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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41.    Leentjens AF, Vreeling FW, Luijckx GJ, Verhey FR. SSRIs in the treatment of depression in Parkinson’s disease. Int J Geriatr Psychiatry. 2003;18(6):552-554.
42.    Weintraub D, Morales KH, Moberg PJ, et al. Antidepressant studies in Parkinson’s disease: a review and meta-analysis. Mov Disord. 2005;20(9):1161-1169.
43.    Wermuth L, Sørensen PS, Timm S, et al. Depression in idiopathic Parkinson’s disease treated with citalopram. Nord J Psychiatry. 1998;52:163-169.
44.    Avila A, Cardona X, Martin-Baranera M, et al. Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial. J Clin Psychopharmacol. 2003;23(5):509-513.
45.    Ceravolo R, Nuti A, Piccinni A, et al. Paroxetine in Parkinson’s disease: effects on motor and depressive symptoms. Neurology. 2000;55(8):1216-1218.
46.    Tesei S, Antonini A, Canesi M, Zecchinelli A, Mariani CB, Pezzoli G. Tolerability of paroxetine in Parkinson’s disease: a prospective study. Mov Disord. 2000;15(5):986-989.
47.    Bayulkem K, Torun F. Therapeutic efficiency of venlafaxin in depressive patients with Parkinson’s disease. Mov Disord. 2002;17(suppl 5):204.
48.    Okun MS, Watts RL. Depression associated with Parkinson’s disease: clinical features and treatment. Neurology. 2002;58(4 suppl 1):63-70.
49.    Paterson NE, Markou A. Animal models and treatments for addiction and depression co-morbidity. Neurotox Res. 2007;11(1):1-32.
50.    Tremblay LK, Naranjo CA, Cardenas L, Herrmann N, Busto UE. Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine. Arch Gen Psychiatry. 2002;59(5):409-416.
51.    Marinelli M, Piazza PV. Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J Neurosci. 2002;16(3):387-394.
52.    Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. 1999;19(1):67-85.
53.    Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev. 2001;22(6):724-763.
54.    Russo-Neustadt AA, Chen MJ. Brain-derived neurotrophic factor and antidepressant activity. Curr Pharm Des. 2005;11(12):1495-1510.
55.    Castren E. Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol. 2004;4(1):58-64.
56.    Sapolsky RM. Is impaired neurogenesis relevant to the affective symptoms of depression? Biol Psychiatry. 2004;56(3):137-139.
57.    Russo-Neustadt AA, Alejandre H, Garcia C, Ivy AS, Chen MJ. Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology. 2004;29(12):2189-2199.
58.    Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev. 2006;58(1):115-134.
59.    Volkow ND, Wang GJ, Fowler JS, et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiatry. 2005;57(6):640-646.
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.
69.    Hauser RA, Salin L, Juhel N, Konyago VL. Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson’s disease. Mov Disord. 2007;22(3):359-365.
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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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20.    Zanardi R, Franchini L, Serretti A, Perez J, Smeraldi E. Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. J Clin Psychiatry. 2000;61(1):26-29.
21.    Zanardi R, Franchini L, Gasperini M, Lucca A, Smeraldi E, Perez J. Faster onset of action of fluvoxamine in combination with pindolol in the treatment of delusional depression: a controlled study. J Clin Psychopharmacol. 1998;18(6):441-446.
22.    Zanardi R, Franchini L, Gasperini M, Smeraldi E, Perez J. Long-term treatment of psychotic (delusional) depression with fluvoxamine: an open pilot study. Int Clin Psychopharmacol. 1997;12(4):195-197.
23.    Stahl SM. Antidepressant treatment of psychotic major depression: potential role of the sigma receptor. CNS Spectr. 2005;10(4):319-323.
24.    Zanardi R, Franchini L, Gasperini M, Perez J, Smeraldi E. Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. Am J Psychiatry. 1996;153(12):1631-1633.
25.    Simpson GM, El Sheshai A, Rady A, Kingsbury SJ, Fayek M. Sertraline as monotherapy in the treatment of psychotic and nonpsychotic depression. J Clin Psychiatry. 2003;64(8):959-965.
26.    Anton RF Jr, Burch EA Jr. Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression. Am J Psychiatry. 1990;147(9):1203-1208.
27.    Minter RE, Mandel MR. The treatment of psychotic major depressive disorder with drugs and electroconvulsive therapy. J Nerv Ment Dis. 1979;167(12):726-733.
28.    Charney DS, Nelson JC. Delusional and nondelusional unipolar depression: further evidence for distinct subtypes. Am J Psychiatry. 1981;138(3):328-333.
29.    Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological treatment of delusional depression. Am J Psychiatry. 1985;142(4):430-436.
30.    Rothschild AJ, Williamson DJ, Tohen MF, et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol. 2004;24(4):365-373.
31.    Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. Am J Psychiatry. 2000;157(4 suppl):1-45.
32.    Minter RE, Mandel MR. A prospective study of the treatment of psychotic depression. Am J Psychiatry. 1979;136(11):1470-1472.
33.    Glassman AH, Kantor SJ, Shostak M. Depression, delusions, and drug response. Am J Psychiatry. 1975;132(7):716-719.
34.    Kantor SJ, Glassman AH. Delusional depressions: natural history and response to treatment. Br J Psychiatry. 1977;131:351-360.
35.    Frances A, Brown RP, Kocsis JH, Mann JJ. Psychotic depression: a separate entity? Am J Psychiatry. 1981;138(6):831-833.
36.    Johnstone EC, Deakin JF, Lawler P, et al. The Northwick Park electroconvulsive therapy trial. Lancet. 1980;2(8208-8209):1317-1320.
37.    Buchan H, Johnstone E, McPherson K, Palmer RL, Crow TJ, Brandon S. Who benefits from electroconvulsive therapy? Combined results of the Leicester and Northwick Park trials. Br J Psychiatry. 1992;160:355-359.
38.    Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry. 2000;57(5):425-434.
39.    Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285(10):1299-1307.
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.



Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Johnson and Johnson, Medicinova, PGxHealth, Pfizer, and Somerset.


Patients with schizophrenia suffer mortality rates estimated to be twice that of the general population and have a foreshortened life expectancy.1,2 The excess mortality associated with the diagnosis of schizophrenia is attributable to greater numbers of fatalities due to both natural and unnatural causes of death.3 Increased suicide rates among patients with schizophrenia is well documented, but other causes of excess mortality in this patient population are less clear. Implicated as contributing factors to the high mortality rate are medical illnesses often associated with schizophrenic disorders and, in some instances, possible adverse effects of antipsychotic treatment.


Schizophrenia and Risk of Suicide

Nearly one-third of the excess mortality in schizophrenia is attributable to the significantly higher risk of suicide, with an additional 12% due to accidental death. Several large cohort studies clearly document the increased rate of suicide among patients with schizophrenia.3,4 Meta-analyses of studies of long-term outcomes over the course of the disorder estimate the incidence of death by suicide in schizophrenia to be 5% over the patient’s lifetime. Young male patients are particularly liable to commit suicide, especially during the early months following diagnosis of the disorder. 


Increased Mortality Due to Natural Causes

Mortality data indicate that patients with schizophrenia also have higher fatality rates due to natural causes of death compared with that of the United States general population.3 Cardiovascular, respiratory, and metabolic disorders are 2–3 times more prevalent in schizophrenia than in the population as a whole and contribute to moderately increased mortality rates from natural causes.5,6 Unhealthy life styles, polypharmacy, and suboptimal health care are all regarded as contributing factors to higher mortality risk. Pleas to implement preventive measures focus on reducing the dramatically increased mortality of schizophrenic patients by more diligent treatment of affective symptoms, improving overall treatment compliance, and greater vigilance in enforcing healthier lifestyles.7,8


Antipsychotics and Adverse Cardiac Effects

In addition to sequelae of medical problems associated with schizophrenia, antipsychotics have been implicated as contributing factors. There is some evidence that antipsychotics may cause sudden cardiac death or stroke. A case-controlled survey of medical practices within a network of 150 general practitioners over a 6-year period (1995–2001) found a 3-fold increase in the rate of sudden cardiac deaths associated with antipsychotics in primary care patients.9 The highest rate of sudden cardiac death was in patients receiving treatment with a butyrophenone, a class of antipsychotics known to prolong the QT interval and a particular concern with thioridazine.9 Increased rates of sudden cardiac death as compared with matched controls were apparent even at low doses of antipsychotics. Although in this study a majority of patients were receiving a conventional antipsychotic, adverse cardiac effects associated with atypical antipsychotic use were also noted.10

Atypical antipsychotics are established risk factors for development of diabetes mellitus and the metabolic syndrome. These adverse effects over time indirectly result in cardiovascular sequelae and higher death rates.5 Diabetes and dyslipidemias from extended exposure to atypical antipsychotics, especially clozapine and olanzapine, can lead to atherosclerosis, coronary artery disease, and other vascular lesions.


Antipsychotics in Elderly Patients

Increased rates of cerebrovascular events in dementia trials evident in 2001 for risperidone11 and in 2004 for olanzepine12 prompted the decision by the United Kingdom Committee on the Safety of Medicines to warn clinicians about potential risk of stroke with these two agents. In April 2005, the US Food and Drug Administration undertook a meta-analysis of 17 controlled clinical trials conducted for aripiprazole, olanzapine, quetiapine, and risperidone, involving >5,000 patients with dementia-related psychotic symptoms. Nearly all the clinical trials in the FDA analysis exhibited at least a small but significant increase in mortality compared with placebo treatment. This suggested that the finding was a class effect and not due to bias introduced by aberrant data from a few clinical trials.13 The FDA analyses found an approximately 50% higher incidence of stroke with atypical antipsychotics in dementia trials. It led to requiring “black box” warnings in the product labeling for all atypical antipsychotics. The FDA further admonished drug prescribers that atypical antipsychotics had not received approval for a dementia indication. Subsequent to the FDA meta-analysis, similar results were reported by a second group of investigators, which appeared to replicate the findings.13

Questions remain whether these stroke data associated with use of atypical antipsychotics are reliable.14 No mechanism accounting for this largely unexpected finding has been clearly delineated. Proposed theories for apparent increased risk of stroke include increased platelet aggregation due to increased prolactin levels; serotonin blocking effects of atypical antipsychotics; hypotension with small vessel disease; and increased coagulability caused by adverse metabolic effects of these agents on triglycerides, cholesterol, leptin, and glucose.

A cohort analysis of Medicare data of first-time recipients of conventional and atypical antipsychotics (22,000 patients ≥65 years of age) found a 37% higher mortality with conventional versus atypical antipsychotics.15 An unexpected finding of the study was the surprising fact that >25% of Medicare beneficiaries in nursing homes within the state where the survey was conducted received an antipsychotic. However, not all studies of hospitalizations for stroke involving dementia patients have confirmed an association of neurologic sequelae and treatment with conventional or atypical antipsychotics.16

The FDA analysis was confined to elderly patients in clinical trials for dementia and applied only to atypical antipsychotics. Consequently, more definitive data are needed to assess risk-benefit of antipsychotic use in older patients. Presently available information is largely extrapolated from experience with treatment of younger patients or elderly patients with dementia.


