    Goldberg ME, Domsky R, Scaringe D, et al. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician. 2005;8(2):175-179.
48.    Green SM, Li J. Ketamine in adults: what emergency physicians need to know about patient selection and emergence reactions. Acad Emerg Med. 2000;7(3):278-281.
49.    Schorn TOF, Whitwam JG. Are there long-term effects of ketamine on the central nervous-system? Br J Anaesth. 1980;52(10):967-968.
50.    Hersack RA. Ketamine’s psychological effects do not contraindicate its use based on a patient’s occupation. Aviat Space Environ Med. 1994;65(11):1041-1046.
51.    Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995;13(1):9-19.
52.    Lahti AC, Warfel D, Michaelidis T, Weiler MA, Frey K, Tamminga CA. Long-term outcome of patients who receive ketamine during research. Biol Psychiatry. 2001;49(10):869-875.
53.    Cho HS, D’Souza DC, Gueorguieva R, et al. Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. Psychopharmacology (Berl). 2005;179(1):136-143.
54.    Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199-214.
55.    Harborne GC, Watson FL, Healy DT, Groves L. The effects of sub-anaesthetic doses of ketamine on memory, cognitive performance and subjective experience in healthy volunteers. J Psychopharmacol. 1996;10(2):134-140.
56.    Newcomer JW, Farber NB, Jevtovic-Todorovic V, et al. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999;20(2):106-118.
57.    Anand A, Charney DS, Oren DA, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry. 2000;57(3):270-276.
58.    Curran HV, Monaghan L. In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction. 2001;96(5):749-760.
59.    Koffler SP, Hampstead BM, Irani F, et al. The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome. Arch Clin Neuropsychol. 2007;22(6):719-729.
60.    Simon RP, Swan JH, Griffiths T, Meldrum BS. Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science. 1984;226(4676):850-852.
61.    Roman R, Bartkowski H, Simon R. The specific NMDA receptor antagonist AP-7 attenuates focal ischemic brain injury. Neurosci Lett. 1989;104(1-2):19-24.
62.    Menniti FS, Pagnozzi MJ, Butler P, Chenard BL, Jaw-Tsai SS, Frost White W. CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodents. Neuropharmacology. 2000;39(7):1147-1155.
63.    Kudoh A, Takahira Y, Katagai H, Takazawa T. Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg. 2002;95(1):114-118.
64.    Malhotra S, Santosh PJ. Loading dose imipramine–new approach to pharmacotherapy of melancholic depression. J Psychiatr Res. 1996;30(1):51-58.
65.    Sallee FR, Vrindavanam NS, Deas-Nesmith D, Carson SW, Sethuraman G. Pulse intravenous clomipramine for depressed adolescents: double-blind, controlled trial. Am J Psychiatry. 1997;154(5):668-673.
66.    Faravelli C, Broadhurst AD, Ambonetti A, et al. Double-blind trial with oral versus intravenous clomipramine in primary depression. Biol Psychiatry. 1983;18(6):695-706.
67.    Guelfi JD, Strub N, Loft H. Efficacy of intravenous citalopram compared with oral citalopram for severe depression. Safety and efficacy data from a double-blind, double-dummy trial. J Affect Disord. 2000;58(3):201-209.
68.    Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-174.
69.    Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61(6):822-825.
70.    Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163(1):153-155.
71.    Porter RH, Greenamyre JT. Regional variations in the pharmacology of NMDA receptor channel blockers: implications for therapeutic potential. J Neurochem. 1995;64(2):614-623.
72.    Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther. 1992;260(3):1209-1213.
73.    Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol. 1997;7(1):25-38.
74.    Hempelmann G, Kuhn DF. Clinical significance of S-(+)-ketamine [German]. Anaesthesist. 1997;46(suppl 1):3-7.
75.    White PF, Ham J, Way WL, Trevor AJ. Pharmacology of ketamine isomers in surgical patients. Anesthesiology. 1980;52(3):231-239.
76.    Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL. Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res. 2000;34(1):35-43.
77.    Breier A, Adler CM, Weisenfeld N, et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse. 1998;29(2):142-147.
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79.    Kegeles LS, Abi-Dargham A, Zea-Ponce Y, et al. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000;48(7):627-640.
80.    Aalto S, Hirvonen J, Kajander J, et al. Ketamine does not decrease striatal dopamine D2 receptor binding in man. Psychopharmacology (Berl). 2002;164(4):401-406.
81.    Krystal JH, Madonick S, Perry E, et al. Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism. Neuropsychopharmacology. 2006;31(8):1793-1800.
82.    Wu JC, Bunney WE. The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry. 1990;147(1):14-21.
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85.    Leibenluft E, Wehr TA. Is sleep deprivation useful in the treatment of depression? Am J Psychiatry. 1992;149(2):159-168.
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88.    Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita M, Smeraldi E. Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. J Clin Psychiatry. 2003;64(6):648-653.
89.    Ruhrmann S, Kasper S, Hawellek B, et al. Effects of fluoxetine versus bright light in the treatment of seasonal affective disorder. Psychol Med. 1998;28(4):923-933.
90.    Lam RW, Levitt AJ, Levitan RD, et al. The Can-SAD study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am J Psychiatry. 2006;163(5):805-812.
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94.    Goel N, Terman M, Terman JS, Macchi MM, Stewart JW. Controlled trial of bright light and negative air ions for chronic depression. Psychol Med. 2005;35(7):945-955.
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Dr. Luo is associate 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.

Disclosure: Dr. Luo reports no affiliation with or financial interest in any organization that may pose a conflict of interest.



Today’s patient has likely researched his or her condition on the Internet before even stepping into a doctor’s office for the first time. Some patients have even read articles from scientific journals and have asked physicians about their opinion on that type of treatment option. Although the Internet has made a wealth of information available to patients, there is still a significant amount of conflicting information even in the medical journals, and even more so on the Internet. This column reviews the trends in patient health information access and discusses strategies for physicians on how to navigate and negotiate with patients surfing for information.



In the past, patients relied mostly on their physicians to have the expertise to manage the majority of their health issues, and oftentimes did not question the validity of recommendations. The advent of the Internet has ushered in the “information overload” age with health information as one of the most popular destinations. In the 2002 Pew Internet and American Life Project report,1 it was estimated that 52 million American adults, or 55% of those with Internet access, have used the Internet to get health/medical information. This report indicated that patients went online at least once a month to get health information, and that the information they find has a direct effect on decisions regarding healthcare and interactions with doctors. Specifically, 70% of patients indicated that the health information on the Internet influenced their decision about how to treat an illness or condition. Fifty percent of patients said that information on the Internet led them to ask their doctor new questions or seek a second opinion from another doctor, while 48% indicated that Internet-based health information has helped them take care of themselves.

Kaplan and Brennan2 described the beginning trend of consumer health informatics, an area regarding the growth of the organization and delivery of health care and changing roles of patient and provider. At the Spring 2000 Congress of the American Medical Informatics Association, three panels examined the trend of health information, patient participation, shared decision making, and clinician responses in the context of the Internet.2 Several themes emerged, including the change in roles of consumers and providers, support for patient-provider-information technology partnership, virtual structure for health care and health information delivery, and health care as an integrated part of each person’s life. Patients clearly wanted more personalized relationships with their providers as well as interactive tools to help manage their health and diseases.


Website Certifications

In the early years of the Internet, it was simple enough for patients and providers alike to determine the potential bias and usefulness of a Website by examining the URL for its domain (either .net, .com, .edu, or .org). It was at that time relatively safe to assume that “.edu” and “.org” were non-profit sites of educational institutions and organizations; therefore. any Website content would not be biased or commercial in nature. Over the years, domain names became a “commodity,” which could demand high prices in the competitive open market. Domain name “squatters” rushed to register the names first or took advantage if registrants who failed to renew their domain in a timely manner. Now, there are numerous additional domain appellations such as “.biz,” “.info,” and even “.md.” To add even more confusion, many Website URLs are actually referrer domain names, which then send the visitor to another site or same site. One example,,3 actually sends visitors to the National Institutes of Health Website, which is normally accessed at Nowadays, the inherent nature of a Website is no longer predetermined by its domain name. The Mayo Clinic operates three sites, MayoClinic.com5 for health information, MayoClinic.org6 for health services, and Mayo.edu7 for education and research.

One way to help patients determine the relative usefulness and reliability of health information on the Internet is for the site to have accreditation. The Health on the Net (HON) Foundation is a not-for-profit and private Swiss foundation which has been granted non-governmental organization status by the Economic and Social Council of the United Nations.8 It serves to accredit Websites that have fulfilled the eight ethical principles of the HON code of conduct (Table). In addition to accreditation, HON also offers MedHunt, a specialized search engine geared toward the public and designed to find health information on the Internet. HONselect is a meta-search engine that offers medical terms, corresponding pictures, bibliographic references, news, and Websites that adhere to the HON code of conduct.


Another accreditation organization is the Utilization Review Accreditation Commission (URAC).9 This organization accredits many types of healthcare organizations. In particular, URAC provides oversight on how an accredited health Website is operated. URAC Health Web Site Accreditation ensures that the site is supervised by clinically trained staff, discloses key information about how the Website operates, and limits how personal health information is used or disclosed to third parties. There are >50 URAC health Website standards, which were developed in conjunction with healthcare providers, consumers, and health Website companies.


Online Tools

As indicated in the Pew Internet Report, patients seek information on the Internet because it is convenient and relatively anonymous, especially on sensitive topics, which may include mental health. A previous Tech Advisor10 discussed how Internet-based assessment tools can be used to help patients check for various conditions. Healthplace.com11 has created a collection of links to other Websites that have screening tools for a variety of psychological disorders, encompassing both free and commercial tools. Organizations, such as the Mental Health Association of America, often sponsor free screening tools to encourage patients to discuss matters with their health provider (eg,

Today’s patients are quite savvy and are often appropriately concerned about medications and drug-drug interactions. Numerous Websites offer drug information and drug-drug interaction tools, such as DoublecheckMD,13,14 and Medscape.15 These Websites are fairly easy to use. However, they can create confusion for the patient and some consternation for the practitioner. In a simple check of drug interactions between risperidone and escitalopram, both DoublecheckMD and indicate a potential for central nervous system depression, whereas Medscape indicates that there are no drug interactions at all. Epocrates Online,16 which has been traditionally used by medical professionals but can be used by patients, indicates that the drug-drug interaction can cause potential increased risperidone levels due to inhibition of hepatic metabolism. One advantage for patients using DoublecheckMD is that its explanation of the risks uses less medical jargon. offers a pill identification wizard and will store lists of drugs and interactions once patients register at the Website. Much of the discrepancy of the interaction checks is based on the drug database employed by the Website and its editorial board.


Online Forums

Online health information comes from a variety of sources, traditionally from textbooks and journal articles that are edited and distilled but delivered via the interface of the Internet. Patients usually rely on Websites such as WebMD,17 RevolutionHealth,18 and the National Institute of Mental Health19 to find general information on various health conditions. A new trend has been the shift toward online support groups. Patients and family members can log in and read other patients’ experiences with medications and treatment in order to attain a better understanding of symptoms and disease course. DailyStrength.org20 has numerous discussion forums where patients share their thoughts and provide support. Furthermore, it has a specific “advice” column where patients explicitly offer each other advice on how to cope, and “recommendations” where patients recommend books and videos. PatientsLikeMe21 takes the sharing of patient experiences further. Although the Website focuses right now on Parkinson’s disease, multiple sclerosis, HIV/AIDS, and amyotropic lateral sclerosis, patients share their symptoms and treatment, which are tabulated in a running total. Patients track their outcomes, treatment, and symptoms over time, which are nicely plotted in a graphical view. At,22 patients not only get information and support from one another on forums, but they can also get advice from members and medical professionals who are responsible for answering questions posted on the forum. Yahoo Health23 takes patient sharing a step further by providing inspirational stories from patients as well as video posts from patients. It also offers an amalgam of information including expert opinion from various providers.


Health Search Engines

Finding relevant information on the Internet has helped Google24 achieve its marketshare and financial success, but one search engine cannot find everything relevant. Specific health search engines, such as Healia,25 Medstory,26 and Healthline,27 do a better job finding useful information by searching the Internet,,28 and Pubmed29 using health-related taxonomies compared to traditional search engines. Healia offers filters such as information based on ethnicity, HON- and URAC-accredited sites, and whether information is easy or harder to read. Medstory also filters information based on keywords identified during the search. For example, upon searching for negative symptoms of schizophrenia, topics such as drugs, procedures, conditions, and personal health can refine the search. A helpful feature is that once the search has been created, an really simple syndication (RSS) feed can be created so any new content can be updated in an RSS reader. Healthline offers information both from its own content as well as the Internet, and the HealthMap creates a flowchart for patients to find new information as well as understand its relevancy.



Soon enough, it will be commonplace for every patient coming into the health practitioner’s office to bring information discovered on the Internet. Patients may even begin to “tag” Websites and articles using services such as Digg30 and Del.ici.ous,31 to be shared with their doctor for further discussion. Although it is impossible for all providers to learn in advance what types of information is on the Internet for their patients, they should be prepared to help patients navigate such information because personal relevancy and medical advice is still in the domain of medical practice. PP



1.    Fox S, Rainie L, Horrigan J, et al. The online health care revolution: how the web helps Americans take better care of themselves. Available at: Accessed March 1, 2008.
2.    Kaplan B, Brennan PF. Consumer informatics supporting patients as co-producers of quality. J Am Med Inform Assoc. 2001;8(4):309-316.
3.    National Institutes of Health. Available at: Accessed March 1, 2008.
4.    National Institutes of Health.  Available at: Accessed March 12, 2008.
5. Available at: Accessed March 1, 2008.
6. Available at: Accessed March 1, 2008.
7. Available at: Accessed March 1, 2008.
8.    Health on the Net Foundation. Available at: Accessed March 3, 2008.
9.    URAC. Available at: Accessed March 3, 2008.
10.    Luo J. Computerized medicine. Primary Psychiatry. 2006;13(9):20-22.
11. Online Psychological Tests. Available at: Accessed March 12, 2008.
12. Available at: Accessed March 5, 2008.
13.    DoublecheckMD. Available at: Accessed March 5, 2008.
14. Drug Interaction Checker. Available at: Accessed March 5, 2008.
15.    Medscape Drug Interaction Checker. Available at: Accessed March 5, 2008.
16.    Epocrates Online. Available at: Accessed March 5, 2008.
17.    WebMD. Available at: Accessed March 10, 2008.
18.    Revolution Health. Available at: Accessed March 10, 2008.
19.    National Institute of Mental Health. Available at: Accessed March 10, 2008.
20. Available at: Accessed March 11, 2008.
21.    PatientsLikeMe. Available at: Accessed March 11, 2008.
22.    MedHelp. Available at: Accessed March 11, 2008.
23.    Yahoo Health. Available at: Accessed March 11, 2008.
24.    Google. Available at: Accessed March 12, 2008.
25.    Healia. Available at: Accessed March 11, 2008.
26.    Medstory. Available at: Accessed March 11, 2008.
27.    Healthline. Available at: Accessed March 11, 2008.
28. Available at: Accessed March 11, 2008.
29.    Pubmed. Available at: Accessed March 11, 2008.
30.    Digg. Available at: Accessed March 12, 2008.
31.    Delicious. Available at: Accessed March 12, 2008.



Needs Assessment: Clinicians need to learn about new psychotherapeutic drugs in late stages of clinical development. This article informs the reader about a new class of antidepressants in development called triple reuptake inhibitors.

Learning Objectives:
• List at least two clinical features of depression thought to be due to deficits in brain dopamine.
• Define what is meant by “triple reuptake inhibitor.”
• Name two triple reuptake inhibitors that have been in Phase II clinical trials.

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Liang is research fellow and Dr. Richelson is principal investigator in the Neuropsychopharmacology Laboratory, Mayo Foundation for Medical Education and Research, and Mayo Clinic in Jacksonville, Florida.

Disclosure: Dr. Liang reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Richelson receives grant support from the National Institutes of Health.

Please direct all correspondence to: Elliott Richelson, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; Tel: 904-953-2439; Fax: 904-953-7117; E-mail:




A major advance in the pharmacotherapy of depression was the introduction of the selective serotonin reuptake inhibitors nearly 2 decades ago. These drugs succeed in treating depressed patients with few of the side effects common to tricyclic antidepressants, which they largely replaced. However, there are still unmet clinical needs with respect to efficacy, onset, and side-effect profile. The effects of the antidepressants occur almost immediately; however, a therapeutic lag is required to affect meaningful symptom improvement. Not all patients respond to antidepressants well, with some patients undergoing adverse events such as sexual dysfunction. Novel therapies or targets that may reduce side effects need to be addressed. Dopaminergic circuit dysfunction has been linked to depressive syndrome for many decades, and research on serotonin/norepinephrine-containing circuits has largely overshadowed its role in depression. It has been hypothesized that a broad-spectrum antidepressant will produce a more rapid onset and better efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine, in part due to the addition of the dopamine component. Triple reuptake inhibitors (serotonin, norepinephrine, and dopamine reuptake inhibitors) are being developed as a new class of antidepressant. This article presents the involvement of the dopaminergic neurotransmission underlying depressive symptoms, as well as preclinical and clinical trials of developing triple reuptake inhibitors.



Depression is a prevalent, heterogeneous, and recurrent mental disorder with a lifetime prevalence in approximately 16% of American adults and as much as 21% of the world population. According to the World Health Organization, depression is among the leading causes of disability worldwide. Despite the numerous improvements in antidepressants, there continue to be many unmet clinical needs regarding efficacy, onset of action, and side-effect profile. Although novel targets (eg, corticotrophin-releasing factor receptor) are being researched, current pharmacotherapies for depression are based on the decades-old monoamine (serotonin, norepinephrine, and dopamine) deficiency hypothesis underlying the etiology and pathogenesis of the depressive disorder.1

Pharmacotherapy of depression aims to elevate synaptic levels of the three key monoamines. However, the neglected neurotransmitter in this equation is dopamine, because the most widely used antidepressants that block reuptake of biogenic amines do not block dopamine transporters. There is compelling reason to add dopamine to the mix. To achieve reuptake blockade of all three neurotransmitters—serotonin, norepinephrine, and dopamine—triple reuptake inhibitors have been in development for at least the past decade. After a discussion of the importance of dopaminergic neurotransmission in depression, this article discusses some preclinical research and clinical trials of triple reuptake inhibitors in development.



The earliest, modern-day antidepressants were monoamine oxidase inhibitors (MAOIs; eg, phenelzine) and tricyclic antidepressants (TCAs; eg, imipramine). These drugs were found to be effective in treating depression, largely by empirical testing, and were subsequently shown to enhance monoamine levels in brain synapses by preventing their metabolism and transport back into the nerve ending (reuptake). Because of various unnecessary receptor blocking effects, these drugs were not always well tolerated. Therefore, “cleaner” drugs were sought and MAOIs and TCAs were largely replaced by selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine, sertraline) and serotonin norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine, duloxetine). These are specifically focused on serotonin and/or norepinephrine transporters with desired effects and fewer interactions with certain neurotransmitters and their receptors, effects that limit the use of MAOIs and TCAs.2-4

Despite higher selectivity and better tolerance by patients, the newer-generation antidepressants are not superior to MAOIs and TCAs in clinical response and remission rates. Their pharmacologic effects occur almost immediately; however, a therapeutic lag occurs before meaningful symptom improvement occurs.5,6 Although the reason for this lag is not completely understood, it is thought to reflect the time required for desensitization of the receptors regulating monoamine release (serotonin [5-HT]1A, 5-HT2C, and α2-adrenergic receptors)7-9 and changes in expression of certain genes (brain-derived neurotrophic factor [BDNF]; neuropeptide VGF).10-12

In addition to the fact that not all depressed patients are satisfactorily treated with these new drugs, there are some unwanted adverse events such as sexual dysfunction, which are hypothetically due in part to the failure of SSRIs or SNRIs to induce similar alterations in dopamine signaling while increasing serotonergic or noradrenergic neurotransmission.13 Despite the dysfunction of dopaminergic circuits, which has been linked to depressive syndrome for decades, research on norepinephrine- and serotonin-containing circuits has largely overshadowed research on the role of dopamine in depression. Dopamine is thought to play a critical role in mediating some depressive symptoms such as anhedonia. Research is being reported on the improvement in depressive symptoms in treatment-resistant patients with addition of a dopamine agonist.14,15 Thus, with this information and the clinical success of SSRIs and SNRIs, there is considerable rationale for targeting all three monoamine reuptake sites (transporters) using drugs that are termed triple reuptake inhibitors (serotonin, norepinephrine, and dopamine transport blockers) in the treatment of depression.16,17


Dopaminergic Mechanism in Depression

The mesocorticolimbic dopamine system is involved in motivation, psychomotor speed, concentration, the ability to experience pleasure, and neurogenesis.13,18 There is considerable evidence linking mesocorticolimbic dopaminergic pathways with depression, especially with anhedonia and the lack of motivation observed in many depressed patients.19 Apathy and anhedonia together, defined as a loss of interest or pleasure in normally rewarding activities, are cardinal criteria for a diagnosis of depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.20 Moreover, hippocampal neurogenesis is implicated in the physiopathology of depression and partially underlies antidepressant therapy.21,22