Mortality Risk of Atypical Antipsychotics in Younger Adults

A recent study examined mortality of patients with schizophrenia during treatment with an atypical antipsychotic in pre-approval clinical trials.17 This review of data derived from FDA summary documents in the public domain permitted assessment of mortality during treatment with several of the newer atypical antipsychotics in clinical trials conducted during the period from 1982–2002. It examined experience in >12,000 patients receiving atypical (investigational) antipsychotics, 2,900 receiving conventional antipsychotics, and 1,200 receiving placebo treatment. Mortality rates based on patient exposure years were 2,055/100,000 for atypical antipsychotics versus 8,081/100,000 for placebo (P<.05). The mortality rate for placebo treatment was significantly higher than that for either atypical or conventional antipsychotic treatment. Suicide was the leading cause of death (28%) during atypical antipsychotic treatment, followed by cardiovascular (18%) and respiratory (17%) disorders. Complete data were unavailable to assess causes of death with the other two treatments. Overall mortality rates for each of three treatment groups, however, exceeded the mortality rate for the general population (850/100,000), an outcome consistent with the finding of higher mortality risk for schizophrenia, as discussed above.



Patients with schizophrenia experience higher mortality rates than the general population. The excess mortality is due to both significant suicide risk and a higher likelihood of death from natural causes. Antipsychotics have been impugned as causing increased mortality and strokes in demented elderly patients, which led to the FDA warning included in the current labeling of atypical antipsychotics. No definitive mechanism for the purported adverse events of atypical antipsychotics in elderly dementia patients has been identified. Recent cohort studies suggest there is a similar increased mortality risk with use of conventional antipsychotics in dementia patients. Analyses of pre-approval clinical trial data for the atypical antipsychotics in schizophrenia find a lower mortality risk during treatment with antipsychotics compared with placebo treatment, although all of the groups experienced higher mortality than for the general population. PP



1.    Amaddeo F, Bisoffi G, Bonizzato P, Micciolo R, Tansella M. Mortality among patients with psychiatric illness. A ten-year case register study in an area with a community-based system of care. Brit J Psychiatry. 1995;166(6):783-788.
2.    Newman SC, Bland RC. Mortality in a cohort of patients with schizophrenia. Can J Psychiatry. 1991;36(4):239-245.
3.    Brown S. Excess mortality of schizophrenia. A meta-analysis. Brit J Psychiatry. 1997;171:502-508.
4.    Palmer BA, Pankratz VS, Bostwick JM. The lifetime risk of suicide in schizophrenia. Arch Gen Psychiatry. 2005;62(3):247-253.
5.    Casey DE. Metabolic issues and cardiovascular disease in patients with psychiatric disorders. Am J Med. 2005;118(suppl 2):12S-22S.
6.    Enger C, Weatherby L, Reynolds RF, Glasser DB, Walker AM. Serious cardiovascular events and mortality among patients with schizophrenia. J Nerv Ment Dis. 2004;192(1):19-27.
7.    Auquier P, Lançon C, Rouillon F, Lader M, Holmes C. Mortality in schizophrenia. Pharmacolepidemiol Drug Saf. 2006;15(12):873-879.
8.    Hawton K, Sutton L, Haw C, Sinclair J, Deeks JJ. Schizophrenia and suicide: systematic review of risk factors. Br J Psychiatry. 2005;187:9-20.
9.    Straus SM, Bleumink GS, Dieleman JP, et al. Antipsychotics and the risk of sudden cardiac death. Arch Int Med. 2004;164(12):1293-1297. Erratum in: Arch Intern Med. 2004;164(17):1839.
10.    Merrill DB, Dec GW, Goff DC. Adverse effects associated with clozapine. J Clin Psychopharmacol. 2005;25(1):32-41.
11.    Wooltorton E. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ. 2002;167(11):1269-1270.
12.    Wooltorton E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ. 2004;170(9):1395.
13.    Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of random placebo controlled trials. JAMA. 2005;294(15):1934-1943.
14.    Friedman JH. Atypical antipsychotics in the elderly with Parkinson disease and the “black box” warning. Neurology. 2006;67(4):564-566.
15.    Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional versus atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341.
16.    Liperoti R, Gambassi G, Lapane Kl, et al. Cerebovascular events among elderly nursing home patients treated with conventional or atypical antipsychotics. J Clin Psychiatry. 2005;66(9):1090-1096.
17.    Khan A, Schwartz K, Stern C, et al. Mortality risk in patients with schizophrenia participating in premarketing atypical antipsychotic clinical trials. J Clin Psychiatry. 2007;68(12):1828-1833.


Dr. Trujillo is professor of psychiatry and director of the Program for Public and Global Psychiatry at New York University School of Medicine in New York City.

Disclosures: Dr. Trujillo reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Manuel Trujillo, MD, Professor of Psychiatry & Vice-Chair, Public & Global Psychiatry, Department of Psychiatry, NYU School of Medicine, 462 First Avenue, Room A648, New York, NY 10016; Tel: 212-263-6220; Fax: 212-263-8097; E-mail:; Website:



Focus Points

• The reduction of health disparities has become a national priority for health and mental health.
• A growing body of knowledge will help clinicians guide the treatment of minorities.
• This body of knowledge encompasses and can serve as a guide to assessment and diagnosis as well as medical, psychiatric, and psychosocial treatments.



Health disparities, defined as population-specific differences in the prevalence, onset, severity of disease, and differential access to health care, is a rising issue in the mental healthcare debate. The populations most seriously affected by adverse health disparities include protected minorities who often seek and receive care through language and cultural barriers. This article discusses a body of knowledge, skills, and attitudes which can help clinicians bridge the care gaps created by such barriers. The article highlights means to overcome these barriers while performing diagnostic interviews, completing mental status examinations, and selecting and implementing pharmacologic and psychosocial treatments.