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in depression and especially in major depressive disorder (MDD). This may result from either diminished dopamine release from presynaptic neurons or impaired signal transduction, including changes in receptor number or function and altered intracellular signal processing.13 Impairments of the mesolimbic dopamine system, including reduction in dopamine levels,23 decreased dopamine (D)2/D3 receptor binding,24 and supersensitivity of dopamine postsynaptic receptors25 were seen in animal models of depression and were reversed by ongoing antidepressant treatment.19,24,26 Transgenic mice with a disruption of the prostate apoptosis-response-4/D2 receptor interaction exhibit depression-like behaviors.27 Clinical studies also found lower concentrations of dopamine metabolites, primarily homovanillic acid (HVA), in the cerebrospinal fluid of depressed patients compared to that for healthy individuals, particularly in patients with psychomotor retardation. Dopamine turnover correlated inversely with the severity of depression as measured by the Hamilton Rating Scale for Depression (HAM-D).28 Genetically, more than one vulnerable dopaminergic-related gene may significantly increase the likelihood of developing MDD via the D4 receptor, dopamine transporter, catechol-O-methyl transferase, or the dopamine β-hydroxylase gene.29-31

Drugs that are known to decrease or increase dopaminergic neurotransmission can have depression-like or antidepressant-like effects, respectively. Treatment with reserpine, which depletes synaptic stores of dopamine and other monoamines, and neuroleptics, which block dopamine receptors, down-regulate dopaminergic circuits and can produce depression-like symptoms in humans.32 Conversely, psychostimulants, which increase synaptic levels of dopamine by releasing dopamine or blocking its reuptake, induce a hedonic mood by activation of mesolimbic dopamine transmission. Several drugs acting on the dopamine system have been evaluated for their efficacy in MDD, such as MAOIs and dopamine agonists.13 The efficacy of MAOIs in atypical depression and anergic bipolar depression partly depends on their effect on dopamine metabolism.33 Dopamine agonists bromocriptine and pramipexole exert antidepressant efficacy in a randomized placebo-controlled study in patients with MDD.34,35 In addition, it is suggested that dopaminergic neurotransmission may be a final pathway common for many antidepressant treatments.36 Chronic antidepressants potentiate dopamine transmission by causing supersensitivity of postsynaptic D2-like receptors (ie, D2 and D3), and subsensitivity of D1 receptors occurs preferentially in the limbic system.19 These receptor sensitivity changes may contribute to therapeutic effects of antidepressants.37

Additional evidence that associates dopamine neurotransmission with depression is the high incidence of depression among patients diagnosed with Parkinson’s disease, a neurologic disease involving the degeneration mainly of dopamine-synthesizing neurons. The incidence of depression in Parkinson’s disease is in the range 30% to 50% and prevalence in some surveys is >60%.38 Anecdotally, depression in Parkinson’s disease is very difficult to treat. Overlapping symptoms between depression and Parkinson’s disease such as apathy, anhedonia, sleep-wake dysregulation, and lack of energy correlate with the dysfunction of mesocorticolimbic or nigrostriatal dopaminergic, serotonergic, and noradrenergic circuits in Parkinsonian depression.38

Dopaminergic medication can bring about improvement in episodes of severely depressed mood in Parkinson’s disease patients. Adjunct treatment with dopamine agonists, either pergolide or pramipexole, had significant antidepressant effects in Parkinson’s disease patients according to the Zung self-rating scores or HAM-D.39 Pramipexole showed the greater effect with 61% of Parkinsonian depressed patients reaching the “recovered” points in HAM-D, as compared with only 27% of those on sertraline.40 SSRIs, including fluoxetine, sertraline, citalopram, and paroxetine failed to improve Parkinson’s disease depression,41-43 while beneficial effects of paroxetine, nefazodone, fluoxetine, and venlafaxine were observed in Parkinson’s disease-associated depression in other clinical trials.44-48 Although SSRIs are still the most commonly used drugs to treat depression in Parkinson’s disease, there is a high risk of worsening Parkinson’s disease tremor (possibly due to effects of serotonin-mediated inhibition of dopamine release). Given that the dopaminergic system is involved in the pathogenesis of both depression and Parkinson’s disease, it is hypothesized that triple reuptake inhibitors might have improved efficacy in treating Parkinson’s disease depression with less likelihood of aggravating tremors.

Disturbances in reward functioning in MDD further implicate dopamine neurotransmission in depression. The drug-addicted state shares some underlying neurobiologic substrates and common symptoms with depression and there is a high rate of comorbidity of drug addiction with depression.49 Anhedonia, in addition to being a cardinal criterion for the diagnosis of depression, is also a core symptom required for the diagnosis of drug withdrawal, which is thought to involve a reduction in mesolimbic dopamine neurotransmission. Severity of MDD has been found to correlate directly with the magnitude of the reward experience after psychostimulant (d-amphetamine) treatment.50 Specifically, medication-free, severely depressed subjects experienced greater reward than controls after treatment with a psychostimulant, while mildly depressed patients did not differ from controls. Compensatory mechanisms resulting from the reduction of dopamine release in MDD, such as up-regulation of postsynaptic dopamine receptors and decreased dopamine transporter density, may contribute to the greater effect of amphetamine in these patients. Additionally, the hyperactivity of the hypothalamic-pituitary-adrenal axis in MDD may selectively facilitate dopamine transmission, thus supporting the theory that a depressed patient has increased reward processing of psychostimulants.51


Broad-Spectrum Antidepressants: Triple Reuptake Inhibitors

Given the critical role of dopamine circuits in mediating some depressive symptoms, a triple reuptake inhibitor—a broad-spectrum drug combining blockade of dopamine, serotonin, and norepinephrine transporters—is an attractive strategy to treat depression. Hypothetically, this type of drug would produce a more rapid onset and better efficacy (higher response and remission rates) than current antidepressants in part due to the addition of the dopamine component.16 In addition, it is possible that some of the sexual dysfunction related to serotonin transport blockade, seen very commonly with SSRIs,52 would be attenuated or even eliminated due to the addition of the dopamine component. In particular, hyperprolactinemia, which causes impotence in males, would be less likely to occur since dopamine opposes serotonin-promoted prolactin release.53 In addition, due to the link to the dysfunction of dopamine neurotransmission, triple reuptake inhibitors may be of benefit in Parkinson’s disease2 and psychostimulant withdrawal with or without depression.49
Enhancements of BDNF gene expression and hippocampal neurogenesis followed by downstream effects are considered to be important mechanisms after chronic antidepressant treatment.54,55 However, neurogenesis more likely relates to their antianxiety rather than their antidepressant effects.56 A triple reuptake inhibitor antidepressant may show a more robust ability to up-regulate BDNF transcripts than SSRIs,57 assumedly via distinct signaling cascades targeting regulatory segments at different exons.58

A concern with drugs that block dopamine transporters is their potential reinforcing effects and abuse liability.59 Thus, triple reuptake inhibitors will likely receive extra scrutiny by regulatory bodies regarding their abuse liability. This will require preclinical (testing for reinforcing effects in animals) as well as clinical testing. However, just because a drug blocks the dopamine transporter does not mean that it will be abused. Using positron emission tomography (PET), Volkow and colleagues59 showed that dopamine transporter-blocking drugs must induce >50% dopamine transporter blockade and the blockade must be timely (within 15 minutes) to produce reinforcing effects. For example, radafaxine, a hydroxy metabolite of bupropion being developed as a new antidepressant, blocks the dopamine and norepinephrine transporters and is not reinforcing in animals, since animals will not self-administer the drug. In PET studies,43 it shows relatively low potency and slow blockade of the dopamine transporter in human brain.59 These animal and human studies suggest that radafaxine is unlikely to have reinforcing effects in humans. For triple reuptake inhibitors, PET studies of dopamine transporter blockade in humans may be an easy way to test for their tendency for abuse.


Developing Triple Reuptake Inhibitors

If these hypotheses are proven correct, the therapeutic profile of triple reuptake inhibitors would offer clear advantages over currently available antidepressants. Although the clinical efficacy of such a broad-spectrum antidepressant has not yet been fully demonstrated, several compounds have entered clinical trials, such as DOV 216,303, DOV 21,947, NS-2359, and SEP-225289. Information on the binding profiles of the known triple reuptake inhibitors is limited. Some data for inhibition at human or rat transporters are listed in the Table (Albany Molecular Research Inc. Drug Discovery Symposium, unpublished data, October 2006).60-63




PRC Series

In collaboration with Paul R. Carlier, PhD (Virginia Tech, Blacksburg, VA), the authors of this article have synthesized a series of compounds based on the structure of venlafaxine (Figure).17 Racemic PRC025 {(1S/1R,2S/2R)-1-cyclohexyl-3-(dimethylamino)-2-(naphthalen-2-yl)propan-1-ol} and racemic PRC050 {(1S/1R,2S/2R)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol} are both highly potent at human serotonin, norepinephrine, and dopamine transporters and also potently inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes.64 Both are active in tests predictive of antidepressant activity in humans including the mouse tail-suspension test and the rat forced swim test.64 PRC200-SS {(1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol} (Figure), which is the more active enantiomer of PRC050, potently binds to the human serotonin, norepinephrine, dopamine transporters (Table) and potently inhibits serotonin, norepinephrine, and dopamine uptake in cells expressing the corresponding transporter.60 Consistent with these in vitro data, in vivo, PRC200-SS (10 mg/kg, ip) significantly increased the extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, HVA, and 5-hydroxyindoleacetic acid compared to levels for saline control (Y Liang, PhD, unpublished data, October 2007). In addition, PRC200-SS dose-dependently decreased immobility in the forced swim test in rats and in the tail-suspension test in mice, with effects comparable to imipramine, but at a much lower dosage.60 The results in these behavioral models do not appear to be from the stimulation of locomotor activity, which would give a false-positive result in these predictive tests of antidepressant activity in humans. Further, PRC200-SS self-administration, which was used as a test of abuse liability, was not observed with rats (Y Liang, PhD, unpublished data, October 2007). To these authors’ knowledge, this is the first study to address the abuse property of a triple reuptake inhibitor. Therefore, it appears that PRC200-SS is a novel triple reuptake inhibitor that possesses antidepressant-like activity. It is expected that PRC200-SS will be in clinical testing in 2009.




DOV Series

DOV Pharmaceutical, Inc. (Somerset, NJ), is developing a DOV series of triple reuptake inhibitors (Table). DOV 216,303 (racemic) is active in the mouse forced swim test, with the reversal of tetrabenazine-induced ptosis and locomotor depression.16 DOV 21,947, as the (+)-enantiomer of DOV 216,303, is effective in the rat forced swim test with an oral minimum effective dose of 5 mg/kg without significant locomotor activity and in the mice tail suspension test in a dose-dependent manner with a minimum effective oral dose of 5 mg/kg.16,61 DOV 102,677 (20 mg/kg, ip) increased extracellular levels of dopamine, serotonin, and norepinephrine in the prefrontal cortex and levels of dopamine and serotonin in the nucleus accumbens, along with reduction of their metabolites in both regions. These results are consistent with the dosage used for antidepressant-like activity in the forced swim test with a minimum effective dose of 20 mg/kg.62 DOV 102,677 was also as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. Further, DOV 102,677 potently blocked volitional consumption of alcohol and reduced the operant response to alcohol.65 DOV 216,303 has already entered into clinical trials. Dose-escalating, placebo-controlled, double-blind Phase Ia trials show rapid absorption following oral administration. Severe side effects in Phase Ia and Phase Ib trials were limited to diarrhea, vomiting, and nausea. Phase I trials indicated DOV 216,303 to be safe and well tolerated at single doses of up to 100 mg and at multiple doses of up to 100 mg/day for 10 days. Phase II trials showed that DOV 216,303 is as effective as the SSRI citalopram in severely depressed patients based on changes in the HAM-D.66


NS-2359 (GSK-372475)

NS-2359 (GSK-372475), which was developed by Neurosearch A/S (Ballerup, Denmark) and subsequently out-licensed to GlaxoSmithKline (GSK; United States and United Kingdom), is another triple reuptake inhibitor entering clinical trials. Phase I trials showed it was well tolerated by patients, with increased attention and improved ability to recall verbal information. It is proposed to be a treatment for attention-deficit/hyperactivity disorder. In 2006, GSK initiated Phase II trials in patients with MDD.66


Tesofensine (NS-2330)

Tesofensine (NS-2330) is another triple reuptake inhibitor developed by NeuroSearch. It indirectly stimulates cholinergic action, and is suggested by NeuroSearch to be a potential therapy for Alzheimer’s disease and Parkinson’s disease.67 Tesofensine has a longer half-life (8 days) in humans than most other antidepressants. It shows antidepressant-like properties with respect to enhancement of hippocampal neurogenesis and BDNF messenger ribonucleic acid (mRNA) augmentation. Chronic (14 days) but not sub-chronic (5 days) treatment with tesofensine induced increases in BDNF mRNA in the CA3 region of the hippocampus, cytoskeleton protein mRNA in the CA1 of the hippocampus. There was also an increase in hippocampal markers for cell proliferation as measured by immunoreactivity for Ki-67 (a marker of proliferating cells) and NeuroD (a transcription factor regulating neurogenesis).68 Such results correspond with the profiles of current antidepressants.54 In a small Phase IIa pilot study of Alzheimer’s disease, NS 2330 (10.75 mg and 12.25 mg over 28 days) improved aspects of cognition, including attention and ability to store and retrieve information. However, due to inadequate inhibition of dopamine reuptake, tesofensine failed to provide clinical benefit as monotherapy in early Parkinson’s disease compared to placebo in a proof-of-concept, randomized, and double-blind trial.69



Sepracor has developed SEP-225289 for treatment of refractory depression and for generalized anxiety disorder. This compound is undergoing Phase I clinical trials. Albany Molecular Research Institute (AMRI; Albany, New York and elsewhere) has developed AMRI CNS-1 and CNS-2 (Table), which have been licensed by Bristol-Myers Squibb (New York, New York; Albany Molecular Research Inc. Drug Discovery Symposium, unpublished data, October 2006). Acenta Discovery Inc. (Tucson, AZ) has designed and synthesized piperidine-based nocaine/modafinil hybrid ligands displaying an improved potency at all three monoamine transporters and particularly for the dopamine transporter and/or norepinephrine transporter.70



Clearly, triple reuptake inhibitors hold great promise for the next generation of antidepressants. In the meantime, the available clinical data are too limited to draw any conclusions. Publicly available preclinical data on these compounds are also limited. Some of the in vitro data, presented in the Table, suggest some pharmacodynamic differences among these compounds. Of the compounds listed, PRC200-SS is the most potent at norepinephrine transporter, and AMRI CNS-1 at the serotonin and dopamine transporters.

The rank-order of potency at the various transporters differs among these compounds as well (Table). For example, PRC200-SS is norepinephrine (N)> serotonin (S)>dopamine (D), while DOV 21,947 is S>D>N (Table). It is reasonable to speculate that triple re-uptake inhibitors will have distinctly different clinical profiles depending on their rank order of potency, as well as on their relative potencies at the three transporters. It is also possible to have a perfectly balanced triple reuptake inhibitor, where the potencies at all three transporters are equal. What are the ideal rank order and the ideal relative potency? It is probably easier to answer the latter question, the answer for which derives from occupancy theory. Simply stated, if a drug has a very large range from its most potent to its least potent effect, it may not be possible clinically to achieve a dosage that blocks all three transporters. Thus, a narrow range (10–30-fold) is better. Additionally, it would probably be better to have serotonin transporter blockade as the weakest of the three, to minimize the adverse effects associated with this blockade (eg, sexual dysfunction). Dopamine transporter blockade as the most potent effect may lead to concerns about the abuse potential of the compound. Therefore, the ideal rank order would probably be N>D>S. This would provide a triple re-uptake inhibitor with some nomifensine-like qualities (Table). PP



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60.    Shaw AM, Boules MM, Williams K, Robinson J, Carlier PR, Richelson E. Antidepressant-like effects of PRC200, a novel norepinephrine, serotonin, and dopamine reuptake inhibitor [abstract]. Biol Psychiatry. 2006;59(8):61S.
61.    Skolnick P, Popik P, Janowsky A, Beer B, Lippa AS. Antidepressant-like actions of DOV 21,947: a “triple” reuptake inhibitor. Eur J Pharmacol. 2003;461(2-3):99-104.
62.    Popik P, Krawczyk M, Golembiowska K, et al. Pharmacological profile of the “triple” monoamine neurotransmitter uptake inhibitor, DOV 102,677. Cell Mol Neurobiol. 2006;26(4-6):857-873.
63.    Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340(2-3):249-258.
64.    Shaw AM, Boules M, Zhang Y, et al. Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050. Eur J Pharmacol. 2007;555(1):30-36.
65.    McMillen BA, Shank JE, Jordan KB, Williams HL, Basile AS. Effect of DOV 102,677 on the volitional consumption of ethanol by Myers’ high ethanol-preferring rat. Alcohol Clin Exp Res. 2007;31(11):1866-1871.
66.    Chen Z, Skolnick P. Triple uptake inhibitors: therapeutic potential in depression and beyond. Expert Opin Investig Drugs. 2007;16(9):1365-1377.
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68.    Larsen MH, Rosenbrock H, Sams-Dodd F, Mikkelsen JD. Expression of brain derived neurotrophic factor, activity-regulated cytoskeleton protein mRNA, and enhancement of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensine. Eur J Pharmacol. 2007;555(2-3):115-121.
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Needs Assessment:
Psychotic depression is a more common illness than previously believed. It differs from other psychotic disorders in the type and manifestation of psychotic symptoms. The purpose of this article is to synthesize the available literature on the phenomenology and treatment of psychotic major depression.

Learning Objectives:

• Understand the unique symptoms of psychotic major depression.
• Learn the limitation of clinical trials in the treatment of psychotic depression.
• Learn about investigational treatments for psychotic depression.

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. DeBattista is associate professor of Psychiatry and Behavioral Sciences, director of Depression Research and Psychopharmacology Clinics, and director of Medical Student Education in Psychiatry; and Dr. Lembke is senior research associate and clinical instructor, both at Stanford University School of Medicine in California.

Disclosure: Dr. DeBattista is on the speaker’s bureaus and/or consultant to Bristol-Myers Squibb, Cephalon, Corcept, Cyberonics, Eli Lilly, Forest, Pfizer, and Wyeth; receives grant support from AstraZeneca, Boehringer-Ingelheim, Cephalon, Cyberonics, Eli Lilly, Forest, Neuronetics, Novartis, Pfizer, and Wyeth; and is a stockholder of Corcept Therapeutics (Corcept is the developer of mifepristone for use in psychotic depression). Dr. Lembke receives research support from the National Institutes of Health.

Please direct all correspondence to: Charles DeBattista, MD, Stanford University School of Medicine, 401 Quarry Rd, Stanford, CA 94305; Tel: 650-723-8324; Fax: 650-723-8331; E-mail:





Psychotic major depression appears to be a unique subtype of depression with its own phenomenology and treatment response. However, the symptom profile of psychotic depression is not well described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the psychotic symptom features of psychotic depression may be distinct. While treatments such as electroconvulsive therapy and the combination of antidepressants and antipsychotics appear effective, data that supports the efficacy of these treatments have substantial limitations. The symptoms and treatment of psychotic major depression are critically reviewed in this article.



Psychotic major depression (PMD) is classified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),1 as a severe form of depression characterized by meeting the full criteria for major depressive disorder (MDD) plus the presence of delusions or hallucinations. Growing evidence suggests that PMD is more common than once believed. It is estimated that at least 14% to 20% of depressive episodes have psychotic features.2,3 Psychotic depression may represent a unique subtype of MDD with a distinct phenomenology and treatment response.4 Psychotic features are not necessarily the only symptoms that distinguish PMD from non-psychotic major depression (NPMD) For example, cognitive deficits may also distinguish PMD form NPMD.5 Furthermore, the psychotic features of PMD may not completely parallel the kinds of symptoms seen in other psychotic disorders such schizophrenia. In fact, specialized scales have been proposed for assessing psychosis in PMD.6,7 Given that the symptoms of PMD differ from other types of depression, it is not surprising that PMD may require different treatment than NPMD. However, relative to NPMD, very few trials have ever been completed in the treatment of PMD, and those trials have significant limitations.



The DSM-IV describes the psychotic features of PMD as predominately delusions that are mood congruent, such as delusions of guilt, delusions of poverty, somatic delusions, or nihilistic delusions.1 Furthermore, the DSM-IV suggests that mood incongruent delusions such as persecutory delusions (without a depressive theme) are less common as are hallucinations. When present, hallucinations are described as transient, auditory, and likely to be mood congruent.

The rate of paranoid delusions in PMD samples has varied considerably. Lykourous and colleagues8 found that paranoid delusions were the most common, with nine of eleven patients presenting with delusions of impending disaster, guilt, and somatization. Likewise, a subsequent study by Lykourous and colleagues9 found that all 22 PMD patients had delusions, with ideas of reference and persecution being the most common. Breslau and Meltzer10 found that delusions of reference occurred in 23% of the PMD, 62% of the schizoaffective, and 32% of the bipolar patients. Persecutory delusions occurred in 38% of the PMD, 56% of the schizoaffective, and 53% of the bipolar patients. Other types of depressive delusions occurred in 49% of the PMD, 41% of the schizoaffective, and 51% of the bipolar patients.

The delusions in PMD may be more subtle than those seen in schizophrenia. Many patients with depressive disorders have ruminations that may not quite meet the threshold of delusion. However, these “near delusions” tend to predict poor response to antidepressant monotherapy.11

Hallucinations have been characterized as being less common in PMD than in schizophrenia but may still be quite common. For example, Breslau and Meltzer10 found that visual hallucinations were somewhat more common in psychotically depressed unipolar than bipolar or schizoaffective patients, occurring in 31% of unipolar patients. In contrast, auditory hallucinations were much less common in unipolar psychotic patients (28%) than in schizoaffective (62%) patients. Lykourous and colleagues8 found that 50% of patients with PMD had hallucinations, but that these only occurred in patients who also had delusions and with whom the content of the hallucinations was consistent with those of the delusions. In general, the hallucinations in PMD have been thought to be less severe than those found in schizophrenia.