Psychiatrists currently practicing in the United States and in many other countries around the world will undoubtedly have the opportunity to treat many patients belonging to ethnic and cultural groups different than their own. Such is the nature and magnitude of population changes since the end of World War II, which has accelerated through globalization in the last 2 decades. Though such changes will ultimately enrich the practice of psychiatry and its scientific knowledge base, it will, for many transitional years, present significant challenges to the practicing clinician, systems of care and training, and policy makers. Many such patients will have limited command of the English language and will probably hold beliefs about illness and health at some variance from the standard biomedical model that supported the psychiatrist’s training and that has evolved in the US and other Western countries over the last century. Fortunately for the practicing psychiatrist, patients in their care, and healthcare systems that support their work, the growing discipline of cultural psychiatry is developing a substantive and increasingly sophisticated body of knowledge that will enhance the psychiatrist’s capacity to provide quality care across language and cultural barriers. As this knowledge base is mastered, the contemporary psychiatrist will be equipped with the attitudes, basic knowledge, clinical skills, and professional attitude necessary. In confronting the clinical task of providing psychiatric treatment to patients from different cultural groups, psychiatrists have a decisive advantage; namely, their familiarity with Engel’s biopsychosocial model,1 which has long facilitated our understanding of the complex interactions that link our biologic systems to the contents of our minds and to the social environment in which we become unique individuals.

In the context of a well-constructed biopsychosocial formulation, it is relatively easy to understand cultural adscription and identity as a significant specifier of our social context. Enriched with the insights provided by cultural psychiatry, the biopsychosocial model can easily become a biopsycho-sociocultural model. The ultimate end of this process is the construction of a science of the person, culture being a very meaningful frame through which personhood emerges and expresses itself. The end result of acquiring relevant cultural knowledge will be, for the psychiatrist, an enhanced ability to provide culturally competent care, which is an increasingly common requirement of professional societies, regulatory agencies, and licensing and accrediting organizations.


Cultural Psychiatry

Before moving on to more clinical grounds, a few basic definitions are in order. Cultural psychiatry is defined as the discipline within psychiatry that studies the numerous interrelationships between culture and psychiatry. As such, it aims to understand variations of the incidence, prevalence, clinical expression, course, and/or outcome of common psychiatric disorders as they appear in different societies and ethnic or cultural groups. The value of such understanding includes the promotion of diagnostic and prognostic accuracy, the development of culturally syntonic interventions, and the achievement of a therapeutic partnership where the patient feels understood and supported. The American Psychiatric Association (APA) has recognized the importance of culture by addressing cultural variations in the text description of most of the major psychiatric disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),2 and by providing guidance to the development of cultural formulations.

A second aim of cultural psychiatry includes the careful description and tracking of patterns of symptoms and behaviors which, first, do not conform to the syndromes described so far in the DSM-IV-TR3 or the International Classification of Diseases, Tenth Edition (ICD-10),4 and second, are closely associated with certain cultural and/or ethnic groups including their belief systems and “idioms of distress.” These syndromes are commonly known as culture-specific or culture-bound syndromes and are recognized and listed in the DSM-IV.

A third aim of cultural psychiatry includes the elucidation and delineation of the pathways that transform culturally derived or mediated stresses into symptoms, syndromes, and adaptive or maladaptive behaviors. This is an area in need of much research if we are to understand basic clinical facts such as the gross variation in incidence and prevalence of major psychiatric disorders observed as a function of a given population ethnic origin, migratory status, and/or acculturation pressures.


Culture, Race, and Ethnicity

The diverse origin and confused utilization of these constructs have represented a significant obstacle to progress in the fields of cultural psychiatry and psychology.

Race typically denotes the description of individuals through compelling (but of questionable biologic significance) phenotypic features such as skin color, hair texture, and a few facial features. Some biomedical scientists have argued for the validity of such racial classifications to understand population’s variance in the prevalence of traits such as sickle cell anemia. However, even in such cases, the correlation between trait and race is far from perfect, since sickle cell anemia traits distribute not only among African blacks but also among other Mediterranean and Middle Eastern people. However limited the true biologic value of the construct of race, its social use has had (and unfortunately still has) devastating personal and group consequences through the attitudes and institutions of racism. The construct of ethnicity, a term much preferred by social scientists and anthropologists, may be of more value to psychiatrists since it denotes groups of individuals sharing a sense of common identity, a common ancestry, and shared beliefs and history. Thus, the construct ethnicity, a major contributor to the person’s cultural identity, is an internalized self-definition resulting for the person’s selective incorporation of values, beliefs, foundation myths, and customs from among those available in that person’s human ecology.

Such cultural identity holds great meaning to the person and needs to be ascertained in the clinical interview if the clinician is to develop a sound cultural formulation of their patient’s presenting complaints. Key dimensions of cultural identity include race, gender, language, sexual orientation, ethnic adscription, and religious and spiritual beliefs.

The term “culture” is as key a concept for psychiatry and psychology as it is difficult to define. As defined by the noted British anthropologist Sir Edward Tylor in 1871,5 culture is “the complex whole which includes knowledge, beliefs and morals and other capabilities and habits acquired by man as a member of society.”

For clinical purposes, the definition provided by the National Institute of Mental Health’s Culture and Diagnosis Group may be the most comprehensive and descriptive:


Culture refers to meanings, values and behavioral norms that are learned and transmitted in the dominant society and within its social groups. Culture powerfully influences cognition, feelings, and self-concept as well as the diagnostic process and treatment decisions.6

Culture is thus best conceptualized as a totality, composed of a complex system of symbols possessing subjective dimensions represented by values, feelings, and ideals, as well as objective dimensions expressed in the form of beliefs, traditions, and behavioral prescriptions, some of which may be articulated into rituals and codified as laws. This unique capacity of culture to bind the objective world of perceived reality to the subjective world of the personal and intimate lends it its powerful role as expressor, mediator, and moderator of psychological processes and, ultimately, emotional well being or disorder.