Thought disorder has historically been most associated with schizophrenia spectrum illnesses. However, disorders of thought may be even more common in mood disorders such as bipolar disorder. The rate of thought disorder in PMD has been considered low. For example, Breslau and Meltzer10 found that only 10% of patients with unipolar depression with psychotic depression had evidence of a thought disorder, versus 40% of bipolar and 50% of schizoaffective patients. Wilcox and colleagues12 found that thought disorders were also predictive of a greater relapse rate over 7 years than other psychotic symptoms in PMD.

While a formal thought disorder may be less common in unipolar patients with psychotic depression, cognitive deficits in general appear quite common. Patients with psychotic depression have more difficulty processing, manipulating, and encoding new information5 than do NMPD patients. Other types of deficits seen in psychotic versus nonpsychotic depressed patients include difficulty with attention, response inhibition, and verbal declarative memory.13 In fact, the cognitive deficits seen in PMD appear to resemble those seen in schizophrenia more than those in patients with non-psychotic depression.14


Antidepressant Monotherapy

Given the unique phenomenology of psychotic depression, it is not surprising that the standard treatment for MDD may not be as consistently useful in PMD. For example, monotherapy with antidepressants is thought to be less useful in PMD. Many of the treatment studies of psychotic depression have employed tricylcic antidepressants (TCAs). While TCA monotherapy has been an established treatment for MDD, studies of amitriptyline, imipramine, and other TCAs in the treatment of PMD have shown poor response. For example, Avery and Lubrano15 considered the DeCarolis study, where 437 patients with and without psychotic features were prospectively treated with imipramine. Only 40% of PMD patients responded to imipramine treatment versus 60% of the non-psychotic depressed patients. Similarly, an analysis of 12 studies by Chan and colleagues16 found that only 35% of PMD patients responded to TCAs versus 67% of NPMD patients. In the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression, 32% of patients with psychotic features responded to amytryptyline or imipramine compared with 37% of nonpsychotic severely depressed patients and 67% of patients with moderate nonpsychotic depression.17 However, the differences between PMD and severely depressed NPMD patients was not significant. Other TCA studies also have not necessarily shown a difference between response to TCAs in PMD versus NPMD patients.18

More recent monotherapy studies have reported efficacy with SSRIs in the treatment of PMD. For example, Gatti and colleagues19 reported that 84% of 57 patients treated for 6 weeks with fluvoxamine responded to treatment. In subsequent PMD trials, fluvoxamine was found to be at least as efficacious as venlafaxine in the treatment20 and even more rapidly efficacious in combination with pindolol.21 Long-term treatment with fluvoxamine was also reported to prevent relapse in PMD patients treated for 18 months.22 The pharmacologic profile of fluvoxamine differs from other SSRIs in that it has substantial effects on the Sigma receptor which is also thought to play a role in the pathophysiology of psychosis.23

Other SSRIs have also been proposed to be effective in the monotherapy of PMD. Zanardi and colleagues24 found that sertraline was more effective than paroxetine in the treatment of 46 patients hospitalized with PMD. In contrast, Simpson and colleagues25 found that sertraline was much less effective in PMD patients than NPMD patients treated with up to 200 mg/day. Thus, the utility of sertraline monotherapy in the treatment of PMD is unclear. As with the TCA studies, methodologic problems limit conclusions that can be surmised from the SSRI studies. Among the limitations of the SSRI studies in PMD include the lack of a placebo group, the lack of a comparison with response NPMD patients, and possibly differences in the criteria for defining PMD.

Amoxapine, a tetracyclic antidepressant related to loxapine and rarely used currently, was also reported to be effective as a monotherapy in the treatment of PMD. Anton and Burch26 compared amoxapine to the combination of amitriptyline and perphenazine in the treatment of PMD. After 4 weeks of treatment, >80% of patients in both the combination group and the amoxapine group exhibited a moderate or marked response without significant differences between treatments. However, the combination treatment was more poorly tolerated. While the Anton and Burch26 study was a double-blind randomized study with a placebo wash out, there was no placebo comparison group in the study.

Thus, there is some evidence that monotherapy with amoxapine and perhaps SSRIs may be effective in the treatment of PMD, and that TCA monotherapy has generally not been effective. However, the methodologic problems of the monotherapy trials are many and it is uncertain whether monotherapy is a reasonable treatment or whether combination treatment with an antipsychotic is generally necessary to achieve response.


Combination Treatment: Antidepressants and Antipsychotics

Numerous studies that found monotherapy with TCAs ineffective in the treatment of PMD found that the addition of a standard antipsychotic significantly improved efficacy. For example, Minter and Mandel,27 in a retrospective chart review of 54 PMD patients, found patients generally did not respond to monotherapy with a TCA but became responders when an antipsychotic was added. Similarly, Charney and Nelson,28 in a retrospective review of 120 PMD and NPMD patients, found that the PMD patients responded poorly to TCAs but well to the combination of TCAs and typical antipsychotics.

In one of the few prospective randomized trials to compare combination treatment with monotherapy, Spiker and colleagues29 compared the efficacy of amitriptyline alone, perphenazine alone, and the combination of amitriptyline and perphenazine in PMD patients. The response rate to treatment after 35 days was as follows. Amitriptyline alone was 41%, perphenazine alone was 19%, and combination of amitriptyline and perphenazine was 78%. Patients who failed to respond to monotherapy tended to respond when the second agent was added.

The combination of fluoxetine and olanzapine has also been evaluated in larger and more rigorous studies than previous combination trials. Patients who met DSM-IV criteria for PMD were randomized to either the combination of olanzapine and fluoxetine, olanzapine alone, or placebo.30 Two studies (study 1 with 124 patients, study 2 with 125 patients) were conducted in parallel at 27 sites under the same protocol. In study 1, the combination treatment was superior to placebo and olanzapine on the primary outcome, which was defined as change from baseline on the Hamilton Rating Scale for Depression (HAM-D). In addition, the categorical response rate (50% improvement on the HAM-D) was significantly higher in the combination treatment in study 1 (63%) compared to olanzapine alone (35%) or placebo (28%). There were no differences between groups in the second trial on the primary outcome measure, response rates, or remission rates. Furthermore, the pooled data of trials 1 and 2 did not apparently show a benefit of combination treatment over placebo or olanzapine. Both studies had much higher placebo response rates than have been typically reported for PMD. The long hospitalization allowed in the study may have contributed to this high placebo response rate. In addition, the lack of a fluoxetine alone arm also prevented a comparison with antidepressant monotherapy.


Electroconvulsive Therapy

Electroconvulsive therapy (ECT) has been reported to be among the most effective treatments for PMD. The American Psychiatric Association Guidelines for the treatment of depression endorse ECT as a first-line treatment only for PMD.31 As with other treatments for PMD, there are few prospective randomized or sham-controlled trials. Retrospective reviews and open trials have generally shown ECT to be highly effective in the treatment of PMD.27,28,32-35 The DeCarolis study, as noted by Avery and Lubrano,15 found that while only 40% of PMD patients responded to TCA monotherapy, 83% of these nonresponders subsequently responded to ECT. While a large prospective trial, the DeCarolis study is an older trial without a control group or clear entry or response criteria.

There are few sham-controlled studies that specifically include PMD patients. In the Northwick Park Electroconvulsive therapy trial, both delusional and nondelusional depressed patients were evaluated.36 Seventy patients who met endogenous depression criteria were randomized to a series of eight ECT treatments or eight sham treatments. While the treating psychiatrists tended to consider the active ECT patients to be better responders than the sham treated patients, the differences between groups were small and there were no differences between groups at 1 and 6 months after treatment. Delusional patients were not separately evaluated in the initial analysis. However, when the results of the Northwick Park ECT trial were combined with results of the subsequent Liecester ECT trial, patients with delusional depression and/or psychomotor retardation appeared to have more benefit than sham-treated patients at 4 weeks.37 Patients without delusions or psychomotor retardation did not show a difference between active ECT treatment and sham treatment. In addition, there were no differences between the active and sham groups at 6 months. The conclusion in both sham-controlled trials was that ECT did not appear effective because there were no sustained benefits. These randomized trials have been criticized as using an ECT stimulus dose that might be considered ineffective currently,38 and as not providing a standardized treatment option after 4 weeks of twice weekly ECT. It has been more recently established that most patients can be expected to relapse within 6 months of successful ECT without effective follow-up treatment.39 Thus, the conclusion that ECT was ineffective because no difference could be observed 6 months after the ECT was discontinued appears invalid in retrospect.

More recent ECT trials comparing response in PMD compared to NPMD patients have suggested that there may be a more favorable response to ECT in PMD patients. Petrides and colleagues40 prospectively compared the efficacy of ECT in 176 patients with NPMD and 77 patients with PMD. Approximately 95% of PMD patients experienced a full remission with acute ECT compared to 83% of patients with NPMD on the HAM-D. Remission also occurred earlier in the PMD patients. Birkenhager and colleagues41 found a 92% response rate (defined as 50% improvement on the HAM-D) in PMD patients compared with only a 55% response rate to ECT in NPMD patients. PMD patients who respond to ECT also may be somewhat less likely to relapse than NPMD patients who respond to ECT. Birkenhager and colleagues42 prospectively followed 29 PMD and 30 NPMD patients who responded to ECT for 1 year. Only 15% of PMD patients relapsed at 12 months compared to 58% of NPMD patients. Since relapse to ECT may be related to factors other than psychosis (eg, number of previous episodes, number of failed previous medication trials),39 it is uncertain in this study whether the PMD and NPMD groups were comparable. Other trials have not found an advantage of ECT treatment in PMD patients compared to NPMD patients, and some trials have suggested a poorer response to ECT in PMD patients.43 Numerous factors might lead to disparate results in the evaluation of ECT for PMD. For example, ECT variables including stimulus dose, lead placement, frequency and number of treatments, and seizure duration tend to differ from trial to trial. In addition, assessment scales and inclusion criteria are also not uniform in ECT studies.

Despite the limitations of the ECT data, there has been a consistent theme in the literature over the past 40 years that suggests that ECT is an effective acute treatment for PMD with reported response and remission rates that are generally higher than those reported in pharmacotherapy trials. However, there are a lack of randomized, head to head comparison trials between ECT and pharmacotherapy in PMD patients, and such trials would be difficult to design and control given the obvious disparities between treatments.


Experimental Treatments

Among the treatments under investigation for PMD include the use of the glucocorticoid receptor antagonist mifepristone and transcranial magnetic stimulation (TMS). The glucocortiod/progesterone receptor antagonist mifepristone has been explored in the treatment of PMD with the rationale that some symptoms of PMD may be driven by abnormalities in the hypothalamic-pituitary-adrenal axis.44 Early open and controlled studies by the authors of this article have suggested that there might be benefits of mifepristone in the treatment of the psychotic symptoms of PMD.45,46 However, the most recent controlled studies of mifepristone failed to replicate these findings. Among the methodologic limitations of the mifepristone trials might include the representativeness of the patient sample, the adequacy of the endpoints, the high placebo response rates, and whether the optimal dose and duration of mifepristone treatment was employed. A summary of the mifepristone studies completed to date in the treatment of PMD can be found elsewhere.47 Additional controlled studies of mifepristone in the treatment of PMD are currently underway.

Another experimental treatment that has been examined in PMD is TMS, which uses a focused electromagnetic field to stimulate very specific areas of the cortex.48 Numerous studies have suggested efficacy for TMS, including a recently completed multi-center American trial of TMS in treatment-resistant depression.49 However, TMS, while more benign than ECT, appears to be substantially less effective than the latter.50-52 In addition, psychotic features of depression appear to predict poorer response to TMS.48 Thus, most recent studies of TMS exclude patients with PMD. It is possible, however, that different stimulation parameters might improve the efficacy of TMS of both PMD and NPMD.



PMD remains a relatively poorly understood illness. The unique symptom profile of PMD is consistent with the finding that standard treatments for NPMD are often not as effective in the treatment of PMD. The increased prevalence of delusions, hallucinations, and more severe cognitive symptoms in PMD might require different strategies for effective treatment. The current standard of care for PMD is either combination treatment with an antidepressant plus an antipsychotic, or ECT. However, this standard is based on relatively limited data. While anecdotal experience tends to support the efficacy of combination treatment and ECT in PMD, there is a paucity of randomized controlled data evaluating these strategies. Furthermore, the few randomized controlled trials have not necessarily supported these strategies as the optimal treatments.
Trends in the treatment data suggest that TCAs alone are not effective in the treatment of PMD. It is conceivable that the anti-muscarinic effects of TCAs such as amitriptyline might exacerbate some of the more severe cognitive deficits in PMD.53 As suggested earlier, the unique pharmacology of some SSRIs, such as the effects of fluvoxamine on the sigma receptor, might be of specific benefit in PMD patients.23 The role of investigational treatments including glucocorticoid antagonists and TMS await further investigation. Given the substantial side-effect burden that antipsychotics may produce, further study is needed to evaluate whether combination treatment, especially with newer atypical antipsychotics, is the optimal pharmacotherapy.

Future treatment studies in PMD are hampered by the lack of adequate measures to assess outcome. It is not at all clear that the HAM-D, which has been used in most PMD studies, is the ideal scale for evaluating improvement in PMD patients. The HAM-D does not capture the unique phenomenology of PMD. Likewise, most scales employed to evaluate psychosis in PMD, such as the Brief Psychiatric Rating Scale, were designed to evaluate symptoms in schizophrenia. The psychotic symptoms in PMD do not necessarily parallel those in schizophrenia. Until better measures are developed and randomized comparison trials are completed with newer agents, the optimal treatment for PMD in most patients cannot be established with confidence. In clinical practice, most clinicians appear to be more likely to treat PMD with an antidepressant alone and seem hesitant to add an antipsychotic.54 The available data would at least suggest that patients who do not respond initially to an antidepressant alone should be treated with the combination of an antidepressant and an antipsychotic or ECT. PP



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40.    Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE. J ECT. 2001;17(4):244-253.
41.    Birkenhäger TK, Pluijms EM, Lucius SA. ECT response in delusional versus non-delusional depressed inpatients. J Affect Disord. 2003;74(2):191-195.
42.    Birkenhäger TK, van den Broek WW, Mulder PG, de Lely A. One-year outcome of psychotic depression after successful electroconvulsive therapy. J ECT. 2005;21(4):221-226.
43.    de Vreede IM, Burger H, van Vliet IM. Prediction of response to ECT with routinely collected data in major depression. J Affect Disord. 2005;86(2-3):323-327.
44.    Schatzberg AF, Rothschild AJ, Langlais PJ, Bird ED, Cole JO. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res. 1985;19(1):57-64.
45.    Belanoff JK, Rothschild AJ, Cassidy F, et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry. 2002;52(5):386-392.
46.    DeBattista C, Belanoff J, Glass S, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiatry. 2006;60(12):1343-1349.
47.    Nihalani ND, Schwartz TL. Mifepristone, a glucocorticoid antagonist for the potential treatment of psychotic major depression. Curr Opin Investig Drugs. 2007;8(7):563-569.
48.    Mitchell PB, Loo CK. Transcranial magnetic stimulation for depression. Aust N Z J Psychiatry. 2006;40(5):406-413.
49.    O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62(11):1208-1216.
50.    Martin JL, Barbanoj MJ, Schlaepfer TE, et al. Transcranial magnetic stimulation for treating depression. Cochrane Database Syst Rev. 2002;(2):CD003493.
51.    Loo CK, Mitchell PB. A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. J Affect Disord. 2005;88(3):255-267.
52.    Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci. 2005;30(2):83-90.
53.    Wadsworth EJ, Moss SC, Simpson SA, Smith AP. Psychotropic medication use and accidents, injuries and cognitive failures. Hum Psychopharmacol. 2005;20(6):391-400.
54.    Andreescu C, Mulsant BH, Peasley-Miklus C, Persisting low use of antipsychotics in the treatment of major depressive disorder with psychotic features. J Clin Psychiatry. 2007;68(2):194-200.



FDA Approves Aripiprazole for Acute Treatment of Manic and Mixed Episodes in Pediatric Patients

The United States Food and Drug Administration approved aripiprazole (Abilify, Bristol-Myers Squibb, Otsuka America Pharmaceuticals) for the acute treatment of manic and mixed episodes affiliated with bipolar I disorder with or without psychotic characteristics in adolescents between 10–17 years of age.

Approval was based on results from a double-blind, placebo controlled study involving 296 pediatric bipolar patients enrolled at 54 US centers and evaluated over a 4-week period using the Young-Mania Rating Scale (Y-MRS) total score. Aripiprazole was initially administered at 2 mg/day. Patients who scored ≥20 on the Y-MRS were randomly assigned to aripiprazole doses of either 10 mg/day (n=98) or 30 mg/day (n=99). By week 4, both aripiprazole doses exhibited statistically significant improvement (P<.001) in bipolar symptoms when compared to placebo as measured by the mean change in the Y-MRS Total Score from baseline to week 4.

The most common adverse reactions to treatment were somnolence, extrapyramidal disorder, fatigue, nausea, akithisia, blurred vision, salivary hypersecretion, slight weight gain (ie, ≥7% change from baseline), and dizziness. The efficacy of aripiprazole for the maintenance treatment of bipolar I disorder in pediatric patients was not evaluated.

The recommended oral aripiprazole dose for the pediatric bipolar population 10–17 years of age is 10 mg/day.

For more information, please consult the medication’s full prescribing information ( –ML


FDA Approves Fluvoxamine Extended Release for Treatment of SAD and OCD in Adults

The United States Food and Drug Administration approved once daily fluvoxamine maleate (Luvox CR, Jazz Pharmaceuticals) extended-release (ER) capsules for the treatment of social anxiety disorder (SAD) and obsessive-compulsive disorder (OCD) in adults. Fluvoxamine in the form of immediate-release tablets was previously approved in late 2007 for the treatment of obsessions and compulsions in patients with OCD.

Effectiveness for fluvoxamine ER capsules for the treatment of SAD and OCD was demonstrated in three 12-week, multicenter, placebo-controlled studies of adult outpatients. In each study, patients were titrated in 50 mg increments over the first 6 weeks on the basis of response and tolerance from a dose of 100 mg/day to that of 100–300 mg once daily. In the two SAD studies and one OCD study, the capsules demonstrated statistically significant superiority over placebo at the 12-week primary endpoint as assessed by the Liebowitz Social Anxiety Scale total score and Yale-Brown Obsessive Compulsive Scale, respectively.

Fluvoxamine ER capsules will be available in 100 mg and 150 mg dose strengths. The most common adverse reactions were nausea, somnolence, asthenia, diarrhea, anorexia, tremor, and sweating.

For more information, please consult the medication’s full prescribing information. ( –DC


Activity Rhythms May Serve as Bipolar Disorder Indicators in Various Illness States

Patients with bipolar disorder often exhibit physiologic or behavioral symptoms such as increased or decreased activity or amount of sleep, in addition to the manic symptoms like euphoric mood and depressive symptoms that occur during the course of the disorder. However, as most of these physiologic indicators are present only during acute illness, their use during other phases of the disorder or when a patient experiences positive treatment response is limited. In addition, a state-independent physiologic indicator would allow clinicians to anticipate possible mood changes in patients throughout different phases of the disorder. 

Paola Salvatore, MD, of the Schizophrenia and Bipolar Disorder Program and International Consortium for Bipolar Disorder Research at the McLean Division of Massachusetts General Hospital in Belmont, and colleagues, investigated activity rhythms among 36 patients with bipolar disorder in acute states as well as clinical recovery and rhythms among 32 participants without bipolar disorder. Typically, activity rhythms are highly abnormal in patients with bipolar disorder. Salvatore and colleagues hypothesized that such abnormalities may persist in other bipolar states, making activity rhythms a state-independent indicator of bipolar disorder.

The authors evaluated patients with bipolar disorder during acute mania or mixed states as well as during full and sustained clinical recovery, and healthy participants using wrist-worn piezoelectric actigraphic monitoring for 72 hours. Piezoelectric actigraphic monitoring measured changes in motility levels and circadian activity rhythms during the 24-hour day and night cycle.

Salvatore and colleagues found that there were significant differences in motility patterns between patients with bipolar disorder in acute phases and healthy participants. Patients with bipolar disorder showed a lower total proportion of activity in the daytime, decreased amplitude of circadian activity, increased amounts of daytime sleeping, and an earlier peak of daily motor activity rhythm (acrophase) as compared to health participants. Patients in sustained recovery also differed from those in acute phases of bipolar disorder.

Recovered patients showed lower daily activity average, increased motility amplitude, higher percentage of nocturnal sleep, and reduced amounts of daytime sleep when compared to patients with acute illness. When compared to healthy participants, euthymic bipolar disorder patients showed 8% less daytime activity, 18% more total sleep with 11% more nocturnal sleep, and an acrophase >1 hour earlier. Results from euthymic patients remained consistent when researchers controlled for ratings of mania as measured by the Young Mania Rating Scale, depression as measured by the Hamilton Rating Scale for Depression, subjective distress, as well as the type and dosage of psychotropic medication currently being taken.

The authors concluded that the presence of an earlier acrophase for bipolar disorder patients in acute illness and those experiencing treatment response may demonstrate a stable psychobiologic trait of bipolar disorder that can act as an indicator of illness in various states. The authors added that if such an indicator is verified, it may be useful in supporting clinical diagnosis. (Bipolar Disord. 2008;10(2):256-265.) —CP


Mild Cognitive Impairment Disrupts Everyday Life and Relationships

Memory loss, contrary to common belief, is not a normal part of the aging process. A study by Rosemary Blieszner, PhD, of Virginia Polytechnic Institute and State University, and colleagues, suggests that memory loss associated with mild cognitive impairment (MCI) interferes with the everyday lives of family members and their relationships with individuals suffering from MCI.

The 3-year study consists of three parts. The first part involved two interviews with 99 economically diverse, 3-member families. The member experiencing MCI was ≥60 years of age; the second member was a non-professional caretaker (eg, spouse); and the third was a non-professional, secondary care partner such as an adult child, friend, or sibling. The first round of interviews identified three types of responses from people with MCI (ie, acceptance and desire to manage their condition, uncertainty and lack of recognition of memory changes, and denial and rejection of their condition) while the second interview analyzed how families coped with the affected individual’s condition. With the addition of 40 ethnically and racially diverse families, the second phase of the study focused on how family members dealt with the transition from MCI to Alzheimer’s disease in the affected member. The third part, which is currently underway, continues to follow and interview the families. Results thus far have found that the family members of elders with MCI had to alter their daily activities and responsibilities, contributing to distress that affects the relationships between them. This reflects patients and families’ need for ongoing information and support targeted to the patient’s particular level of incapacity and symptoms.

“[Families and patients with MCI] do not find information and support groups for Alzheimer’s disease and other dementias to be relevant or useful,” Dr. Blieszner said. “Many do not have good information about what changes are occurring in the brain and do not understand the sources of the problems they are experiencing.”

That the findings are not based on a national sample is a significant limitation, as they are from three memory clinics located in one state. However, the availability of data from the patient and two other family members in addition to interviews repeated three times over 3 years provide multi-perspective results about changes over time that are otherwise not available for MCI.

Funding for this research was provided by the Alzheimer’s Association. (Family Relations. 2007;56(2):196-209.) –ML


Depression Improvement and Five Secondary Outcomes

According to a recent study, patients receiving selective serotonin reuptake inhibitor (SSRI) treatment for depression may see a shorter time to alleviation of depressive symptoms than for some secondary symptoms of depression, such as hopelessness or lingering somatic symptoms.The study tracked the improvement of secondary deficits associated with depression and then compared those outcomes with the outcome of the actual depressive symptoms.

James E. Aikens, PhD, at the University of Michigan in Ann Arbor, and colleagues, noted that secondary outcomes tend to worsen after depression onset and improve with its remission. Secondary outcomes have been assumed to not only depend upon improvement in depressive symptoms, but to also follow identical trajectories of change. Accordingly, Aikens and colleagues tested this convention based on two alternative hypotheses: first, that secondary outcomes could respond independently of depressive symptoms, or secondly, that secondary outcomes could respond somewhat independently of depressive symptoms.

The data for this study are from A Randomized Trial Investigating SSRI Treatment (ARTIST). The purpose of ARTIST was to evaluate clinical response to SSRIs in a primary care environment with as little research interference as possible. The two most significant ways in which ARTIST study protocol differed from primary care were randomization to one of three initial SSRIs and participation in telephone-based outcome reports during follow up.

The main outcome measure for depressive symptoms was the Symptom Checklist–20 (SCL-20). Each of the remaining five secondary outcomes—positive well-being, social functioning, hopefulness, physical symptoms, and work functioning—were assessed with separate, individual scales.

Seventy-nine percent of the baseline study population (n=573) were women (mean age=46.2 years) and 73% had a diagnosis of major depressive disorder (MDD). An average of 191 patients were randomized to one SSRI group each, including paroxetine (189), fluoxetine (193), and sertraline (191) groups. At study outset, 74% of patients met criteria for MDD, which decreased to 26% of patients by month 9. The mean SCL-20 symptom severity measure decreased as well from 1.66 to 0.78. There was no significant difference between the three SSRIs. Positive well being, one of the five secondary outcomes, and depressive symptoms followed a nearly identical outcome trajectory, improving along the same timeline.

The most significant finding, according to the authors, was that improvement in somatic complaints plateaued earlier than improvement in depressive symptoms. That is, improvement in overall somatic complaints occurred mainly during the first month of therapy, whereas depressive symptoms continued to improve through month 9 (1.2±1.0). Moderate effects were also noted in social functioning (0.9±1.1), work functioning (0.6±0.8), hopefulness (0.7±1.0), and somatic complaints (0.6±1.1).

According to Dr. Aikens, such rapid leveling of the improvement in somatic complaints was rather unexpected.

“I think we have suspected for quite some time that hopelessness cognitions may respond slower to treatment than mood symptoms,” he said. “But to see medical complaints reduce so sharply, especially at a time when initial medication side effects would be peaking—that was surprising.”

Hopelessness is sometimes associated with suicidality, but Dr. Aikens cautions that “the linkage between [the] results and suicidality can only be inferred indirectly” because the trial was not designed to assess suicidal ideation or related constructs. Instead, it was suggested that the results of this trial could guide clinicians when monitoring depressive patients who exhibit pronounced traits of hopelessness or physical pain. In addition, future investigations may determine why the improvement of somatic complaints and depressive symptoms diverge soon after treatment onset.

Funding for this research was provided by Eli Lilly. (Gen Hosp Psychiatry. 2008;30(1):26–31.) –LS


Increased Risk for Postpartum Depression in Low-income and African-American Women

Postpartum depression (PPD) is prevalent in approximately 10% to 20% of women in the United States. Studies by Lisa Segre, PhD, of the University of Iowa, and colleagues, suggest that women of low income are at a higher risk of experiencing PPD than their more affluent counterparts and African-American women are more likely to suffer from PPD than both Latino and white women.

The first study focused on the income, education, marital status, number of children, and occupational prestige of 4,332 women who gave birth 4.6 months prior to the research evaluation. They completed sociodemographic interviews and the Inventory to Diagnose Depression, which is a scale used to identify a major depressive episode according to standards in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision. Data revealed that 40% of the women who were suffering from PPD had a low household income of <$20,000. These results indicate that social status is a significant predictor of PPD, with income as the strongest predictor.

The second study examined race and ethnicity as a factor for PPD. The Iowa Barriers to Prenatal Care Project Survey asked 26,877 English-speaking women with newborns whether they felt excessively miserable over the 2 weeks after they gave birth. Data from the survey revealed that 15.7% of the women exhibited a single depressive item, with African-American women as the most likely candidates to report a depressive mood compared to white women. Hispanic women were least likely to report a depressive mood compared to both African-American and white women.

Both studies emphasize the need for early PPD identification programs and strong social support for women with newborns. (Social Psychiatry and Psychiatric Epidemiology. 2007;42(4):316-321; Journal of Reproductive and Infant Psychology. 2006;24(2):99-106.) –ML

Dispatches is written by Dena Croog, Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.


Dr. Ghanizadeh is assistant professor of Child and Adolescent Psychiatry and director of the Research Center for Psychiatry and Behavioral Sciences and Dr. Kianpoor is assistant professor of psychiatry, both at Shiraz University of Medical Sciences at Hafez Hospital in Iran.

Disclosures: Drs. Ghanizadeh and Kianpoor report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Ahmad Ghanizadeh, MD, Assistant Professor of Child and Adolescent Psychiatry, Shiraz University of Medical Sciences, Hafez Hospital, Shiraz, Iran; Tel: +98-711-627-93-19; Fax: +98-711-627-93-19; E-mail:


Focus Points

• There are several cases of risperidone-induced incontinency.
• There is no treatment for risperidone-induced incontinency except for two cases reports that suggested desmopressin.
• Further studies might show the possible effect of valproate for management of this problem.



Risperidone is effective and well tolerated for treatment of some behavioral problems in children. Risperidone might double the rate of urinary incontinency. There are several cases of risperidone-induced incontinency (ie, in autistic children). Some studies report enuresis in patients who were taking risperidone plus selective serotonin reuptake inhibitors. Desmopressin was suggested in only two case reports as treatment for risperidone-related enuresis. No alternative medication has been suggested to manage this problem. The following is a case report of possible association of risperidone and urinary incontinency in a young male with pervasive developmental disorder; the case report also discusses cessation of the incontinency by taking valproate. Although there are some explanations for the possible association of risperidone and enuresis, the authors have no explanation for the possible effect of valproate on cessation of incontinency. The adverse effect of risperidone-related enuresis should be discussed with parents and children before a child takes risperidone, as the side effect might be disturbing and persistent. Controlled trial data are required to determine the possible efficacy and safety of sodium valproate in the management of risperidone-related incontinency.



Risperidone, an atypical antipsychotic, is effective and well tolerated for the treatment of some of the behavioral problems in children with autistic disorder.1 Risperidone doubled the rate of enuresis in a clinic population.2 The enuresis is most commonly reported in children treated with risperidone in combination with serotonergic antidepressants or in combination with mood stabilizers.3,4 The rate of risperidone-related enuresis is <1%.4 One study found that enuresis is under-reported by 50%.5 Another study reported the rate of risperidone-related enuresis as 31% in children with autistic disorders taking risperidone. The rate in the control group was 29%, which does not support a causal relation.1 Andrenergic blockade via α1 and blockage of pudendal reflexes via antagonism of serotonin (5-HT)2 or 5-HT3 are possible mechanism of risperidone-related enuresis.6 Risperidone is an antagonist of both dopamine2 and serotonin (5-HT2A and others) receptors.7 Risperidone has little or no affinity for the muscarinic receptor.8 It increases bladder capacity only at the highest dose and decreases the micturition volume and expulsion time of the bladder. It decreases the activity of the external urethral sphincter.6 Valproate is an important anticonvulsant currently in clinical use for the treatment of seizures as well as for autism.9

There are several cases of risperidone-induced enuresis, including in children with autistic disorder.10,11 One study reported enuresis in individuals who were taking risperidone plus selective serotonin reuptake inhibitors.12 Only two case reports of desmopressin treatment for risperidone-related enuresis were found by the author of this article.3,13 No alternative medication has been suggested for management of this problem.


Case Report

A boy, 4 years and 3 months of age, was presented to the author’s outpatient clinic to be treated for behavioral problems, including limited social relationship, eye to eye contact, and facial expression; stereotypic behavior; aggression; failure to develop appropriate peer relationships, preferring solitary activities; marked impairment in the ability to initiate or sustain a conversation with others; restricted patterns of interest; nonfunctional routines or rituals; destructive behavior; and hyperactivity. The boy had childhood disintegrative disorder. His disruptive behaviors improved on risperidone monotherapy 1 mg QHS for 9 months. Family history was negative for primary enuresis. Medical history and workups, including neurologic exam, fasting glucose, urinalysis, and thyroid stimulating hormone were unremarkable. He had no history of urinary incontinency.

Incontinency occurred while taking risperidone but ceased after discontinuation of the medication. It reappeared 3 days after taking risperidone approximately 3–5 times/day. This trial happened many times in 9 months. The boy never experienced nighttime incontinency during this period; incontinency was only limited to daytime. The family discontinued the medication because of daytime incontinency. The child was referred again approximately 6 months later. He had not taken risperidone and did not suffer from incontinency during those 6 months. Risperidone was started again to achieve a better control of his disruptive behaviors, including aggressiveness, stereotypic behavior, hyperactivity, agitation, and destructiveness. Just after initiating the medication, daytime incontinency occurred. Incontinency continued for approximately 2 weeks. Another physician added sodium valproate to control the patient’s behavior problem. Interestingly, in addition to the behavioral problem being controlled, the incontinency ceased. There was no nocturnal incontinency even while taking risperidone. The patient never experienced incontinency while taking sodium valporate. In a rechallenge, incontinency reappeared after discontinuation of valproate. Incontinency never resolved spontaneously while he was taking risperidone alone. Although his intelligence was not assessed, clinically it appeared to be borderline. While taking valproate, he had never lost bowel control, there was no specific finding after taking an electroencephalograph, and urologic evaluation was negative.



The temporal sequence of incontinency and medication, cessation of incontinency after discontinuation of risperidone, lack of other medication, and lack of any medical cause are suggestive of a possible causal effect of risperidone. However, it is a single cross-sectional case study. Thus, it is impossible to definitively link risperidone with incontinency in this report.

Changing risperidone to another antipsychotic with a lower α-adrenergic blockade effect (eg, quetiapine, olanzapine) is suggested by another study.10 Also lowering the dose may be another strategy. For disruptive behaviors, valproate is not a commonly used drug. However, valproate was added to control the patient’s behavior problem by another physician.

The pathophysiology of risperidone-induced persistent incontinency remains unclear. However, numerous mechanisms including α1-adrenergic blockade, dopamine blockade, and antimuscarinic effects has been suggested.10 Urinary incontinency associated with antipsychotics is more likely due to detrusor overactivity.14 In the case presented, it seems it was a stress or urge incontinency. The author does not have any explanation for this possible effect of valproate on cessation of incontinency.

There is still a controversy about the risperidone-valproate interaction. Some studies show that risperidone increases the blood level of valproate,15,16 but some reports found no interaction.17,18 In the case provided, it seems that valproate may lower the level of risperidone.

This adverse effect should be discussed with parents and children before children take risperidone, as it might be disturbing and persistent. Early identification and treatment of this side effect might increase treatment adherence.

The study is limitated in that it includes only a patient with pervasive developmental disorder and a mental handicap; it is also one case design and drug blood levels are lacking.

To the author’s knowledge, this is the first report of cessation of risperidone-related incontinency with valproate. The mechanism of antipsychotic-induced incontinency is not fully understood. Moreover, treatment of this side effect is not clearly reported. Fuller and colleagues19 proposed ephedrine (α agonist) for the treatment of clozapine-induced incontinency. Only two case reports proposed desmopressin for the treatment of risperidone-induced incontinency.3,13 It is impossible to conclude the usefulness of valproate in the treatment of risperidone-induced incontinency. Additional case reports and open-label studies to support this finding must occur before randomized studies are created.



Risperidone-induced incontinency should be discussed with parents and children before risperidone is administered to a child. Controlled trial data are required to determine the possible efficacy and safety of sodium valproate in the management of risperidone-related incontinency. PP



1.    McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347(5):314-321.
2.    Vokas CS, Steele VM, Norris JI, Vernon LT, Brescan DW. Incidence of risperidone induced incontinence. Schizophr Res. 1997;24(1):267.
3.    Took KJ, Buck BJ. Enuresis with combined risperidone and SSRI use. J Am Acad Child Adolesc Psychiatry. 1996;35(7):840-841.
4.    Physicians’ Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005.
5.    Couture JA, Valiquette L. Urinary incontinence. Ann Pharmacother. 2000;34(5):646-655.
6.    Vera PL, Miranda-Sousa A, Nadelhaft I. Effects of two atypical neuroleptics, olanzapine and risperidone, on the function of the urinary bladder and the external urethral sphincter in anesthetized rats. BMC Pharmacol. 2001;1:4.
7.    Leysen JE, Gommeren W, Eens A, de Chaffoy de Courcelles D, Stoof JC, Janssen PA. Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther. 1988;247(2):661-670.
8.    Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci. 2000;68(1):29-39.
9.    Myers SM. The status of pharmacotherapy for autism spectrum disorders. Expert Opin Pharmacother. 2007;8(11):1579-1603.
10.    Herguner S, Mukaddes NM. Risperidone-induced enuresis in two children with autistic disorder. J Child Adolesc Psychopharmacol. 2007;17(4):527-530.
11.    Aman MG, Arnold LE, McDougle CJ, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol. 2005;15(6):869-884.
12.    Kandil ST, Aksu HB, Ozyavuz R. Reversible nocturnal enuresis in children receiving SSRI with or without risperidone: presentation of five cases. Isr J Psychiatry Relat Sci. 2004;41(3):218-221.
13.    Bennett JA, Keck PE Jr, Wallhausser LJ. Desmopressin for risperidone-induced enuresis. Ann Clin Psychiatry. 1994;6(2):139-140.
14.    Vera PL, Miranda-Sousa AJ, Ordorica RC, Nadelhaft I. Central effects of clozapine in regulating micturition in anesthetized rats. BMC Pharmacol. 2002;2:6.
15.    Bertoldo M. Valproic acid and risperidone. J Am Acad Child Adolesc Psychiatry. 2002;41(6):632.
16.    Good CR, Petersen CA, Krecko VF. Valproic acid and risperidone. J Am Acad Child Adolesc Psychiatry. 2003;42(1):2.
17.    Yoshimura R, Shinkai K, Ueda N, Nakamura J. Valproic acid improves psychotic agitation without influencing plasma risperidone levels in schizophrenic patients. Pharmacopsychiatry. 2007;40(1):9-13.
18.    Ravindran A, Silverstone P, Lacroix D, van Schaick E, Vermeulen A, Alexander J. Risperidone does not affect steady-state pharmacokinetics of divalproex sodium in patients with bipolar disorder. Clin Pharmacokinet. 2004;43(11):733-740.
19.    Fuller MA, Borovicka MC, Jaskiw GE, Simon MR, Kwon K, Konicki PE. Clozapine-induced urinary incontinence: incidence and treatment with ephedrine. J Clin Psychiatry. 1996;57(11):514-518.



Dr. Sussman is editor of Primary Psychiatry and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


In this issue, Ahmad Ghanizadeh, MD, and Mohsen Kianpoor, MD, provide a case report on the cessation of risperidone-induced incontinency by valproate in a child with pervasive developmental disorder. They begin by noting that risperidone may be associated with a high rate of urinary incontinency among children with developmental disorders. There are several cases of risperidone-induced incontinency (eg, in autistic children). Some of the studies reported enuresis in cases where patients were taking both risperidone and a selective serotonin reuptake inhibitor. Although there are some explanations for the possible association of risperidone and enuresis, the authors do not have any explanation for this possible effect of valproate on cessation of incontinency.

It is generally agreed that existing pharmacologic agents for psychiatric disorders leave much to be desired both in terms of efficacy and tolerability. The same can be said about the various forms of psychotherapy. Thus, the search for drugs with new mechanisms is ongoing, as are attempts to match existing treatments to symptom subtypes and to apply all types of treatment, both “drug” and “talk,” more effectively. The remaining articles in this issue address this situation.

No area of psychopharmacology research has caught my imagination as much as the studies of the mood effects of ketamine. Ketamine is an anesthetic agent that has also been used recreationally as a so-called “club drug.” Interest in its use as a therapeutic agent in psychiatric disorders has come from observation that some depressed patients given ketamine during surgery experience a dramatic improvement of their mood.

Marije aan het Rot, PhD, and colleagues, report on intravenous ketamine for treatment-resistant major depressive disorder (MDD). The unique aspect of ketamine, apart from its mechanism of action, is that unlike conventional pharmacologic treatments for MDD it does not take several weeks to several months to have a clinically meaningful effect. The authors note that two published studies have provided evidence for rapid and robust antidepressant efficacy of a single intravenous (IV) infusion with a sub-anesthetic dose of ketamine compared with an infusion of saline. Moreover, in >50% of patients who responded, therapeutic benefits were maintained for several days and up to 2 weeks. The authors review the pathophysiologic rationale for ketamine’s antidepressant activity and the clinical evidence for the use of IV ketamine for treatment of MDD, its safety uncertainty to be explored in future studies.

Regarding antidepressant treatment, recent decades have been dominated by selective or dual reuptake inhibitors, which involve serotonin, norepinephrine, or dopamine. In an article about triple reuptake inhibitors, Yanqi Liang, PhD and Elliott Richelson, MD, describe research on possible next-generation antidepressants. They note that preclinical data on these compounds remains limited, but that it is reasonable to speculate that a broad-spectrum antidepressant will produce a more rapid onset and better efficacy than agents that only inhibit the reuptake of serotonin and/or norepinephrine. The triple reuptake agents would also target dopamine. Some triple reuptake inhibitors (serotonin, norepinephrine, and dopamine reuptake inhibitors) are being developed.This article presents preclinical and clinical trials of developing these agents.

One type of depression, psychotic major depression, is both poorly understood and difficult to treat. Treatment is complicated by the presence of delusions, hallucinations, and more severe cognitive symptoms. In their article on psychotic major depression, Charles DeBattista, MD, and Anna Lembke, MD, note that current standard of care for this illness is either combination treatment with an antidepressant plus an antipsychotic, or electroconvulsive therapy (ECT), but that this standard is based on relatively limited data. They review the strength of evidence supporting the use of currently available treatments as well as the risks of treatment. The authors also note how the role of investigational treatments, including glucocorticoid antagonists and transcranial magnetic stimulation, await further investigation.  In the meantime, they suggest that the available data would at least suggest that patients who do not respond initially to an antidepressant alone should be treated with the combination of an antidepressant and an antipsychotic or ECT.

In addition to having expertise in the selection and use of pharmacologic agents, clinicians need to understand the cultural context of the patient. This is an important and often overlooked dimension of mental illness and its management. Manuel Trujillo, MD, discusses the necessary body of knowledge, skills, and attitudes which can help clinicians bridge the care gaps created by cultural barriers. His article highlights means to overcome these barriers when performing diagnostic interviews, completing mental status examinations, and selecting the most appropriate interventions. He argues that a desired end result of training to treat mental disorders will be an enhanced ability to provide “culturally competent care.” PP


Funding for this supplement has been provided by Forest Pharmaceuticals, Inc.


Dr. Schatzberg is Kenneth T. Norris, Jr. Professor and Chairman of psychiatry and behavioral science at Stanford University School of Medicine in California.

Disclosures: Dr. Schatzberg is a consultant to Abbott, Bristol-Myers Squibb, Corcept, Eli Lilly, Forest, Merck, NeuroPharmaBoost, Roche, Synosis, and Wyeth; is in receipt of intellectual property royalties from Corcept and Pathways Diagnostics; and holds equity or options in BrainCells, Corcept, Forest, Merck, Neurocrine, Pfizer, and Somaxon.

Acknowledgments: Dr. Schatzberg wishes to thank Eileen McGee, Marsha Kellar, and Hudson Medical Communications for their editorial assistance with this manuscript.


Dr. Weiss is professor of psychiatry at Harvard Medical School in Boston, and clinical director of the Alcohol and Drug Abuse Treatment Program at McLean Hospital in Belmont, both in Massachusetts.

Disclosure: Dr. Weiss is a consultant to Novartis and receives research support from Eli Lilly and Forest. He has received grants from the National Institute on Drug Abuse.