Through little known mechanisms, culture influences cognitions, feelings, emotional conflicts, self-concept, and the underlying brain functions that control mood and behavior. Culture also represents a normative framework that defines normality and deviance, thus promoting certain behaviors while suppressing others. This process may set the stage for psychological stress and intrapsychic conflict.

It is important to emphasize the great diversity and heterogeneity of each ethnic group. The labels African American, Asian, Hispanic, and Native American, among others, are super-ordinate constructs that hide more than reveal a tremendous diversity of racial features, historic legacies, belief systems, behavioral traits, and the like. As such, clinicians should use these generalized labels as a step in the road to understanding the unique individual that becomes their client. Beyond such provisional labels one must inquire the specific parameters of racial background, native language, religious coordinates, and socioeconomic conditions that define the specific and unique person.


Culture and Clinical Psychiatry

The relationship between culture and clinical psychiatry can certainly be studied through three vantage points. First, the presence of health disparities. Second, the clinical encounter across the language and cultural barrier. Last, the presence of culture-bound syndromes.


Health Disparities

Health disparities represent a clearly visible effect of cultural and linguistic minority status and are generally defined as population specific differences in domains of health such as incidence of illness, access to care, or outcomes of care.

In the US, health disparities are well documented in minority populations such as African Americans, Asians Americans, Native Americans, and Hispanics. Though much additional research is needed, health disparities can be causally related to barriers to prompt access to care of adequate quality; problems in providing such care across the language, culture, and health beliefs divide; and the compounding health effect of poverty and its attendant adverse environmental conditions.

The most common barriers to care affecting the presence of health disparities include lack of health insurance (or underinsurance), stigma, consumer’s unawareness of the availability or underappreciation of the efficacy of treatment, and health providers’ lack of awareness of the availability of culturally syntonic treatments.

The impact of the linguistic barriers in the clinical encounter needs to be highlighted. In so far as oral communication is the main vehicle for the transmission of mental health information, clinicians need to make significant efforts to compensate for its relative absence when examining and treating monolingual patients (or limited bilinguals) who speak a language different than their own. Language is the key for the patient’s symbolic universe; it determines which words access what emotions and, in bilinguals, which language serves to enhance communication and emotional contact with the therapist and which language can be used as a defense.

When compensating for a linguistic barrier through translation and interpretations, the clinician is best served by some skepticism. A clinician should ask a question several times and from different angles so that the composite picture has additional chances to approximate the clinical reality.

The Surgeon General Culture Race and Ethnicity supplement to the Mental Health Report7 highlights recognized minority health disparities. Tables 1–4 aggregate and summarize minorities’ clinical and health behavior observations for underrepresented groups in the US who experience documented health disparities.








Culture and Psychiatric Diagnosis

Cumulative cross-cultural research can help the clinician arrive at a comprehensive diagnosis of patients evaluated across the language and cultural barriers. Such patients could in theory present three different diagnostic pictures. First, the patient may suffer an episode of illness easily clarifiable as a typical DSM-IV-TR syndrome. Alternatively, the patient may present with a syndrome with specific cultural features which warrant special evaluative care. In this regard, the DSM-IV-TR  discusses cultural features for most major diagnoses. Last, the patient meets the description of one (or more) of the culture-bound syndromes reported in the literature, congruent with the patients’ culturally mediated idioms of distress.


Cultural Features of Major Psychiatric Diagnosis

The diagnosis of schizophrenia depends on the significant presence over a 1-month period of two out of five of the following symptoms: delusions, hallucinations, disorganized speech, disorganized behavior and negative symptoms, and social dysfunction. Social dysfunction is further defined as a significant erosion of work, interpersonal roles or self-care below the level of achievement prior to the onset of illness. All these criteria are subject to attained distortion through the cultural lens. In some cultures (eg, Mediterranean and Hispanic) visual or auditory hallucinations of religious objects, persons, or theme, may be a component of certain religious experiences or may appear as part of other disorders such as dissociative phenomena or psychomotor epilepsy. Some care should be exercised while diagnosing delusional ideas. The boundaries between ideas, overvalued ideas, beliefs, and delusions are also heavily mediated by culture, especially around issues such as demonic possession and paranormal influences (hexing, sorcery, witchcraft) in general.

The criterion “disorganized speech” is extremely difficult to assess in a monolingual patient by a clinician who is unfamiliar with the patient’s language. The articulation of language, sentence structure, and the logical order and focus of speech are also mediated by culture, educational level, and by perceived power differential between speakers.

The evaluation of affect (another key criterion for a schizophrenia diagnosis) is also complex, especially as it pertains to evaluating its congruence with mental content that is produced in a language that the clinician may not understand. Intensity and range of affect are also heavily mediated by culture and by the authority differentials in the therapeutic relationship. Finally, the evaluation of dysfunction has to be adjusted to the norm which constitutes the patient’s adaptive ecology, since “functioning” is heavily shaped by expectations derived from culture and dependent on socioeconomic status.

In the case of depression, culture can influence the prevalence rates, subjective experience of depression, and preferred channel for the expression of emotions. In some cultures (and socioeconomic conditions) depression may be communicated to the clinician in somatic terms such as fatigue, anergia, headaches, and malaise (“malestar” for some Hispanic populations). Symptoms such as sadness, guilt, and other psychological representations of the depressive experience may not be reported spontaneously during the clinical interview, and its elicitation may need a more active inquiry from the clinician than is the norm when interviewing patients from their own ethnic group.

The experience of anxiety may also be culturally mediated. As in the case of depression, the somatic expression (palpitations, tachycardia, fainting sensations) is emphasized in many cultures over the psychic content. The situational triggers for some episodes of anxiety, including panic, are also often culturally mediated. The fear of being “hexed” or subjected to witchcraft or other forces with malevolent intent may reach to panic proportions.


Culture-Bound Syndromes

In evaluating a patient to establish a differential diagnosis for a possible culture-bound syndrome, the clinician should consider the following. First, reflect on the cultural assumptions under which the Western biomedical model of diagnosis and treatment operates. After all, the constructs of illness defined in the DSM-IV-TR and ICD-10 classifications systems represent a uniquely western amalgam of objective knowledge and culturally mediated ideas, as derived from repeated medical observations on patients acculturated to the “Western” medical and social explanatory framework. A dose of cultural humility is the optimum result of such reflection.

Second, as psychiatric disorders, whatever their biologic determinants, usually find expressions through ideas, beliefs, and behavior, all societies have found ways to separate the normal from the abnormal. They all devise rules to attribute causality and motivation to such behaviors. Each culture (and person for that matter) creates an “explanatory framework” for such behaviors which must be teased out during the clinical encounter since it represents a rich lode for therapeutic intervention.

Third, be alert to the presence of symptoms such as unusual forms of anxiety, apathy, and significant withdrawal; sudden outbursts of angry and difficult to explain aggressive behavior; bizarre and unconventional motor behaviors (such as trance-like taking off of clothes, thrashing about, shouting swearing); prominent dissociation; sleep problems with parasomnias; and many others.

Last, ask patients (and their families and other culturally aware informants) about their own and their cultural group’s explanations for those symptoms and behaviors, and assess their “fit” with known culture-bound syndromes.

The APA’s glossary lists3 and describes succinctly some of the best studied culture-bound syndromes and idioms of distress that may be encountered in clinical practice in North America.

A dissociative episode characterized by a period of brooding followed by an outburst of violent, aggressive, or homicidal behavior directed at people and objects. The episode tends to be precipitated by a perceived slight or insult and seems to be prevalent among men. The episode is often accompanied by persecutory ideas, automatism, amnesia, exhaustion, and return to a premorbid state after the episode. Some instances of amok may occur during a brief psychotic episode or constitute the onset or exacerbation of a chronic psychotic process. Severe bereavement and serious interpersonal results have been noted as precipitants.

Ataque de Nervios
Ataque de nervios is an idiom of distress that is principally reported among Latinos from the Caribbean but recognized among many Latin American and Latin Mediterranean groups. Commonly reported symptoms include uncontrollable shouting, attacks of crying, trembling, heat in the chest rising into the head, and verbal or physical aggression. Dissociative experiences, seizure-like or fainting episodes, and suicidal gestures are prominent in some attacks but absent in others. A general feature of an ataque de nervios is a sense of being out of control. Ataques de nervios frequently occur as a direct result of a stressful event relating to the family (eg, news of the death of a close relative, a separation or divorce from a spouse, conflicts with a spouse or children, witnessing an accident).

Boufée Délirante
Boufée Délirante is a syndrome observed in West Africa and Haiti. This French term refers to a sudden outburst of agitated and aggressive behavior, marked confusion, and psychomotor excitement. It may sometimes be accompanied by visual and auditory hallucinations or paranoid ideation. These episodes may resemble an episode of brief psychotic disorder and need careful differential diagnosis.

Brain Fag
Brain fag is a term initially used in West Africa to refer to a condition experienced by high school or university students in response to the challenges of schooling. Symptoms include difficulties in concentrating, remembering, and thinking. Students often state that their brains are fatigued. Additional somatic symptoms are usually centered around the head and neck and include pain, pressure or tightness, blurring of vision, heat, or burning. Brain tiredness or fatigue from too much thinking is an idiom of distress in many cultures and resulting syndromes can resemble certain anxiety, depression, and somatoform disorders.

Dhat is a folk diagnostic term used in India to refer to severe anxiety and hypochrondriacal concerns associated with the discharge of semen, whitish discoloration of the urine, and feelings of weakness and exhaustion. It is similar to jiryan (India), sukra prameha (Sri Lanka) and shen-k’uei (China).

Falling Out or Blacking Out
Episodes of falling out or blacking out occur primarily in the southern US and in Caribbean groups. They are characterized by a sudden collapse, which sometimes occurs without warning but sometimes is preceded by feelings of dizziness. The individual’s eyes are usually open, but the person may claim an inability to see. The person usually hears and understands what is occurring around him or her but feels powerless to move. This may correspond to a diagnosis of conversion disorder or a dissociative disorder.

Ghost Sickness
A preoccupation with death and the deceased (sometimes associated with witchcraft) frequently observed among members of many American Indian tribes. Various symptoms can be attributed to ghost sickness, including bad dreams, weakness, feelings of danger, loss of appetite, fainting, dizziness, fear, anxiety, hallucinations, loss of consciousness, confusion, feelings of futility, and a sense of suffocation.

Hwa-byung (also known as Wool-Hwa-Byung) is a Korean folk syndrome that is literally translated into English as anger syndrome and is attributed to the suppression of anger. The symptoms include insomnia, fatigue, panic, fear of impending death, dysphoric affect, indigestion, anorexia, dyspnea, palpitations, generalized aches and pains, and a feeling of a mass in the epigastrium.

Koro is a term, probably of Malaysian origin, that refers to an episode of sudden and intense anxiety that the penis (or, in women, the vulva and nipples) will recede into the body and possibly cause death. The syndrome is reported in south and East Asia, where it is known by a variety of local terms such as shook yong and suo yang (Chinese), jinjinia bemar (Assam), or rok-joo (Thailand). It is occasionally found in the West. Koro at times occurs in localized epidemic form in east Asian areas. This diagnosis is included in the Chinese Classification of Mental Disorders, Third Edition (CCMD-3).8 Subjective ideas of genital change may be more common in the general population and among other psychiatric disorders than generally realized.