Acknowledgments: Dr. Weiss wishes to thank Joyce Waskelo and Hudson Medical Communications for their editorial assistance with this manuscript.


Dr. Brady is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences and associate dean for Clinical Research at the Medical University of South Carolina in Charleston.

Disclosures: Dr. Brady is a consultant to Abbott, Eli Lilly, Embera NeuroTherapeutics, Forest, GlaxoSmithKline, Marinus, Novartis, Ovation, Pfizer, and Wyeth; is on the speaker’s bureaus of Abbott, Eli Lilly, Forest, GlaxoSmithKline, and Pfizer; and has received research support from Abbott, Forest, GlaxoSmithKline, Titan, and Wyeth.

Acknowledgments: Dr. Brady wishes to acknowledge Marsha Kellar and Hudson Medical Communications for their editorial assistance with this manuscript.


Dr. Culpepper is professor of family medicine and chairman at the Boston University School of Medicine in Massachusetts.

Disclosures: Dr. Culpepper is a consultant to AstraZeneca, Eli Lilly, Forest, Neurocrine, Pfizer, and Wyeth; and is on the speaker’s bureaus of Forest, Pfizer, and Wyeth.

Acknowledgments: Dr. Culpepper wishes to thank Marsha Kellar and Hudson Medical Communications for their editorial assistance with this manuscript.



Substance abuse and mental disorders commonly occur together and place an incalculable burden on individuals, families, and society at large. Left untreated, co-occurring psychiatric and substance use disorders may result in troubled and unproductive lives, as this comorbidity is associated with underachievement or failure at work and school, poor health, problems fulfilling family responsibilities, abuse, violence, and legal difficulties. Co-occurring disorders frequently have a complex and bidirectional relationship and may require longitudinal, repeated assessments to establish correct diagnosis. A number of reliable instruments have been developed to improve screening and assessment in both primary care and mental health settings, but controversy persists regarding the best approach to treatment. A fundamental issue, for example, is whether to treat a mood or an anxiety disorder in the presence of ongoing alcohol or drug abuse. Although recent recommendations suggest that concurrent substance abuse should not impede treatment of psychiatric symptoms, more evidence is required to facilitate decision making during acute treatment. Further, relapse and recurrence are common among individuals with co-occurring disorders, and the issue of long-term treatment typically needs to be addressed. Optimal patient management requires a collaborative effort by mental health care professionals, addiction specialists, and primary care physicians. Therefore, it is important that physicians who care for this patient population weigh the most recent evidence on effective and integrated treatment of individuals with co-occurring mood, anxiety, and alcohol use disorders.





By Alan F. Schatzberg, MD


It has been said that “co-occurring mental and substance use disorders represent a public health crisis.”1 Although this statement might seem hyperbolic, historic as well as recent epidemiologic surveys consistently support it.2-5 Mood, anxiety, and substance use disorders (SUDs) are each highly prevalent, and the co-occurrence of mood and anxiety disorders with SUDs is the rule rather than the exception.1

The National Comorbidity Survey Replication study found a 12-month prevalence of 18.1% for any anxiety disorder (3.1% for generalized anxiety disorder), 9.5% for mood disorders (6.7% for major depressive disorder and 2.6% for bipolar disorders), and 3.8% for SUDs (3.1% for alcohol abuse and 1.3% for alcohol dependence).4  Meanwhile, the National Epidemiologic Survey on Alcohol and Related Conditions found a positive and significant association between most SUDs and independent mood and anxiety disorders (P<.05).5 During a 12-month period, 19.7% of respondents with SUD had at least one independent mood disorder, and 17.7% had at least one independent anxiety disorder. Conversely, among respondents with either a mood disorder or an anxiety disorder occurring during a 12-month period, at least one SUD was found among 20% and 15% of the respondents, respectively. Among individuals with bipolar disorders, the 12-month rate for any alcohol use disorder was even higher, at ~24% for both mania and hypomania; conversely, among all respondents with any drug use disorder, the rate of mania was 10% and the rate of hypomania was 4.3%.

The bidirectional, reciprocal relationship between mood and anxiety disorders and SUDs represents a challenge to the healthcare system, and one that has not been fully met. While it is increasingly recognized that these disorders require integrated treatment, such programs are not widespread. Thus, the onus to provide comprehensive management for patients with dual disorders falls to individual practitioners. Understandably, many are reluctant to take on this responsibility, given the daunting hurdles involved, including the paucity of clinical trial data and evidence-based guidelines to help navigate unfamiliar waters.

This supplement is designed to help physicians overcome these obstacles. Readers will benefit from the discussion by Roger D. Weiss, MD, on the importance of early diagnosis, as well as his pragmatic approach to the screening and diagnosis of these disorders. Kathleen T. Brady, MD, PhD, focuses on general treatment considerations that guide the management of these patients and also provides practical guidelines in the selection of the most appropriate pharmacotherapy. Alan F. Schatzberg, MD, addresses issues regarding the risk of recurrence and effective long-term management. Finally, Larry Culpepper, MD, MPH, discusses the formidable challenges faced by primary care physicians in the diagnosis and management of patients with co-occurring depression/anxiety disorders and SUDs.

It should be noted that patients with bipolar disorders are particularly at risk of developing SUD. However, for the purpose of this supplement, our discussion will focus primarily on diagnosing and treating patients with co-occurring depression/anxiety disorders and alcohol dependence.

All of the articles in this supplement are based on a roundtable discussion by the authors—all recognized leaders in the field of co-occurring psychiatric disorders and SUDs. It is hoped that this publication will provide physicians with the insight, information, and tools they need to be more confident in addressing the special healthcare needs of these patients.



1.   O’Brien CP, Charney DS, Lewis L, et al. Priority actions to improve the care of persons with co-occurring substance abuse and other mental disorders: a call to action. Biol Psychiatry. 2004:56:703-713.
2.    Kessler RC, Nelson CB, McGonagle KA, Edlund MJ, Frank RG, Leaf PJ. The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization. Am J Orthopsychiatry. 1996;66:17-31.
3.    Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA. 1990;264:2511-2518.
4.    Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617-627.
5.    Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61:807-816.


Identifying and Diagnosing Co-occurring Disorders

By Roger D. Weiss, MD


Prevalence of Co-Occurring Disorders

Epidemiologic studies have shown a significantly greater likelihood of substance misuse in persons with psychiatric disorders.1 One of the largest studies showed that 60.7% of people with bipolar I disorder had a lifetime diagnosis of a substance use disorder (SUD).2 Moreover, 32% of individuals with any mood disorder, including depression, were found to suffer from substance abuse or dependence. In general population surveys, it has been found that the presence of a mood disorder at least doubles the odds of having SUD.3

Why should clinicians be interested in these comorbidities? A key reason is that patients with co-occurring disorders tend to have poorer prognoses and worse overall outcomes than those with either disorder alone. Primary negative outcomes include increased suicidal behavior, increased likelihood of homelessness, more hospitalizations, and poor medication adherence.

Losses that occur in the course of life—death of a loved one, job loss, reduced physical function—tend to be more devastating in people with SUDs than in those with depressive disorders and are more likely to result in suicide. One study found that 50% of alcoholics, as opposed to 20% of patients with depression, had a close personal loss within 1 year of suicide, and approximately one third had a loss within 6 weeks.4 Therefore, a high level of vigilance is warranted when individuals with co-occurring depression and substance abuse suffer a major loss.

Another study showed that patients with co-occurring major depressive disorder (MDD) and alcohol dependence were significantly more likely to have suicidal ideation and suicidal behavior than those with either disorder alone.5 The patients with co-occurring disorders were also found to be more impulsive. Impulsivity, coupled with the use of a disinhibiting agent, further increases the likelihood of suicidal behavior.


Dually Diagnosed Patients: A Heterogeneous Population

It is important to recognize the heterogeneity and multidimensionality of patients who have the dual diagnoses of MDD and alcohol dependence. Some areas of heterogeneity include6: severity of SUD (in a long-term study of alcoholism, it was suggested that persons at the mild-to-moderate end of the spectrum were more likely to continue drinking7); stage in the course of illness (first treatment recovery, recent relapse); presence and severity of coexisting medical or psychiatric illness; degree of insight into—and explanation for—the nature of his or her problem; motivation for treatment and stage of readiness for change; and sociodemographic variables (age, gender, marital status, employment status, and ethnicity).

Both mood disorders and SUDs should also be viewed as multidimensional, as a host of problems frequently occur in patients with either disorder or their combination. Some individuals have relatively few problems, and others have multiple difficulties. The Addiction Severity Index (ASI) is a frequently used assessment tool that captures the complexity of SUDs.8 The ASI examines the severity of alcohol use, drug use, employment or legal problems, medical problems, family and social problems, and psychiatric problems. Severity ratings are based on the patient’s history of problems, present condition, and subjective assessment of treatment needs in one or more areas. The ASI can be helpful in conducting a comprehensive interview, treatment planning, and follow-up.


The Diagnostic Process

Accurate diagnosis and successful treatment of SUDs and co-occurring psychiatric disorders rely on a careful, comprehensive assessment (Slide 1).9 During an initial assessment, it can be difficult to distinguish between psychiatric symptoms resulting from substance use and those occurring due to an independent psychiatric disorder. Anxiety, depression, mania, and psychosis are all commonly induced by various substances and can be observed with chronic use as well as during specific substance-induced states, including intoxication and withdrawal.9



However, the following factors increase the probability that the psychiatric disorder is independent and not the result of substance abuse9: a clear history of psychiatric symptoms that preceded onset of SUD; symptoms that remain evident during extended substance-free periods; symptoms that are not typically observed in conjunction with using a particular substance; and having at least one first-degree relative with a documented history of a similar disorder.


Timeline Approach to Evaluation

Evaluation of psychiatric symptoms in persons with SUDs can be enhanced with repeated, longitudinal assessments. One of the most effective techniques is to develop a timeline for the co-occurring disorders, relating one to the other. This approach can help determine the chronology of symptom development, the presence or absence of symptoms during extended substance-free periods, and the impact of each disorder on the presentation, clinical course, and outcome of the other.

It is helpful to first establish the chronology of substance use and any associated problems, as well as periods of stable abstinence—especially those lasting at least 3 months, which are most likely to reveal independent psychiatric symptoms.10 Then the patient’s psychiatric symptoms and signs can be reviewed across his or her lifespan. The patient’s recollection can be improved by framing the interview around important landmarks in time, and any available collateral information. This helps to accurately reconstruct the chronology of the patient’s disorders and also helps the patient to recognize any relationships between substance use and mood disorders.

In patients with co-occurring substance abuse and mood disorder, the diagnostic process does not take the traditional path of assessment, diagnosis, and treatment. It begins by identifying current problems and instituting appropriate initial treatment interventions (eg, detoxification) even when the relationship between the two disorders is not yet clear. Whether psychiatric symptoms are the result of a mood disorder or substance abuse might not be determined until stable abstinence is achieved, unless the symptoms are of sufficient intensity or duration that they are unlikely to have been caused by the specific substances used by the patient. On the modified assessment path, reassessment can help lead to a clear diagnosis (Slide 2).11



Clinical Screening Tools

“At-risk drinking” has been defined as consuming more than seven drinks per week or three drinks per occasion for women, and more than 14 drinks per week or four drinks per occasion for men.12 However, the threshold for at-risk alcohol consumption may be lower for patients who have mood and anxiety disorders.13

Several screening instruments have been shown to be highly accurate in identifying people who have an alcohol problem and are brief and easy to use.14 These include the CAGE questionnaire and the Alcohol Use Disorders Identification Test (AUDIT) (Slide 3).



The CAGE is a four-question screening instrument used primarily in clinical settings to identify people who have ever been alcohol dependent.15 It asks: Have you ever felt you should Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt bad or Guilty about your drinking? Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (ie, an Eye-opener)? Because of its simplicity, the CAGE can be self-administered. A positive response to two or more of the four questions suggests a need for further assessment. The AUDIT is a 10-question screening instrument developed to identify hazardous and harmful alcohol consumption in primary care settings.16 Simple enough to be completed by the patient, the resulting score helps to differentiate between risky and harmful drinking patterns.

Some laboratory tests may help to provide objective evidence of problem drinking.17 Certain blood tests can detect biochemical changes associated with excessive drinking and provide biologic markers that suggest the presence of an alcohol use disorder. These markers include: elevated γ-glutamyl transferase levels after 4–8 weeks of chronic drinking of four or more drinks/day; elevated carbohydrate-deficient transferrin levels after 1–2 weeks of excessive alcohol consumption; and increased mean corpuscular volume (an index of red blood cell size) after 4–8 weeks of excessive alcohol intake.

The tests are generally less sensitive and specific than questionnaires but are valuable for corroborating the results of interviews. Moreover, abnormalities in these tests can raise a clinician’s suspicion that the patient’s self-report does not reflect their true level of drinking. The accuracy of these biological markers is affected by several factors, including nonalcoholic liver damage, use of medications and drugs, and metabolic disorders.17

Screening for psychiatric disorders in persons with SUDs has not been well explored and may be especially challenging because of symptom overlap.1 The Patient Health Questionnaire (PHQ) is a self-administered instrument that has been tested extensively in primary care settings.18 The PHQ depression scale (PHQ-9) consists of the nine criteria on which the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of depressive disorders is based and offers a briefer version of the three-page PHQ questionnaire to screen for depression (Slide 4).19




A careful and accurate assessment can provide the necessary information for intervention and treatment planning. It can also engage the patient and provide motivation to begin the process of change. Using the timeline approach, clinicians can often arrive at a working diagnosis that helps predict the most likely course of the co-occurring disorders and begin to develop a treatment plan.10 It is important to continue with the process of assessment and re-assessment, monitor the patient’s course, and, if necessary, revise the diagnosis.



1.   Brady KT, Verduin ML. Pharmacotherapy of comorbid mood, anxiety, and substance use disorders. Subst Use Misuse. 2005;40(13-14):2021-2041.
2.   Regier DA, Farmer ME, Rae DS. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA. 1990;264(19):2511-2518.
3.   Nunes E, Rubin E, Carpenter K, Hasin D. Mood disorders and substance use. In: Textbook of Mood Disorders. Washington, DC: American Psychiatric Publishing; 2005:653-671.
4.   Murphy GE, Armstrong JW Jr, Hermele SL, Fischer JR, Clendenin WW. Suicide and alcoholism. Interpersonal loss confirmed as a predictor. Arch Gen Psychiatry. 1979;36(1):65-69.
5.   Cornelius JR, Salloum IM, Mezzich J, et al. Disproportionate suicidality in patients with comorbid major depression and alcoholism. Am J Psychiatry. 1995;152(3):358-364.
6.   Greenfield SF, Hennessy G. Assessment of the patient. In: Galanter M, Kleber HD, eds. Textbook of Substance Abuse Treatment, 3rd ed. Washington, DC: American Psychiatric Publishing; 2004:101-119.
7.   Vaillant GE. The Natural History of Alcoholism. Cambridge, Mass: Harvard University Press; 1983.
8.   McLellan AT, Luborsky L, Woody GE, O’Brien CP. An improved diagnostic evaluation instrument for substance abuse patients: the Addiction Severity Index. J Ment Nerv Dis. 1980;168:26-33.
9.   American Psychiatric Association. Practice Guideline for the Treatment of Patients with Substance Use Disorders. 2nd ed. New York, NY: American Psychiatric Association; 2006.
10. Shivani R, Goldsmith J, Anthenelli RM. Alcoholism and psychiatric disorders: diagnostic challenges. Alcohol Res Health. 2002;26:90-98.
11. Hendrickson EL, Schmal MS, Ekleberry SC. Assessment. In: Treating Co-Occurring Disorders. A Handbook for Mental Health and Substance Abuse Professionals. Binghamton, NY: Haworth Press; 2004:77-95.
12. Saitz R. Clinical practice: unhealthy alcohol use. N Engl J Med. 2005;352(6):596-607.
13. Brady KT, Tolliver BK, Verduin ML. Alcohol use and anxiety: diagnostic and management issues. Am J Psychiatry. 2007;164(2):217-221.
14. Cherpitel CJ. Brief screening instruments for alcoholism. Alcohol Health Res World. 1997;21(4):348-351.
15. Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry. 1974;131(10):1121-1123.
16. Babor TF, Higgins-Biddle JC, Saunders JB, Montero MG. The Alcohol Disorders Identification Test: Guidelines for Use in Primary Care, 2nd Edition. Washington, DC: World Health Organization. 2001.
17. National Institute on Alcohol Abuse and Alcoholism. Alcohol Alert, No. 56. Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism; 2002.
18. Spitzer RL, Kroenke K, Williams JB, et al. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study: primary care evaluation of mental disorders: patient health questionnaire. JAMA. 1999;282(18):1737-1744.
19. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-613.


Evidence-Based Pharmacotherapy for Mood and Anxiety Disorders with Concurrent Alcoholism

By Kathleen T. Brady, MD, PhD



Co-occurring psychiatric and alcohol use disorders can have devastating personal and societal effects, yet little evidence exists to guide clinical treatment. In the face of scant data, individual practitioners must rely instead on professional experience and those limited practice guidelines that currently exist. The American Psychiatric Association (APA) advises that failure to treat a concurrent psychiatric disorder reduces the likelihood that the treatment for a substance use disorder (SUD) will be effective.1 Indeed, the effects of nontreatment were demonstrated in a prospective study assessing alcohol-dependent patients for 1 year following hospitalization for alcohol dependence,2 in which untreated depression was directly associated with a shorter time to first drink. The results also showed that among those patients with depression (Slide 1),2 taking antidepressants at the time of discharge increased the likelihood of an individual remaining abstinent during the follow-up period.




Recommendations for Pharmacotherapy

Alcohol-dependent patients commonly present with symptoms of depression or anxiety, which may be a part of acute intoxication or substance withdrawal and therefore may remit with time. The APA suggests allowing at least 3 weeks of monitored abstinence to permit identification of transient, alcohol-induced, and other substance-induced symptoms before making a decision to use pharmacologic treatment.1 Certain circumstances, however, might warrant earlier treatment, such as the presence of severe affective or anxiety symptoms that worsen rather than improve over the initial period of abstinence; a history of affective or anxiety disorders unrelated to periods of alcohol use; and/or a strong family history of mood or anxiety disorders. In cases of severe mental illness, abstinence is perhaps seen more realistically as a goal of treatment rather than as a prerequisite.3

When selecting and using pharmacotherapy for co-occurring alcohol dependence and psychiatric disorders, clinicians should consider the following1: unwanted synergy between prescribed medications and abused substance (eg, benzodiazepines and alcohol); drug-drug interactions affecting the efficacy of psychiatric treatment; nonadherence due to intoxication and withdrawal states; drug-seeking behavior; intentional or unintentional overdose; and the abuse potential of medications. Benzodiazepines are commonly prescribed to manage alcohol withdrawal, but their use beyond the withdrawal period should be restricted in patients with co-occurring disorders due to a high potential for abuse.1,3 The use of benzodiazepines should be limited to acute episodes targeting specific symptoms, and patients should be closely monitored while taking them. To encourage medication adherence and prevent possible overdose, physicians are advised to dispense drugs in limited amounts, restrict the number of refills, and use random blood or urine toxicology screening to determine the use of both prescribed and nonprescribed drugs.1


Treatment of Mood Disorders

Data from controlled trials that inform pharmacologic treatment of co-occurring mood disorders and SUDs have been relatively scarce.4 A recent meta-analysis,5 however, evaluated 14 randomized, placebo-controlled, double-blind trials of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and other classes of antidepressants in the treatment of patients with a unipolar depressive disorder and concurrent alcohol or other drug dependence (N=848). Results were variable, yet overall, the trials showed a modest beneficial effect of antidepressants on depressive symptoms. As shown in Slide 2,6-19 the significant heterogeneity in effect across studies was strongly linked to placebo response; such a high placebo response (>25%) in several trials was thought to reflect inclusion of individuals with transient, substance-induced depression. Pooled effect size of the medication treatment on depression was 0.38 (95% CI=.18-.58), representing an effect in the small-to-medium range. Importantly, there was no direct impact of antidepressant treatment on alcohol consumption, but in those studies in which the medication had a positive effect on the treatment of depression, a significant reduction in alcohol use also occurred.



Investigations of pharmacologic treatments for alcohol- or other substance-dependent individuals with bipolar affective disease have also been limited. A recent double-blind, placebo-controlled trial, which examined actively drinking bipolar patients treated with valproate plus treatment as usual (lithium and psychosocial intervention) versus placebo plus treatment as usual found lower levels of alcohol consumption in the valproate-treated group.20 No differences occurred in terms of mood outcome, but those individuals receiving valproate demonstrated a trend to remit from mania earlier.


Treatment of Anxiety Disorders

Nearly all of the anxiety disorders co-occur more commonly with alcohol dependence than would be expected by chance alone, yet few controlled trials have investigated treatment for these indications. In the following section, existing evidence is reviewed by disorder. In the face of limited data, the best course may be to treat with agents known to be effective for the specific anxiety disorder while being mindful of contraindications to the use of these agents in individuals with alcohol dependence.


Generalized Anxiety Disorder

Multiple agents, including SSRIs, TCAs, venlafaxine, and anticonvulsants, have demonstrated benefits in reducing the symptoms of generalized anxiety disorder (GAD) in individuals without SUDs. While benzodiazepines are effective in treating GAD, their use in patients with SUDs is controversial. Several older studies have evaluated buspirone, a partial serotonin agonist nonbenzodiazepine anxiolytic, for the treatment of GAD with concurrent alcohol dependence, with mixed results regarding alcohol intake.21 Future studies of SSRIs—which have demonstrated efficacy in GAD in individuals without alcohol dependence—could be informative.


Social Phobia

Irreversible monoamine oxidase inhibitors (MAOIs), reversible MAOIs, SSRIs, and benzodiazepines all have documented efficacy in the treatment of social anxiety disorder.22 One small, placebo-controlled trial of patients with social anxiety disorder and alcohol dependence found that the SSRI paroxetine improved alcohol outcomes and decreased symptoms of social anxiety.23 A larger controlled trial demonstrated that the anticonvulsant gabapentin was efficacious in treating uncomplicated social anxiety disorder in alcoholics.24


Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is one of the most common anxiety disorders in individuals with alcohol use problems. A number of placebo-controlled trials involving relatively large numbers of patients have demonstrated that SSRIs—specifically sertraline, fluoxetine, and paroxetine—are effective in the treatment of PTSD.25-27 A more recent, placebo-controlled trial investigated the use of sertraline in the treatment of PTSD with co-occurring alcohol dependence.28 Both patient cohorts demonstrated a significant decrease in alcohol use, but cluster analysis revealed robust effects in a subgroup of individuals with early trauma, leading investigators to conclude that certain subtypes of alcoholics might respond differently to SSRI treatment.


Using Medication to Treat Alcohol Dependence

The APA supports the use of pharmacotherapy to treat alcohol dependence in individuals with concurrent psychiatric disorders based on evidence in populations without psychiatric comorbidity.1 The United States Food and Drug Administration has approved several “anti-alcoholism” treatments, including disulfiram, naltrexone, and acamprosate.29 Earlier trials exploring the use of disulfiram and naltrexone in patients with co-occurring disorders demonstrated that these agents can be effective in treating alcoholism without worsening psychiatric symptoms.30-33 A recent, open-label trial found that in subjects with co-occurring bipolar disorder and alcohol dependence, the combination of valproate and naltrexone versus valproate alone led to better outcomes with regard to alcohol use (0% versus 75% relapse rate, respectively) and to improvement in manic and depressive symptoms.34 The largest controlled trial to date evaluating anti-alcoholism agents in patients with psychiatric comorbidity assessed the efficacy and safety of disulfiram and naltrexone in 254 alcoholics with an Axis I psychiatric disorder.35 Baseline diagnoses included 70% with major depression, 42% with PTSD, and 19% with bipolar disorder. Patients were randomized to one of four groups taking naltrexone or disulfiram alone, placebo alone, or naltrexone or disulfiram combined. Groups receiving either active medication had longer periods of abstinence and less craving; however, combined treatment showed no advantage.


Selecting Pharmacotherapeutic Agents

Practice guidelines recommend the use of newer antidepressants, such as SSRIs, to treat depressive and/or anxiety disorders in patients with alcohol dependence (Slide 3).1,3 For the treatment of depression, SSRIs are preferred over TCAs and MAOIs due to fewer adverse effects and a lower risk of morbidity and mortality in overdose situations. For the treatment of anxiety disorders, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or buspirone are recommended. The SSRIs escitalopram, fluoxetine, paroxetine, and sertraline, as well as the SNRIs duloxetine and venlafaxine, are indicated for both major depression and specific anxiety disorders, such as GAD, panic disorder, PTSD, social phobia, and obsessive-compulsive disorder.29 Each of these agents, however, is indicated for one or more particular anxiety disorder(s), and clinicians are advised to consult relevant prescribing information when selecting treatment.





Progress has been made in the recognition and treatment of co-occurring psychiatric disorders and alcohol dependence, but much work remains to be done in the area of treatment.4 Relatively few studies have evaluated the use of pharmacotherapeutic agents that specifically target alcohol use disorders concurrent with psychiatric illness. Studies that have been conducted indicate that similar agents work for depressive and anxiety disorders with or without the presence of alcohol dependence. Treatment considerations for individuals with alcohol dependence and concurrent mood and/or anxiety disorders should include safety, toxicity, and abuse liability. Considering the insufficiency of existing evidence, additional controlled trials are clearly needed to help clinicians guide their patients with co-occurring disorders toward sustained remission and recovery.



1.  American Psychiatric Association. Practice Guideline for the Treatment of Patients with Substance Use Disorders. 2nd Edition. New York, NY: American Psychiatric Association; 2006.
2.  Greenfield SF, Weiss RD, Muenz LR, et al. The effect of depression on return to drinking. Arch Gen Psychiatry. 1998;55(3):259-265.
3.  Substance Abuse and Mental Health Services Administration, United States Department of Health and Human Services. Treatment Improvement Protocols (TIP) 9: Assessment and treatment of patients with coexisting mental illness and alcohol and other drug abuse. Rockville, MD; 2002.
4.  O’Brien CP, Charney DS, Lewis L, et al. Priority actions to improve the care of persons with co-occurring substance abuse and other mental disorders: a call to action. Biol Psychiatry. 2004;56(10):703-713.
5.  Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.
6.  Altamura AC, Mauri MC, Girardi T, Panetta B. Alcoholism and depression: a placebo controlled study with viloxazine. Int J Clin Pharmacol Res. 1990;10(5):293-298.
7.  Roy A. Placebo-controlled study of sertraline in depressed recently abstinent alcoholics. Biol Psychiatry. 1998;44(7):633-637.
8.   Mason BJ, Kocsis JH, Ritvo EC, Cutler RB. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. JAMA. 1996;275(10):761-767.
9.    Nunes EV, Quitkin FM, Donovan SJ, et al. Imipramine treatment of opiate-dependent patients with depressive disorders. A placebo-controlled trial. Arch Gen Psychiatry. 1998;55(2):153-160.
10.    Nunes EV, McGrath PJ, Quitkin FM, et al. Imipramine treatment of cocaine abuse: possible boundaries of efficacy. Drug Alcohol Depend. 1995;39(3):185-195.
11.    Cornelius JR, Salloum IM, Ehler JG, et al. Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1997;54(8):700-705.
12.    McGrath PJ, Nunes EV, Stewart JW, et al. Imipramine treatment of alcoholics with primary depression: A placebo-controlled clinical trial. Arch Gen Psychiatry. 1996;53(3):232-240.
13.    Roy-Byrne PP, Pages KP, Russo JE, et al. Nefazodone treatment of major depression in alcohol-dependent patients: a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2000;20(2):129-136.
14.    Moak DH, Anton RF, Latham PK, Voronin KE, Waid RL, Durazo-Arvizu R. Sertraline and cognitive behavioral therapy for depressed alcoholics: results of a placebo-controlled trial. J Clin Psychopharmacol. 2003;23(6):553-562.
15.    Carpenter KM, Brooks AC, Vosburg SK, Nunes EV. The effect of sertraline and environmental context on treating depression and illicit substance use among methadone maintained opiate dependent patients: a controlled clinical trial. Drug Alcohol Depend. 2004;74(2):123-134.
16.    Schmitz JM, Averill P, Stotts AL, Moeller FG, Rhoades HM, Grabowski J. Fluoxetine treatment of cocaine-dependent patients with major depressive disorder. Drug Alcohol Depend. 2001;63(3):207-214.
17.    Kleber HD, Weissman MM, Rounsaville BJ, Wilber CH, Prusoff BA, Riordan CE. Imipramine as treatment for depression in addicts. Arch Gen Psychiatry. 1983;40(6):649-653.
18.    Petrakis I, Carroll KM, Nich C, Gordon L, Kosten T, Rounsaville B. Fluoxetine treatment of depressive disorders in methadone-maintained opiate addicts. Drug Alcohol Depend. 1998;50(3):221-226.
19.    Pettinati HM, Volpicelli JR, Luck G, Kranzler HR, Rukstalis MR, Cnaan A. Double-blind clinical trial of sertraline treatment for alcohol dependence. J Clin Psychopharmacol. 2001;21(2):143-153.
20.    Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Arch Gen Psychiatry. 2005;62(1):37-45.
21.    Goldstein BI, Diamantouros A, Schaffer A, Naranjo CA. Pharmacotherapy of alcoholism in patients with co-morbid psychiatric disorders. Drugs. 2006:66(9):1229-1237.
22.    Lydiard RB, Brawman-Mintzer O, Ballenger JC. Recent developments in the psychopharmacoloy of anxiety disorders. J Consult Clin Psychol. 1996;64(4):660-668.
23.    Randall CL, Johnson MR, Thevos AK, et al. Paroxetine for social anxiety and alcohol use in dual-diagnosed patients. Depress Anxiety. 2001;14(4):255-262.
24.    Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol.1999;19(4):341-348.
25.    Brady K, Pearlstein T, Asnis GM, et al. Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA. 2000;283(14):1837-1844.
26.    Marshall RD, Beebe KL, Oldham M, Zaninelli R. Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry. 2001;158(12):1982-1988.
27.    Davidson JR, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM. Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry. 2001;58(5):485-492.
28.    Brady KT, Sonne S, Anton RF, Randall CL, Back SE, Simpson K. Sertraline in the treatment of co-occurring alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res. 2005;29(3):395-401.
29.    Physicians Desk Reference 2006: Guide to Drug Interactions, Side Effects, and Indications.  60th ed. Montvale, NJ: Thomson PDR; 2006:1175-3419.
30.    Brown ES, Beard L, Dobbs L, Rush AJ. Naltrexone in patients with bipolar disorder and alcohol dependence. Depress Anxiety. 2006;23(8):492-495.
31.    Larson EW, Olincy A, Rummans TA, Morse RM. Disulfiram treatment of patients with both alcohol dependence and other psychiatric disorders: a review. Alcohol Clin Exp Res. 1992;16(1):125-130.
32.    Kofoed L, Kania J, Walsh T, Atkinson RM. Outpatient treatment of patients with substance abuse and coexisting psychiatric disorders. Am J Psychiatry. 1986;143(7):867-872.
33.    Sernyak MJ, Glazer WM, Heninger GR, et al. Naltrexone augmentation of neuroleptics in schizophrenia. J Clin Psychopharmacol. 1998;18(3):248-251.
34.    Salloum IM, Cornelius, JR, Chakravorthy S. Utility of combined naltrexone valproate treatment in bipolar alcoholics: a randomized, open-label, pilot study. In: Diamond I, ed. Abstracts of Papers, 26th Annual Scientific Meeting of the Research Society on Alcoholism, Ft. Lauderdale, FL, June 21-25, 2003. Baltimore, MD: Lippincott, Williams & Wilkins; 2003:843, 146A.
35.    Petrakis IL, Poling J, Levinson C, et al. Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder. Biol Psychiatry. 2006;60(7):777-783.


Achieving Remission and Favorable Outcomes in Patients with Depression/Anxiety and Substance Use Disorders

By Alan F. Schatzberg, MD



Given the frequency with which patients with substance use disorders (SUDs) and those with psychiatric disorders, such as major depressive disorder (MDD) and generalized anxiety disorder (GAD), suffer relapses and recurrences, the issue of long-term treatment for SUDs warrants special attention.1-3 Faced with recommending long-term treatment, the clinician must discern the primacy of disorder, which may have been only obliquely addressed at the time of the patient’s presentation and then solved by concurrent treatment. Establishing primacy relies on determining whether the psychiatric symptoms were induced by SUD or the psychiatric disorder emerged first and substance use was a means of coping with it. A third possibility exists—that the two disorders developed independently of each other, albeit becoming intermingled over time and serving to exacerbate each other. Clues to the temporal relationship of the disorders can be deduced from a meticulous history obtained from multiple sources, the effects that acute treatment has had on either condition, and the patient’s willingness to remain abstinent from the addictive substance.4 Hasin and colleagues5 demonstrated the importance that a history of depression has on long-term remission and relapse outcomes in substance dependence (Slide 1).


That depression leads to poorer long-term outcomes in patients with SUDs may be due, in part, to the impaired psychosocial function associated with depression, and the effect that patient impairment may have on the ability to engage in activities supporting remission and avoiding relapse.5 Similarly, the presence of GAD with co-occurring SUDs also affects outcomes, with worse 1-year treatment outcomes reported in patients with dual diagnosis than when GAD is absent.6 When both GAD and depression are present in patients with SUDs, the outcomes are even poorer. This was demonstrated in a study of 326 patients presenting for addiction treatment, in which abstinence at 6 months was achieved by 73% of patients with co-occurring depression, but by only 40% of patients with both depression and anxiety.7


Acute Treatment Versus Continuum of Management

Many SUDs are chronic,1 as is GAD,2 and depression is a recurring disorder for at least 60% of patients. Therefore, patients with these disorders may require a continuum of ongoing management, with treatment modalities, intensity of treatment, and monitoring varying by individual needs and over time.

The continuum of treatment begins with the acute phase (6–12 weeks), a stage marked by initiation of treatment and achievement of remission. The subsequent continuation phase (4–9 months) and maintenance phase (≥1 year) are characterized by a continuing of the initial medication at the dosage that helped induce remission and, when the patient’s condition and mode of treatment warrant it, a reduction in the frequency of clinician monitoring. The decision to continue with maintenance treatment in depression is based on factors that include the likelihood of recurrence (Slide 2),8,9 the severity of depressive episodes, any treatment side effects experienced by the patient, and patient preference.


In a manner similar to the treatment of patients with depression, patients with GAD who have responded to acute treatment with antidepressants or with buspirone therapy should remain on the medication for 6 to 12 months as a means of preventing relapse/recurrence.10 Clinical monitoring can be stepped down from intervals of every 2 to 4 weeks at initiation of therapy to every 3 to 4 months during maintenance therapy.


Long-Term Outcomes in Depression and Generalized Anxiety Disorder

The agent(s) that induced remission in patients with MDD or GAD should be used during the continuation and maintenance phases of treatment. Virtually all of the selective serotonin reuptake inhibitors (SSRIs)—citalopram, escitalopram, fluoxetine, paroxetine, and sertraline—as well as venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), have demonstrated efficacy in maintaining remission of MDD.11 As noted elsewhere,12 the SSRIs escitalopram and paroxetine and the SNRIs duloxetine and venlafaxine are approved for the treatment of GAD. Slide 3 lists long-term studies of three of these agents; no long-term studies are yet available for duloxetine.13-17




Long-Term Management of Substance Use Disorders with Co-occurring Depression or Generalized Anxiety Disorder

Patients with SUDs have a lifelong vulnerability to relapse.1 Risk of relapse is higher in the first 12 months after remission, but many patients experience several cycles of relapse and remission during the first several years of treatment before concluding that “controlled” use of their favored substance(s) is not possible. Treatment recommendations for patients with SUDs issued by the American Psychiatric Association favor a combination of psychosocial interventions (eg, cognitive-behavioral therapy, motivational enhancement therapy, interpersonal therapy, and 12-step programs) to address issues such as motivation, coping skills, dysfunctional thoughts, or social relationships, and pharmacotherapy to address the physiologic responses to substance use. Disulfiram, naltrexone, and acamprosate may be helpful for patients with alcohol dependence; bupropion may be beneficial for individuals with nicotine dependence; and according to recent studies, disulfiram may be useful in the treatment of cocaine dependence.1,18


Long-Term Studies in the Pharmacologic Management of Alcohol Dependence

Concerned with the toxicity and contraindications associated with alcohol-sensitizing drugs (eg, disulfiram), researchers began in the 1980s to explore the possibility that SSRIs might be a better alternative in the treatment of alcohol use disorders.19 Yet 20 years of clinical studies have yielded decidedly mixed results, and a 2006 randomized, placebo-controlled multicenter study designed specifically to address the methodological shortcomings of previous studies found that treatment with the SSRI sertraline did not produce significantly better results than those seen in placebo-treated patients.20 It appears, then, that alcohol dependence in patients with co-occurring depression requires specific, targeted treatment. 

Alcohol-sensitizing drugs remain a therapeutic option. A 9-year, prospective, open-treatment study by Krampe and colleagues21 that evaluated drinking outcomes and use of alcohol deterrents (eg, disulfiram) among 180 patients found that long-term outpatient treatment resulted in a  >50% abstinence rate. Recently, the nine-cell, 16-week Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence study found that alcoholics treated with naltrexone 100 mg/day, acamprosate 3 g/day, combined behavioral intervention (CBI), or both, had substantial reductions in drinking.22 The combination of naltrexone and CBI was associated with significantly more days of abstinence (P=.009), and naltrexone was significantly more effective than placebo in delaying the first day of heavy drinking (P=.02). While there was no statistically significant difference in efficacy between acamprosate and placebo in this study, many other controlled studies23-35 have demonstrated that agent’s efficacy.


Preventing Recurrence and Relapse

Because patients with SUDs are subject to relapse and are inconsistent in reporting these incidents, testing of breath, blood, saliva, and urine is helpful in the early detection of relapse.1 Long-term abstinence is more likely to occur in patients with less premorbid psychopathology than in those who are able to develop new relationships, and in those who participate in self-help groups.



Patients with co-occurring SUDs and MDD and/or GAD require a continuum of long-term care as a means of avoiding relapse and recurrence. Long-term treatment is associated with better outcomes, but the type of treatments used, their intensity, and the frequency of patient monitoring must be tailored to the individual patient’s needs. The strength of the physician-patient alliance can go far in helping patients achieve remission, avoid relapse, and regain psychosocial functioning.



1.   American Psychiatric Association. Practice Guideline for the Treatment of Patients with Substance Use Disorders. 2nd ed. New York, NY: American Psychiatric Association; 2006.
2.     Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2004:372-474.
3.     Yonkers KA, Warshaw MG, Massion AO, Keller MB. Phenomenology and course of generalised anxiety disorder. Br J Psychiatry. 1996;168(3):308-313.
4.     Lehman AF, Myers CP, Corty E. Assessment and classification of patients with psychiatric and substance abuse syndromes. Psychiatr Serv. 2000;51(9):1119-1125.
5.     Hasin D, Liu X, Nunes E, McCloud S, Samet S, Endicott J. Effects of major depression on remission and relapse of substance dependence. Arch Gen Psychiatry. 2002;59(4):375-380.
6.     Compton WM 3rd, Cottler LB, Jacobs JL, Ben-Abdallah A, Spitznagel EL. The role of psychiatric disorders in predicting drug dependence treatment outcomes. Am J Psychiatry. 2003;160(5):890-895.
7.     Charney DA, Palacios-Boix J, Negrete JC, Dobkin PL, Gill KJ. Association between concurrent depression and anxiety and six-month outcome of addiction treatment. Psychiatr Serv. 2005;56(8):927-933.
8.     Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. Am J Psychiatry. 2000;157(4 Suppl):1-45.
9.     Kessler RC, Berglund P, Demler O, et al. National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.
10.     Fricchione G. Generalized anxiety disorder. N Engl J Med. 2004;351(7):675-682.
11.     Physicians Desk Reference 2006: Guide to Drug Interactions, Side Effects, and Indications.  60th ed. Montvale, NJ: Thomson PDR; 2006:1177-3418.
12.     Brady KT. Evidence-Based Pharmacotherapy for Mood and Anxiety Disorders with Concurrent Alcoholism. CNS Spectr. 2008;13:4(Suppl 6):7-9.
13.     Davidson JR, Bose A, Wang Q. Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder. J Clin Psychiatry. 2005;66(11):1441-1446.
14.     Allgulander C, Huusom AK, Florea I. Prevention of relapse in generalized anxiety disorder by escitalopram treatment. Int J Neuropsychopharmacol. 2006;9(5):495-505.
15.     Stocchi F, Nordera G, Jokinen RH, et al. Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder. J Clin Psychiatry. 2003;64(3):250-258.
16.     Bielski RJ, Bose A, Chang CC. A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder. Ann Clin Psychiatry. 2005;17(2):65-69.
17. Montgomery SA, Sheehan DV, Meoni P, Haudiquet V, Hackett D. Characterization of the longitudinal course of improvement in generalized anxiety disorder during long-term treatment with venlafaxine XR. J Psychiatr Res. 2002;36(4):209-217.
18.     Suh JJ, Pettinati HM, Kampman KM, O’Brien CP. The status of disulfiram: a half of a century later. J Clin Psychopharmacol. 2006;26(3):290-302.
19.     Naranjo CA, Sellers EM. Serotonin uptake inhibitors attenuate ethanol intake in problem drinkers. Recent Dev Alcohol. 1989:7:255-266.
20.     Kranzler HR, Mueller T, Cornelius J, et al. Sertraline treatment of co-occurring alcohol dependence and major depression. J Clin Psychopharmacol. 2006;26(1):13-20.
21.     Krampe H, Stawicki S, Wagner T, et al. Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome. Alcohol Clin Exp Res. 2006:30(1):86-95.
22. Anton RF, O’Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-2017.
23.     Pelc I, Le Bon O, Verbanck P, Lehert PH, Opsomer L. Calcium acetyl homotaurinate for maintaining abstinence in weaned alcoholic patients: A placebo-controlled double-blind multicentre study. In: Naranjo C, Sellers E, ed. Novel Pharmacological Interventions for Alcoholism. New York, NY: Springer-Verlag; 1992:348-352.
24.     Ladewig D, Knecht T, Leher P, Fendl A. Acamprosate–a stabilizing factor in long-term withdrawal of alcoholic patients (in German). Ther Umsch. 1993;50(3):182-188.
25.     Geerlings PJ, Ansoms C, van den Brink W. Acamprosate and prevention of relapse in alcoholics. Eur Addict Res. 1997;3:129-137.
26.     Poldrugo F. Acamprosate treatment in a long-term community-based alcohol rehabilitation programme. Addiction. 1997;92(11):1537-1546.
27.     Chick J, Howlett H, Morgan MY, Ritson B. United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol. 2000;35(2):176-187.
28.     Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A. Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol. 2000;35(2):202-209.
29.     Gual A, Lehert P. Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. Alcohol Alcohol. 2001;36(5):413-418.
30.     Mason BJ, Goodman AM, Chabac S, Lehert P. Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res. 2006;40(5):383-393.
31.     Barrias JA, Chabac S, Ferreira L, Fonte A, Potgieter AS, Teixeira de Sousa E. Acamprosate: multicenter Portuguese efficacy and tolerance evaluation study. Psiquiatr. Clín. 1997;18:149-160.
32.     Paille FM, Guelfi JD, Perkins AC, Royer RJ, Steru L, Parot P. Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol Alcohol. 1995;30(2):239-247.
33.     Sass H, Soyka M, Mann K, Zieglgänsberger W. Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996;53(8):673-680.
34.     Whitworth AB, Fischer F, Lesch OM, et al. Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet. 1996;347(9013):1438-1442.
35.     Besson J, Aeby F, Kasas A, Lehert P, Potgieter A. Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcohol Clin Exp Res. 1998;22(3):573-579. 