The fact that genital retraction symptomatology has been reported in association with stimulant abuse (amphetamines) and heroin withdrawal, as well as in the context of epileptic confusional states, cerebral syphilis, brain tumors, and other alterations of brain physiology, should prompt physicians confronted with a complaint of genital retraction to carefully rule out the presence of organic pathology.

Latah is hypersensitivity to sudden fright, often with echopraxia, echolalia, command obedience, and dissociative or trance-like behavior. The term latah is of Malaysian or Indonesian origin, but the syndrome has been found in many parts of the world. Other terms for this condition are amurakh, irkunii, ikota, olan, myriachit, and menkeiti (Siberian groups); bah tschi, bahtsi, and baah-fi (Thailand); imu (Ainu, Sakhalin, Japan); and mali-mali and silok (Philippines). In Malaysia, it is more frequent in middle-aged women.

Locura is a term used by Latinos in the US and Latin America to refer to a severe form of chronic psychosis. The condition is attributed to an inherited vulnerability, the effect of multiple life difficulties, or a combination of both factors. Symptoms exhibited by people with locura include incoherence, agitation, auditory and visual hallucinations, inability to follow rules of social interaction, unpredictability, and possible violence.

Mal de Ojo
Mal de ojo is a concept widely found in Mediterranean cultures and elsewhere in the world. Mal de ojo is a Spanish phrase translated into English as evil eye. Children are especially at risk. Symptoms include fitful sleep, crying without apparent cause, diarrhea, vomiting, and fever in a child or infant. Sometimes adults (especially women) have the condition.

Nervios if a common idiom of distress among Latinos in the US and Latin America. A number of other ethnic groups have related, although often somewhat distinctive, ideas of nerves (such as nervra among Greeks in North America). Nervios refers to a general state of vulnerability to stressful life experiences and to a syndrome brought on by difficult life circumstances. The term nervios includes a wide range of symptoms of emotional distress, somatic disturbance, and inability to function. Common symptoms include headaches and brain aches, irritability, stomach disturbances, sleep difficulties, nervousness, easy tearfulness, inability to concentrate, trembling, tingling sensations, and mareos (dizziness with occasional vertigo-like exacerbation). Nervios tends to be an ongoing problem, although variable in the degree of disability manifested. Nervios is a broad syndrome that spans the range from cases free of a mental disorder to presentations resembling adjustment, anxiety, depressive, dissociative, somatoform, or psychotic disorders. Differential diagnosis depends on the constellation of symptoms experienced, the kind of social events that are associated with the onset and progress of nervios, and the level of disability experienced.

Pibloktoq is an abrupt dissociative episode accompanied by extreme excitement of as long as 30 minutes’ duration and frequently followed by convulsive seizures and coma lasting as long as 12 hours. This is observed primarily in arctic and subarctic Eskimo communities, although regional variations in name exist. The individual may be withdrawn or mildly irritable for a period of hours or days before the attack and typically reports complete amnesia for the attack. During the attack, the individual may tear off his or her clothing, break furniture, shout obscenities, eat feces, flee from protective shelters, or perform other irrational or dangerous acts.

Qi-Gong Psychotic Reaction
Qi-Gong is a term describing an acute, time-limited episode characterized by dissociative, paranoid, or other psychotic or nonpsychotic symptoms that may occur after participation in the Chinese folk health-enhancing practice of qi-gong (meaning exercise of vital energy).

Rootwork is a set of cultural interpretations that ascribe illness to hexing, witchcraft, sorcery, or the evil influence of another person. Symptoms may include generalized anxiety and gastrointestinal complaints (eg, nausea, vomiting, diarrhea), weakness, dizziness, the fear of being poisoned, and, sometimes, the fear of being killed (voodoo death). Roots, spells, or hexes can be put or placed on other people, causing a variety of emotional and psychological problems. The hexed person may even fear death until the root has been taken off (eliminated), usually through the work of a root doctor (a healer in this tradition), who can be called on to bewitch an enemy. Rootwork is found in the southern US among African American and European American populations and in Caribbean societies. It is also known as mal puesto or brujeria in Latino societies.

Sangue Dormido (Sleeping Blood)
Sangue dormido is found among Portuguese Cape Verde Islanders (and immigrants from there to the US) and includes pain, numbness, tremor, paralysis, convulsions, stroke, blindness, heart attack, infection, and miscarriage.

Shenjing Shuairuo (Neurasthenia)
In China, shenjing shuairuo is a condition characterized by physical and mental fatigue, dizziness, headaches, other pains, concentration difficulties, sleep disturbance, and memory loss. Other symptoms include gastrointestinal problems, sexual dysfunction, irritability, excitability, and various signs suggesting disturbance of the autonomic nervous system. In many cases, the symptoms would meet the criteria for a DSM-IV-TR mood or anxiety disorder. This diagnosis is included in the CCMD-3.

Shen-K’uei (Taiwan); Shenkiu (China)
Shen-k’uei or shenkui is a Chinese folk label describing marked anxiety or panic symptoms with accompanying complaints for which no physical cause can be demonstrated. Symptoms include dizziness, backache, fatigability, general weakness, insomnia, frequent dreams, and complaints of sexual dysfunction (such as premature ejaculation and impotence). Symptoms are attributed to excessive, or passing of white, turbid urine believed to contain semen. Excessive semen loss is feared because of the belief that it represents the loss of one’s vital essence and can thereby be life threatening.