Primary Care Management of Patients with Co-occurring Disorders

By Larry Culpepper, MD, MPH



Primary care physicians (PCPs) often provide the first line of care for the vast number of United States adults—~30% at any given time—with either a psychiatric or a substance use disorder, or both.1 The widespread prevalence of this comorbidity bears reiterating: During the same 12-month period, 20% of national survey respondents with a substance use disorder (SUD) had at least one mood disorder, and 17% had at least one anxiety disorder.2 Conversely, at least one SUD was found among 20% of respondents with a mood disorder and 15% of those with an anxiety disorder. However, because PCPs are often not aware of or alerted to these problems, it would seem advisable that patients presenting with either a psychiatric or an alcohol use disorder should be evaluated for both conditions.3 Establishing the presence of co-occurring disorders may be difficult, but it is necessary for appropriate and realistic treatment planning.


Starting the Diagnostic Process

Given the high rates of co-occurrence of mood, anxiety, and alcohol use disorders, PCPs may want to identify patients likely to have comorbid mood and alcohol use disorders by screening all new patients, as well as those with associated medical conditions or other risk factors, somatic presentations, and high healthcare utilization.

A thorough evaluation can determine whether psychiatric symptoms are caused by a medical illness, medications, or SUD.3 For example, certain medical conditions, including stroke, parkinsonism, HIV infection, endocrinopathies (eg, diabetes), cardiac disease, chronic renal failure, and chronic pain syndromes, are strongly associated with major depression. In addition, chronic conditions that do not respond to treatment, such as depression, diabetes, chronic pain, heart disease, gastrointestinal disorders, and hypertension, may indicate underlying alcohol abuse or dependence.4

Risk factors that are helpful in identifying and monitoring those patients who may be at risk for alcohol misuse and/or psychiatric illness include: personal or family history of mental illness and/or substance abuse; recent loss (eg, death of a loved one, divorce); domestic abuse/violence; multiple somatic symptoms not attributable to specific medical conditions; fatigue; sleep disturbance; weight gain or loss; irritable bowel syndrome; flattened affect; complaints of stress or mood disturbance; work or relationship dysfunction; changes in interpersonal relationships; and decreased adherence to treatment recommendations and self care.5

Valuable information can be gained by contacting a spouse, family member, or friend who can elaborate on past and current symptoms and supply a family history of addictions and mental illness. To facilitate history taking, focused questions can help establish the chronology of symptom development and clarify the effects of each disorder on the clinical course of the other (Slide 1).6



Screening for Alcoholism

The US Preventive Services Task Force (USPSTF) recommends routine screening of all patients for alcohol abuse or dependence,7 and a single question about heavy drinking can start the diagnostic process: For men, “How many times in the past year have you had five or more drinks in a day?” For women, “How many times in the past year have you had four or more drinks in a day?”4 In this screen, a standard drink is equivalent to 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof spirits. A response of 1 or more heavy drinking days during the past year constitutes a positive screen and can be followed by a written self-report instrument, such as the CAGE screen for alcohol-related problems8 or the CAGE-AID (CAGE-Adapted to Include Drugs) for both alcohol and drug misuse.9,10 Once a potential problem has been identified, further clinical assessment is needed to determine the pattern of drinking (ie, number of drinking days per week and drinks per day) and to confirm alcohol dependence.4 Screening tools and related materials are available at the National Institute on Alcohol Abuse and Alcoholism Web site.11


Screening for Depression and/or Anxiety

Depression and anxiety are highly comorbid, and experts advise that a screening for one should always be accompanied by an assessment for the other.12 In the primary care setting, a two-step screening tool can be time-efficient and productive. The USPSTF found that asking two questions is just as effective as using longer instruments for the initial recognition of depression (Slide 2).13 If the response to either of these questions is “yes,” a more thorough screen, such as the Patient Health Questionnaire-9,8 can be administered to gather additional information and facilitate a diagnosis.



A similar approach could be used to identify an anxiety disorder. Evidence has demonstrated that the first two items of the Generalized Anxiety Disorder-7 (GAD-7) scale constitute an effective screen for several anxiety disorders (Slide 2).12 Responses of “more than half the time/days,” or “nearly every day” to both questions can be followed by administration of the full GAD-7.14 The GAD-7 reliably identifies anxiety disorders other than GAD, including panic disorder, posttraumatic stress disorder, and social anxiety disorder, all of which have a documented association with alcohol use disorders. A clinical interview of patients with a positive screen (score ≥8) can subsequently verify the diagnosis of an anxiety disorder as well as other psychiatric comorbidities.



Initial Interventions

In primary care, effective physician interventions for alcoholism include a brief initial counseling session, feedback, advice, and goal setting.7 The process of physician assessment and brief intervention for alcoholism has been summarized as the “5 A’s” approach: First, Assess alcohol consumption. Second, Advise patients to reduce consumption to moderate levels. Third, Agree on individual goals to reduce alcohol intake or achieve abstinence (abstinence is the safest goal for dependence4). Fourth, Assist patients in acquiring the motivations, self-help skills, or supports needed for behavior change. Fifth, Arrange follow-up support and repeated counseling.

The patient’s acceptance of an alcohol use problem and willingness to engage in treatment substantially affect clinical outcomes.3 Evidence shows that brief interventions, especially motivational interviewing (MI), have been effective in reducing alcohol use in patients with co-occurring mental illness.15

MI can help patients resolve ambivalence about current or potential problems and assess their readiness to change.16 This counseling technique shifts the physician away from an authoritarian stance toward a more empathetic and collaborative approach that seeks to elicit the patient’s viewpoint about using substances and reasons for quitting. Indeed, MI may improve adherence with treatment recommendations not only for alcoholism but also for depression and anxiety disorders.


Issues Surrounding Treatment

The treatment of co-occurring disorders should strive to achieve both abstinence and psychiatric stabilization.17 A practical approach might be to encourage abstinence while offering psychosocial strategies (eg, referral to a support program or self-help group) and/or pharmacotherapy to help initiate abstinence. Several Food and Drug Administration-approved medications are available to help alcohol-dependent patients,18 and the American Psychiatric Association advocates the use of these agents in individuals with a concurrent psychiatric disorder.19

Although several weeks of abstinence are recommended to differentiate alcohol-induced symptoms from psychiatric symptoms, many outpatients will be unable to achieve this. In these cases, a tentative diagnosis of depression or anxiety can be made after 1 week of abstinence, based on changes in the patient’s psychiatric status, including severity and number of symptoms.3

As a rule, antidepressant treatment of a depressive or an anxiety disorder should not be delayed beyond a reasonable period, even if abstinence is not achieved, due to the unfavorable impact of comorbidity on prognosis.20 A history of depression or an anxiety disorder prior to the development of alcoholism is also supportive of early initiation of such treatment.

Furthermore, simultaneous treatment of co-occurring disorders may encourage adherence as patients gain relief from depressive or anxiety symptoms and alcohol cravings. When initiating pharmacotherapy, clinicians must be mindful of potential drug-drug interactions with any medications that are being taken concomitantly for medical comorbidities.

Medication adherence is especially daunting for dually diagnosed patients. Individuals in recovery frequently have complex and conflicting feelings about taking prescribed drugs and may consider the use of medication as a sign of failure or weakness.21 While remaining sensitive to the implications of pill-taking for these individuals, physicians might improve adherence by framing medication use as a tool to help patients achieve the goals they desire.


Importance of Psychosocial Support

In general, pharmacotherapy alone cannot adequately address all the treatment requirements of patients with co-occurring disorders. Because of a continuing need to manage recurring symptoms, patients often benefit from participation in a long-term community support network, such as Alcoholics Anonymous or a specialized 12-step groups for people with dual disorders.22 In these “Double Trouble” meetings, medication adherence is considered part of “working the program.”

For those individuals who desire and can afford psychotherapy, cognitive-behavioral therapy (CBT) has demonstrated effectiveness in treating depression, anxiety, and alcoholism separately and could be integrated successfully for alcohol-dependent patients with anxiety or depression.23 CBT seeks to modify negative or self-defeating thoughts or behaviors and is focused on achieving change in both.


Continuity and Integration

The role of the PCP is changing, from focusing on the medical consequences of alcoholism and addiction to a more active involvement in assessment, treatment, and referral to appropriate services.22 Organizations such as the American Society of Addiction Medicine and the American Academy of Psychiatrists on Alcohol and Addiction can provide physicians and other healthcare providers with information and education about the biopsychosocial nature of addiction and treatment. 

A national movement is afoot to integrate services for patients with co-occurring disorders.24 The separate mental health, substance use treatment, and primary care systems in the US have delivered fragmented and often inadequate care. As a result, many state mental health systems have implemented integrated dual diagnosis services, wherein teams of clinicians, typically working in one setting, provide coordinated mental health and substance use interventions, and in some, linkage to primary care services.

In practice, however, many patients continue to participate in treatment at different sites or require varying treatment services during different phases of treatment. In the long term, the PCP may be the health professional best positioned to detect the reemergence of psychiatric symptoms and to help these individuals maintain sobriety.



1.  Kessler RC, Demler O, Frank RG, et al. Prevalence and treatment of mental disorders, 1990 to 2003. N Engl J Med. 2005;352(24):2515-2523.
2.    Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61(8):807-816.
3.    Ziedonis D, Brady K. Dual diagnosis in primary care: detecting and treating both the addiction and the mental illness. Med Clin N Amer. 1997;81(4):1017-1036.
4.    National Institute on Alcohol Abuse and Alcoholism. Helping Patients Who Drink Too Much: A Clinician’s Guide. Updated 2005 ed. Washington, DC: National Institutes of Health; 2007. Publication No. 07-3769.
5.    Institute for Clinical Systems Improvement. Health Care Guideline: Major depression in adults in primary care. 10th ed. Bloomington, MN: Institute for Clinical Systems Improvement; 2007.
6.    Kranzler HR, Rosenthal RN. Dual diagnosis: alcoholism and co-morbid psychiatric disorders. Am J Addictions. 2003;12(Suppl 1):26-40.
7.    US Preventive Services Task Force. Screening and behavioral counseling interventions in primary care to reduce alcohol misuse: recommendation statement. Ann Intern Med. 2004;140:554-556.
8.    Weiss RD. Identifying and diagnosing co-occurring disorders. CNS Spectr.
 2008;13:4(Suppl 6):4-6.
9.    Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94(3):135-140.
10.     CAGEAID. Accessed December 2007.
11.     National Institute on Alcohol Abuse and Alcoholism. Accessed December 2007.
12.     Kroenke K, Spitzer RL, Williams JB, Monahan PO, Löwe B. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med. 2007;146(5):317-325.
13.     US Preventive Services Task Force. Screening for depression: recommendations and rationale. Ann Intern Med. 2002;136(10):760-764.
14.     Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder—The GAD-7. Arch Intern Med. 2006;166(10):1092-1097.
15.     Hulse GK, Tait RJ. Six-month outcomes associated with a brief alcohol intervention for adult in-patients with psychiatric disorders. Drug Alcohol Rev. 2002;21(2):105-112.
16.     Miller WR, Rollnick S. Motivational Interviewing: Preparing People to Change Addictive Behavior. New York, NY: The Guilford Press; 1991.
17.     Hendrickson EL, Schmal MS, Ekleberry SC. Treating Co-Occurring Disorders: A Handbook for Mental Health and Substance Abuse Professionals. Binghamton, NY: Haworth Press; 2004:97-105.
18.     Brady KT. Evidence-based pharmacotherapy for mood and anxiety disorders with concurrent alcoholism. CNS Spectr. 2008;13:4(Suppl 6):7-9.
19.     American Psychiatric Association. Practice Guideline for the Treatment of Patients with Substance Use Disorders. 2nd ed. New York, NY: American Psychiatric Association; 2006.
20.     Nunes E, Rubin E, Carpenter K, Hasin D. Mood disorders and substance use. In: Stein DJ, Kupfer DJ, Schatzberg AF, ed. The American Psychiatric Publishing Textbook of Mood Disorders. Washington, DC: American Psychiatric Publishing; 2005:653-671.
21.     Brady KT, Verduin ML. Pharmacotherapy of comorbid mood, anxiety, and substance use disorders. Subst Use Misuse. 2005;40(13-13):2021-2041.
22.     Substance Abuse and Mental Health Services Administration, United States Department of Health and Human Services. Treatment Improvement Protocols (TIP) 9: Assessment and Treatment of Patients with Coexisting Mental Illness and Alcohol and Other Drug Abuse. Rockville, MD; 2002.
23.     Petrakis IL, Gonzalez G, Rosenheck R, Krystal JH. Comorbidity of alcoholism and psychiatric disorders: an overview. Bethesda, Md: National Institute on Alcohol Abuse and Alcoholism; 2002.
24.     Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv. 2001;52(4):469-476.



Needs Assessment: There is no agreed upon medical clearance process for patients who present to an emergency department with psychiatric complaints. There is often a difference of opinion regarding need for testing these patients. A medical clearance protocol utilized in this research used clinical criteria as a determinate for laboratory testing.

Learning Objectives:
• Understand the controversy concerning the medical clearance process for psychiatric patients in the emergency department.
• Review effectiveness of medical clearance protocol for use in psychiatric patients.
• Determine the need for testing of psychiatric patients evaluated in the emergency department.

Target Audience:
Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: February 20, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by March 1, 2010 to be eligible for credit. Release date: March 1, 2008. Termination date: March 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Zun is chairman and professor of emergency medicine in the Department of Emergency Medicine at Rosalind Franklin University of Medicine and Science/Chicago Medical School and chairman in the Department of Emergency Medicine at Mount Sinai Hospital in Chicago, Illinois. Dr. Downey is assistant professor in Public Policy at Roosevelt University in Chicago.

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

Acknowledgments: The authors would like to thank Roma Hernandez for her assistance in data collection and Louis Shicker, MD for his review of the patients who were transferred to a psychiatric faculty. We wish to acknowledge the Medical Clearance Work Group: Carol Black, MD, Grace Carag, Lambros Chrones, MD, Willie Earley, MD, Chris Fichner, MD, Deepak Kapoor, MD, Bruce McNulty, MD, Jeff Schaider, MD, and Kristen Welch, MD.

Please direct all correspondence to: Leslie S. Zun, MD, Chair, Department of Emergency Medicine, Mount Sinai Hospital Medical Center, 15th and California, Chicago, IL 60608; Tel: 773-257-6957; Fax: 773-257-6447; E-mail:



Introduction: A protocol for the prospective evaluation of patients presenting to the emergency department with psychiatric complaints has been described but not tested. The purpose of this study is to validate a protocol for the medical clearance of patients with behavioral complaints.
Methods: A checklist based on the protocol for patients presenting with psychiatric complaints was applied to a prospective sample of patients. The inclusion criteria were patients with behavioral complaints seen in one of five test urban emergency departments transferred to a state-operated psychiatric hospital (SOPH). The exclusion criteria included patients transferred to other psychiatric facilities and those that were clinically intoxicated without other behavioral complaints. The test protocol was validated to the usual physicians’ medical clearance procedure. Patients who were transferred back to an emergency department within 7 days of admission to a psychiatry facility for 6 months in 2001 were compared to those in 2000. The study was approved by the Institutional Review Boards as exempt because it was considered data collection study.
Results: There were 401 patients who met criteria, were enrolled, and had the checklist completed from January 1, 2001–June 30, 2001. The protocol was completed in 60.9% (401 of 659 patients) of all eligible cases. A majority of the patients were males (66.7%), with known psychiatric condition (82.2%), without prior medical illness (87.3%), with normal vital signs (98.0%), with normal physical exam (91.0%), and with normal mental status (96.2%). Approximately half had laboratories ordered (49.9%) and approximately half of these tests were abnormal (51.3%). No significant difference was found in the number of patients sent back to an emergency department after transfer to an SOPH in the study periods. One patient transferred in 2001 as compared to three patients in 2000 was found to have medical conditions necessitating emergency care that was related or possibly related to the medical clearance process.
Discussion: The study demonstrated that the similar number of patients returned to an emergency department before and after the use of the protocol. This study did not answer many of the key questions concerning the use of a new evaluation protocol. Further study is needed to answer these questions.
Conclusion: The test protocol for medical clearance of psychiatric patients was found valid as compared to the usual medical clearance evaluation performed in the emergency department. Further studies in the cost and time savings with the use of this protocol is needed.



“Medical clearance” of psychiatric patients is the initial medical evaluation of patients in the emergency department whose symptoms appear to be psychiatric in origin, the purpose being to determine whether serious underlying medical illness exists which would render admission to a psychiatric facility unsafe or inappropriate. A protocol for the prospective evaluation of patients presenting to the emergency department with psychiatric complaints has been described but not tested.1 This medical clearance in the emergency department has not been standardized and is commonly fraught with problems.2

Weissberg3 commented on the fact that non-psychiatrists prematurely refer patients as “medically clear” because of their unfamiliarity or discomfort with psychiatric patients. Psychiatrists frequently require extensive testing on psychiatric patients in the emergency department to ensure that these patients do not need any acute medical intervention and to hide their discomfort with medical assessment.3-5 Emergency physicians believe that the emergency department evaluation should not be routine but should be tailored to the patient’s presentation.

In order to resolve these concerns, a team of emergency physicians and psychiatrists developed a consensus medical clearance protocol.1 The protocol for the evaluation of patients presenting with psychiatric symptoms standardizes the process and includes both a psychiatric assessment and clinically indicated physical assessment. The performance of any laboratory tests is the emergency physicians’ prerogative based on the clinical indications and not by routine.

This study examines the use of this written protocol for the “medical clearance” of patients who present to an emergency department with psychiatric complaints. The purpose of this study was to compare a standardized protocol for the medical clearance of patients with psychiatric complaints to the current procedure for medical clearance. The authors hypothesize that the number of missed medical conditions with the use of the protocol will be no worse than the numbers missed prior to the use of the protocol.



Study Setting and Population

The medical clearance checklist (Figure) was applied at five test urban emergency departments that varied in volume from 26,000 to >150,000 visits per year, and with 17–63 emergency department beds that included teaching and non-teaching hospitals from January to June 2001. These emergency departments transfer patients to three of the 10 state-operated psychiatric hospitals (SOPH) with an average bed size of 150 beds and 2,200 admissions per year.



Study Protocol

A medical clearance protocol was developed by a statewide team of psychiatrists and emergency physicians to establish an acceptable evaluation methodology for psychiatric patients who need hospitalization in a SOPH.1 The protocol was reviewed for content validity by a team of SOPH psychiatrists and emergency medicine medical directors of five test facilities that transfer patients to the SOPH. The protocol was based on a sound history of the present illness, unclothed physical examination, mental status evaluation, and clinically-guided laboratory testing. A checklist was developed from the protocol so the emergency physician could accurately complete the steps of this medical clearance protocol, so to provide adequate documentation for the medical clearance and to aid in the communication between the emergency physician and the psychiatrist (Figure). Normality of physical examination, vital signs, mental status, laboratories, and radiographics are determined by the emergency physician.

The checklist was to be used on all patients presenting to five test emergency departments with psychiatric complaints, in need of hospitalization in a SOPH. The exclusion criteria included those who were admitted to another psychiatric facility, drug or alcohol intoxication without other significant psychiatric illness, and individuals <18 years of age. The study was approved by the Institutional Review Boards as exempt.

The emergency physicians in the test emergency department were informed that the patients would only be accepted for transfer if the medical clearance checklist was completed in total and faxed to the SOPH. Patients from the non-test facilities used the traditional transfer process that includes communication of the patient’s condition and may include routine testing. SOPHs require that the emergency department transmits information concerning the mental disorder of the patient requiring admission as well as voluntary or emergency admission paperwork to the SOPH intake worker for his or her review and acceptance (personal communication, Illinois State Mental Hospitals, 2001).


Measurements or Key Outcome Measures

In order to compare the standardized protocol to the “gold standard,” the patients sent back from a SOPH to an emergency department within 7 days in the study year were compared to the number transferred in the prior year. The “gold standard” was considered the usual and customary practice that occurred as the evaluation process performed in the emergency department prior to initiation of the protocol. The authors of this study reviewed the charts of the returned patients to determine if the protocol missed diagnoses. The decision of related, unrelated, or indeterminate relatedness to medical clearance process was based on whether a test or process could have identified an existing medical condition that would have influenced the decision to transfer a patient.


Data Analysis

The checklists from all the test hospitals were collected and the data were abstracted and analyzed using the Statistical Package for the Social Sciences, version 10.6 Descriptives, frequencies, and correlations were computed from the data. Pearson coefficients and independent t-tests were performed on the data. Completion of the protocol was a checkmark in at least the first five questions. The use of t-test to determine any significant differences in equality of means was used to account for differences in outcomes from using the medical clearance checklist.



Of the 659 patients who met criteria, 401 were enrolled (60.9%) and had the checklist completed from January 1 2001 to June 30 2001; 16.4% (659 of 4,026 patients) of all patients transferred to a SOPH were from a test emergency department. All items in the protocol were completed in 55.6% (223 of 401) of patients.

A majority of the patients had known psychiatric condition (82.2%; 327 of 398), were without prior medical illness (87.3%; 240 of 275), had normal vital signs (98.0%; 388 of 396), exhibited normal physical exam (91.0%; 363 of 399), and showed normal mental status (96.2%; 375 of 390). Eighty-six of 401 (21.4%) were currently taking medication. The age range was 18–80 years with a mean age of 37 years.

Approximately half of the patients had laboratories evaluations (49.9%; 200 of 317) and in these patients approximately half of the reported test results were abnormal (51.3%; 79 of 154; 46 not documented). The most frequent laboratories ordered were urine toxicology (25.2%; 109 of 433), complete blood count (CBC; 22.4%; 97 of 433), and chemistries (23.3%; 101 of 433). When multiple tests were ordered, the most frequent combination of tests was urine toxicology and alcohol (23.3%; 44 of 189) as well as CBC, chemistries, urinalysis, and urine toxicology (22.8%; 43 of 189; Table 1). Radiographs were ordered in 12% (48 of 292) and were reported as normal in 85.4% (35 of 41; 7 not documented). In 13.5% (54 of 277), medical treatment was needed prior to medical clearance; 55.1% (86 of 245) were currently on medications. Continued medical treatment at the SOPH was required in eight of 375 patients.



The most frequent psychiatric diagnoses were depression (125), schizophrenia or psychosis (129), and suicidal ideation (79). Few patients had substance-induced mood disorder (1), dysthymia (1), panic disorder (1), posttraumatic stress disorder (1), or an eating disorder (1). The most frequent medical diagnoses were related to physical trauma (18), diabetes (12), asthma (9), and hypertension (8). Many patients had a history of alcohol or substance abuse (207)—most frequently cocaine (69), alcohol (67), and heroin (17).

There was no increase in the number of patients sent back to an emergency department after transfer to an SOPH in the study and comparative time periods (Table 2). One patient was transferred in 2001, as compared to three patients in 2000, that was found to have medical conditions that needed emergency care related or possibility related to the medical clearance process. These medical conditions included pain secondary to physical trauma (2), leg swelling (1), and seizure (1). One indeterminate case and nine unrelated patients were returned in 2001 and two indeterminate cases and four unrelated cases were returned in 2000.


The ordering of laboratory tests was correlated with obtaining radiographs (Pearson coefficient=.178, P=.002) and receiving medical treatment needed in the emergency department (Pearson coefficient=.263, P=.000), and currently taking medications (Pearson coefficient=.183, P=.039), but was not correlated with age, presentation of a new psychiatric condition, abnormal physical exam, or abnormal mental status examination (P<.05). Abnormal test results were correlated with the abnormal mental status examination (Pearson coefficient=.168, P=.04), obtaining radiographs (Pearson coefficient=.178, P=.002), medical treatment needed in the emergency department (Pearson coefficient=.263, P=.000), and those currently taking medications (Pearson coefficient=.183, P=.039), but was not correlated with age, presentation of a new psychiatric condition, or abnormal physical exam (P<.05).

Significant difference in outcome using the checklist was found if patients had a psychiatric diagnosis (95% CI .1344, 19.1156 sig .047), had any abnormal physical exam (95% CI -.4765, -3.08 sig .027), or had any abnormal mental status examination (95% CI -.4765, -2.35 sig .032). Significance was also found with the presentation of a new psychiatric condition (95% CI 9.99, 22.3 sig .03), medical diagnosis (95% CI .8496, 10.63 sig .02), patient’s age (95% CI -6.02, -.4551 sig .023), substance abuse diagnosis (95% CI 3.01, 2.39 sig .04), or the performance of radiographs (95% CI -.232, -2.22 sig .01).



This study is the first prospective study of the medical clearance of unselected adult emergency department patients with psychiatric complaints. The study demonstrated that a similar number of patients returned to an emergency department before and after the use of the protocol. This study did not answer many of the key concerns regarding the use of a new evaluation protocol, including whether the use of the protocol reduces cost, the throughput time and error rate of missed diagnoses while enhancing quality of care, the ease of transfer, or improved customer satisfaction. The authors of this article did not evaluate these criteria in the study protocol but further study is needed to answer these questions.

The protocol establishes the  standard  of  evaluation  of psychiatric patients and the role of the emergency  physician  in  the  evaluation  and  transfer of  psychiatric  patients. The protocol also deals with the information that the psychiatrists require on the chart prior to transfer. A few authors have written about the poor emergency department chart documentation of psychiatric patients.2,4 Riba and Hale4 found that only 33% of the patients had a history of present illness, 68% had vital signs, 8% had a complete neurologic exam, and none had a mental status examination documented on the chart.
The importance of performing a medical clearance of psychiatric patients in the emergency department is well established to screen patients with medical illnesses that may have caused or exacerbated their psychiatric illness.7-22 In order to detect those patients with medical conditions in need of treatment, many studies have recommended extensive testing.8-14,18,20,22 More recent retrospective studies of psychiatric patients who present to the emergency department did not recommend extensive testing of all psychiatric patients, rather most testing should be abandoned in favor of a more clinically driven and cost-effective process.23-30 Hennenman and colleagues,6 in a prospective study of patients with new onset of psychiatric symptoms, refined these guidelines and recommended a battery of tests for these patients. It is probable that patients with new-onset psychiatric illness will need a different work-up than those with known psychiatric illness.

The study was limited by the usual medical clearance process as the “gold standard” for comparative purposes since no other such standard is generally accepted. One could argue that this process is no standard at all, but no better medical clearance has been presented in the literature. The authors of this article did not perform any side-by-side comparison from year to year because the evaluation varied between institutions and doctors. The study examined only those patients from a test emergency department who transferred to a SOPH rather than to another institution. Although the protocol was mandated prior to transfer, the compliance and completeness of the protocol varied in the test emergency departments. There was no observation of the type of evaluation that was actually performed to determine if the protocol was followed. The protocol did not establish the need for selective laboratory testing being performed but removed the requirement for testing. Emergency physicians were asked if the patient had a normal mental status, although prior studies have determined that emergency physicians do not perform an adequate mental status examination.31 The mental status determination was primarily an evaluation of the patients’ cognitive abilities, an evaluation not usually performed by psychiatrists. The number of patients sent back from a state-operated facility was small before and after the implementation of the protocol, limiting the data analysis. The study was limited by the non-blinded nature of the reviews concerning the need to return patients to an emergency department. Satisfaction analyses of both the emergency physicians and psychiatrists in the use of the checklist and interactions with their colleagues would be valuable.

Many physicians did utilize the protocol, but still ordered tests based on their own routine or their presumption that the transferring facility will request such testing. The next step is to establish stricter treatment guidelines based on the protocol where testing is established by set criteria in the protocol rather than based on physician judgment. It is uncertain if a tool can be developed to reduce the number of patients who were inappropriately transferred to a psychiatric facility.

Future study is needed to confirm the findings of the pilot. The study would be a randomized, controlled trial where half receive the medical clearance protocol and the other half would be evaluated in the usual evaluation. The two patient groups could then be compared for demographics, examination performed, tests and procedures ordered, and outcome measures.



This pilot study demonstrated that this medical clearance protocol for patients with behavioral complaints was similar to the prior means of medical clearance. Further testing in various settings is necessary to determine if a broader applicability is possible. PP



1.    Zun LS, Leikin JB, Stotland NL, Blade L, Marks RC. A tool for the emergency medicine evaluation of psychiatric patients. Am J Emerg Med. 1996;14(3):3.
2.    Tintinalli JE, Peacock FW, Wright MA. Emergency medical evaluation psychiatric patients. Ann Emerg Med. 1994;23(4):859-862.
3.    Weissberg MP. Emergency room medical clearance: an educational problem. Am J Psychiatry. 1979;136(6):787-790.
4.    Riba M, Hale M. Medical clearance: Fact or fiction in the hospital emergency room. Psychosomatics. 1990;31(4):400-404.
5.    McIntyre JS, Romano J. Is there a stethoscope in the house and is it used? Arch Gen Psychiatry. 1977;34(10):1147-1151.
6.    SPSS Inc. Statistical Package for the Social Sciences. Version 10. Chicago, IL; 2001.
7.    Henneman PL, Mendoza R, Lewis RJ. Prospective evaluation of emergency department medical clearance. Annals Emerg Med. 1994;24(4):672-677.
8.    Thomas C. The Use of screening investigations in psychiatry. Br J Psychiatry. 1979;135:67-72.
9.    Roca RP, Breakey WR, Fisher PJ. Medical care of chronic psychiatric outpatients. Hosp Commun Psych. 1987;38(7):741-745.
10.    Hall RC, Popkin MK, Devaul RA, Faillace LA, Stickney SK. Physical illness presenting as psychiatric disease. Arch Gen Psych. 1978;35(11):1315-1320.
11.    Bunce DF, Jones LR, Badger LW, Jones SE. Medical illness in psychiatric patients: barriers to diagnosis and treatment. Southern Med J. 1982;75(8):941-944.
12.    Hall RC, Beresford TP, Gardner ER, Popkin MK. The medical care of psychiatric patients. Hosp Commun Psych. 1982;3(1):25-34.
13.    Ferguson B, Dudleston K. Detection of physical disorder in newly admitted psychiatric patients. Acta Psychiatr Scand. 1986;74(5):485-489.
14.    Hall RC, Gardner ER, Stickney SK, LeCann AF, Popkin MK. Physical illness manifesting as psychiatric disease II analysis of a state inpatient population. Arch Gen Psych. 1980;37(80):989-995.
15.    Koran L, Sox HC, Marton KI, et al. Medical evaluation of psychiatric patients I: results in a state mental health system. Arch Gen Psych. 1989;46(8):733-740.
16.    Koranyi EK. Morbidity and rate of undiagnosed physical illnesses in a psychiatric clinic population. Arch Gen Psych. 1979;36(4):414-419.
17.    Hoffman RS. Diagnostic errors in the evaluation of behavioral disorders. JAMA. 1982;248(8):964-967.
18.    Summers WK, Munoz RA, Read MR, Marsh GM. The psychiatric physical examination – Part II: findings in 75 unselected psychiatric patients. J Clin Psychiatry. 1981;42(3):99-102.
19.    Hall RC, Gardner ER, Popkin MK, Lecann AF, Stickney SK. Unrecognized physical illness prompting psychiatric admission: a prospective study. Am J Psychiatry. 1981;138(5):629-635.
20.    Beresford TP, Hall RC, Wilson FC, Blow FB. Clinical laboratory data in psychiatric outpatients. Psychosomatics. 1985;26(9):731-741.
21.    Herridge CF. Physical disorders in psychiatric illness. A study of 209 consecutive admissions. Lancet. 1960;(2)949-951.
22.    McHugh P. William Osler and New Psychiatry. Ann Intern Med. 1987;107(6):914-8.
23.    Korn CS, Currier GW, Henderson SO. Medical clearance of psychiatric patients without medical complaints in the emergency department. J Emerg Med. 2000;18(2):173-176.
24.    Williams ER, Shepherd SM. Medical clearance of psychiatric patients. Emerg Med Clin North Am. 2000;18(2):173-176.
25.    Allen MH, Currier GW. Medical assessment in the psychiatric service. New Dir Ment Health Serv. 1999;82(82):21-28.
26.    McCourt JD, Weller JP, Broderick KB. Mandatory laboratory testing for emergency department (ED) psychiatric medical screening exam (PMSE): useful or useless? [abstract]. Acad Emerg Med. 2001;8(8):572-573.
27.    Olshaker JS, Browne B, Jerrard DA, Prendergast H, Stair TO. Medical clearance and screening of psychiatric patients in the emergency department. Acad Emerg Med. 1997;4(2):124-128.
28.    Allen MH, Currier GW. Medical assessment in the psychiatric emergency service. New Dir Ment Health Serv. 1999;82:21-28.
29.    Johnson DW. The evaluation of routine physical examination in psychiatric cases. Practitioner. 1968;200:686-691.
30.    Dolan JG, Mushlin AL. Routine laboratory testing for medical disorders in psychiatric inpatients. Arch Intern Med. 1985;145(11):2085-2088.
31. Zun LS, Gold I. A survey of the form of the mental status examination administered by emergency physicians. Ann Emerg Med. 1986 Aug;15(8):916-922.


Needs Assessment:
Stigma against depressed people who abuse alcohol leads to inadequate assessment and management. The resulting poor care compromises prognosis and leads to relapse, engendering negative feelings from healthcare professionals. Teaching better attitudes and treating both conditions hopefully improves outcome, reduces suicide risk, and fosters professionalism.

Learning Objectives:
• Recognize stigma against people with alcoholism and depression.
• Teach better attitudes toward patients with alcoholism and depression.
• Educate residents and medical students about management of these disorders.
• Identify the need for simultaneous treatment of alcoholism and depression.
• Counter stigma in medical systems and in healthcare professionals to improve approach toward these patients, especially when facing concerns about suicide.

Target Audience: Primary care physicians and psychiatrists.

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

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

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

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: February 20, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by March 1, 2010 to be eligible for credit. Release date: March 1, 2008. Termination date: March 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Surja is psychiatry addiction fellow, Dr. Talari is psychiatry extern, Dr. Nair is psychiatry extern, Mr. Mettu is medical student, and Dr. Lippmann is professor, all in the Department of Psychiatry at the University of Louisville School of Medicine in Kentucky.

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

Please direct all correspondence to: Steven B. Lippmann, MD, University of Louisville Hospital, ACB- First Floor Psychiatry Clinic, 550 S Jackson St, Louisville, KY 40202; Tel: 502-852-5859; Fax: 502-562-4044; Email:





Depression comorbid with alcohol abuse is common but often stigmatized. Suicide gestures and attempts are frequent in this population and are often followed by subsequent self-induced injury or death. However, physicians and other healthcare professionals may not always regard these dual diagnoses as seriously as they do other presentations. All physicians, including medical school faculty, should teach consideration of suicidal issues in depressed patients who abuse alcohol and be knowledgeable in the management of both conditions. A dualistic approach to evaluation and treatment is recommended. A coordinated, simultaneously delivered intervention for depression and alcohol abuse is important in developing optimal therapy.



Affective disorders are a group of common illnesses that sometimes result in suicide, the third leading cause of death in people between 15 and 34 years of age.1 Alcohol abuse is also prevalent and strongly associated with depression and suicide.2 People who abuse alcohol commonly become depressed, and individuals with affective symptoms often drink ethanol to self medicate.3 Death by suicide is approximately six times as likely in those who are alcohol abusers as compared to non-drinkers,4 and many suicide attempts are made while under the influence of alcohol.

When dual diagnosis patients present with suicidal complaints, the depth of their distress is often less uniformly addressed. At times, one or the other condition is not specifically considered in planning intervention.5 Furthermore, access to treatment for this comorbidity is limited6 and some physicians are not fully informed about therapeutic resources available in their community.7 These deficiencies should be corrected. Psychiatrists ought to seriously consider and provide treatment for suicidal concerns in all depressed people, especially those who abuse alcohol.

It is important that medical students and residents be made aware of these issues; doctors should also provide such guidance to other healthcare professionals.8 As a patient advocate, educators have a responsibility to teach a positive attitude toward clinical recognition of depression and alcohol abuse, the means of identifying those at risk for suicide, and management for both of these conditions.



Unfortunately, psychiatric patients and those with substance abuse are often met with scorn in our society. They are frequently stigmatized and considered to be weak or inadequate. Many medical professionals share this bias as well.9 Using counter-transference, they may sometimes view these disorders as a behavioral dysfunction, unworthy of medical attention. Such negativity affects healthcare quality even in the best hospitals. Lack of training, inadequate knowledge of resources, and administrative or insurance barriers to comprehensive treatment potentially compromise good care. Improved teaching could correct this deficiency.8,9 Education about the needs for treatment and the ethical responsibility for providing good health care should fortify the trainees with more zeal at patient advocacy. Subsequently, it would be an expectation that the medical staff, while now knowing the available options, would be empowered to make the extra effort to overcome difficulties and secure the proper interventions.


The Challenges of Comorbidity

The comorbidities of affective illnesses and abuse of ethanol are common. Diagnosis is often a challenge as these two disorders can mimic one another and compound dysfunction. In addition, depression compromises sobriety and alcoholism worsens mood. Having both of these conditions often creates a problem leading to rejection from appropriate treatment.9 For example, many psychiatric facilities may refuse to accept such patients saying that the person just needs to quit drinking.5 Similarly, substance abuse units occasionally deny care on the basis of the psychiatric needs preclude admission. Often, alcohol treatment is refused with the commentary that people taking mind-altering substances will not be admitted, even if they are suicidally depressed and require antidepressant pharmacotherapy. Treatment for both problems requires greater effort and therapeutic expertise than for a single pathology. This approach requires teaching consideration of both the mood component and the addictive problem; each one needs an individualized intervention, provided simultaneously. Some communities offer too few therapeutic options for these dually diagnosed cases. Even when services are available, they are hard to access and rarely well coordinated.6


Depression and Alcohol Abuse are Chronic Brain Disorders

Like many other ailments such as diabetes or hypertension, depression and abuse of alcohol are often chronic. Relapse is expected and frequent emergency room visits are the norm. Despite today’s healthcare trends of inpatient admissions being more difficult to secure, some patients who recurrently present in crisis are in need of hospital restabilization with sobriety and long-term clinical follow up. The chronicity of these disorders can be linked to their physiologic basis. This perspective is well supported by research but is contrary to beliefs about weakness of character or lack of will. Abnormal brain function is documented in both depression and alcohol abuse. For example, males with a family history of alcoholism reportedly have a tendency toward abnormal electroencephalograms that mimic those of recovering addicts,10 and also have a significantly heightened risk of abusing alcohol themselves. Positron emission tomography studies demonstrate central nervous system pathology in these conditions.11 Even though initially the decision to drink is voluntary, prolonged ethanol exposure further alters brain function, making abstinence difficult and inducing changes in mood, loss of control over drinking, and compulsive ingestion despite adverse consequences. Health care improves when it is recognized that these mood and substance abuse conditions are not a matter of simple unwillingness to change.

Understanding these concepts is important to change the way clinicians deal with these debilitating situations. Teaching these principles in medical schools and at healthcare facilities should result in a better appreciation for the need of addressing such issues and applying this knowledge clinically.8


Clinical Awareness

The three important factors leading to suicide attempts in depressed individuals include hopelessness, impulsiveness, and abuse of alcohol. The ingestion of ethanol increases dangerousness for suicide due to disinhibition, impaired cognition, and poor judgment. Intoxication, therefore, becomes an additional risk factor for depression, dysfunction, dyscontrol, and self harm. A full assessment of mood and substance abuse is important in designing a therapeutic regimen since depression and alcohol are so prominently associated with suicide attempts and/or completions. These approaches include matching patients to appropriate treatment programs.5 Trainees and hospital personnel should understand that suicidal behaviors could occur acutely or be a long-term, recurrent issue.8 Most people who commit suicide have seen a doctor within 1 month prior to their demise, and many completers have communicated suicidal plans to close relatives.12 Patients who become actively suicidal need psychiatric attention and may be difficult to manage in some residential or even inpatient substance abuse facilities. Additional concern is required as these individuals often experience deprived social supports, personal losses, and/or have access to lethal means of self harm.

Education must also be provided about detoxification, vitamin repletion, and the management of alcohol withdrawal. Safe detoxification is only the beginning of a comprehensive treatment plan. Faculty should assure thorough trainee knowledge of antidepressant therapies. Additional important approaches include anti-craving pharmaceuticals (eg, acamprosate or naltrexone) and adverse reaction-to-alcohol medicinals (eg, disulfiram) that complement behavioral interventions like Alcoholics Anonymous membership. Halfway houses and many other community outreach or support services are among other valuable therapeutic options. Such inclusive offerings enhance the likelihood of success.

The learning process begins when psychiatrists demonstrate this knowledge as compassionate role models in their own patient care while stressing the need for comprehensive treatment. One should know the appropriate resources available from outpatient clinics to residential and inpatient units. Beyond familiarity with the options, they must manage medical systems in negotiation with insurance companies or hospitals to procure patient-focused appropriate services.7 Trainees learn best when receiving consistent guidance and following examples set by their educators.8



The presence of alcohol abuse reduces the likelihood of compliance with therapy. A depressed person who feels hopeless is unlikely to follow an antidepressant or sobriety regimen since the efforts seem in vain. Hopelessness compromises attendance at psychotherapy or Alcoholics Anonymous meetings if recovery appears to be impossible. When depression and its associated symptoms are present, treatment is mandatory. For example, anyone with chronic insomnia would respond poorly to pharmacotherapies or psychotherapeutic interventions. These patients also may require altered doses of psychotropic medication since alcohol induces hepatic enzymes and can result in liver dysfunction. Interventions are frequently needed for social, occupational, or legal disruptions. These important psychosocial issues should be addressed along with applying appropriate medical treatments. In addition, substance abuse therapies must always be made available. Focusing on both illnesses facilitates recovery. Concern for suicidal issues among dual diagnoses cases should remain active. Since these patients have significant risk for self injury, assessment of suicide potential, with family involvement if possible, is mandatory. Aggressive treatment, hospitalization, or very careful outpatient monitoring is important with a positive, therapeutic approach individualized to the patients’ needs. Clinical educators can play an important role in diminishing negative thinking by demonstrating an affirmative behavioral attitude and guiding their trainees and coworkers to be receptive to such practice.8 Attentiveness to these concepts fosters a better outcome.



People with depression, suicidal concerns, and/or alcoholism are frequently stigmatized in our culture. Even physicians and other healthcare professionals can have such negative attitudes. This detrimental approach compromises dual diagnosis patient evaluations, treatment, and prognosis. These individuals should be carefully assessed, especially if they are suicidal, and both conditions should be vigorously treated. Countering stigma is an important goal and teaching better attitudes should be provided to all levels of trainees, healthcare workers, and our own colleagues. It is important to show respect to these individuals regardless of personal feelings. Hopefully, better attitudes by the medical team leads to improved patient care and greater professionalism. PP



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