Shin-byung is a Korean folk label for a syndrome in which initial phrases are characterized by anxiety and somatic complaints (general weakness, dizziness, fear, anorexia, insomnia, and gastrointestinal problems), with subsequent dissociation and possession by ancestral spirits.

A spell is a trance state in which individuals communicate with deceased relatives or with spirits. At times, this state is associated with brief periods of personality change. This culture-specific syndrome is seen among African Americans and European Americans from the southern US. Spells are considered to be medical events in the folk tradition but may be misconstrued as psychotic episodes in clinical settings.

Susto (Fright or Soul Loss)
Susto is a folk illness prevalent among some Latinos in the US and among people in Mexico, Central America, and South America. Susto is also referred to as espanto, pasmo, tripo ida, perdida del alma, or chibih. Susto is an illness attributed to the experience of a frightening event that causes the soul to leave the body and results in unhappiness and sickness. Individuals with susto also experience significant strains in key social roles. Symptoms may appear any time from days to years after the fright is experienced. It is believed that, in extreme cases, susto may result in death. Typical symptoms include appetite disturbances, inadequate or excessive sleep, troubled sleep or dreams, a feeling of sadness, lack of motivation to do anything, and feelings of low self-worth or dirtiness. Somatic symptoms accompanying susto include muscle aches and pains, headache, stomachache, and diarrhea. Ritual healings are focused on calling the soul back to the body and cleansing the person to restore bodily and spiritual balance. Different experiences of susto may be related to major depressive disorder, posttraumatic stress disorder, and somatoform disorders. Similar etiologic beliefs and symptom configurations are found in many parts of the world.

Taijin Kyofusho
Taijin Kyofusho is a culturally distinctive phobia in Japan, in some ways resembling social phobia in the DSM-IV-TR. This syndrome refers to an individual’s intense fear that his or her body, its parts, or its functions displease, embarrass, or are offensive to other people in appearance, odor, facial expressions, or movements. This syndrome is included in the official Japanese diagnostic system for mental disorders.

Zar is a general term applied in Ethiopia, Somalia, Egypt, Sudan, Iran, and other North African and Middle Eastern societies to the experience of spirits possessing an individual. People possessed by a spirit may experience dissociative episodes that may include shouting, laughing, hitting the head against a wall, singing, or weeping. Individuals may show apathy and withdrawal, refusing to eat or to carry out daily tasks, or may develop a long-term relationship with the possessing spirit. Such behavior is not considered pathological locally.


The Clinical Encounter Across the Language and Cultural Barrier

Key tasks of the psychiatric clinical encounter, such as an accurate diagnostic assessment and the mobilization of rapport along the axis of understanding (for the clinician) and feeling understood (for the patient), may be seriously compromised when the clinical encounter occurs across the language and cultural barriers. The following case vignette illustrates some of these difficulties:

Several years ago I was called to provide a cultural consultation on a patient (Helen) recently admitted to an inner-city inpatient hospital unit with the diagnosis of schizophrenia. The physician in charge of Helen’s care, a non-Hispanic psychiatrist, requested a cultural consultation to facilitate making a decision on a discharge disposition for Helen. He asked me whether this patient should be transferred for long-term care to a state-supported psychiatric hospital, or else discharged to a community based intensive rehabilitation facility. His working diagnosis for Helen was schizophrenia, chronic undifferentiated type, and his prognosis for a socially functional recovery was, at best, guarded.

My first impression as the patient walked into the consultation room supported the physician’s diagnosis. The patient displayed many of the stigmata seen in the later phases of illness in patients suffering from chronic schizophrenia, including a somewhat disheveled appearance, expressionless facial features, a slow somewhat shifting gait, and a relative indifference to her surroundings. As the interview proceeded in perfectly coherent Spanish, the patient gave the following account of her problems. With no prior psychiatric history, she started to develop symptoms shortly after the death of her only son, a 21-year-old substance abuser fatally shot in the aftermath in a narcotic dealer’s power and turf struggle. The patient reacted to her son’s death with intense and prolonged grief which lasted many months. At times, during that grief process, she heard the voice of her son beckoning her to join him in the afterlife. Additionally, having lost her son—her only close bridge to the English-speaking community—Helen became increasingly isolated, prompting the concern of some of her few relatives and friends. One of her nieces finally took Helen to the emergency room for evaluation as she was worried about Helen’s increasing isolation and a potential for suicide should Helen act out her expressed wish to join her son and obtain some “rest.”

Upon arrival to the emergency room, the report of the clinician in charge of her care highlighted in his notes the presence of “auditory hallucinations, possibly delusional, exhibits flat affect.”

Since the patient’s command of English was extremely limited, the physician focused his intake efforts on eliciting the basic set of signs and symptoms which would allow him to establish a working diagnosis and to evaluate clinical risks. While the patient was held in the emergency room, the patient’s increasing desperation was interpreted as “agitation” and the patient received several doses of haloperidol. Upon admission to the ward, the patient—partly in fear of a process that she could not understand, and partly due to the extrapyramidal side effect of the haloperidol—exhibited extremely passive and avoidant behavior, comparable to the stance often seen in cases of severe chronic mental illness.

The case of Helen illuminates some of the difficulties of arriving at an accurate diagnosis when evaluating and treating a patient across the language and cultural barrier. The psychiatric consultant, who first evaluated the patient upon arrival to the emergency room, evidently interpreted her anguished, anxious pacing and rapid “unintelligible” speech in a language which he could not understand, as a sign of psychiatric agitation. The history of “withdrawal” from social interaction supplied by the ambulance attendant was assessed as evidence of schizoid/schizophrenic isolation. The presence of “auditory hallucinations,” the content/type of which could not be fully ascertained because of the clinician’s lack of knowledge of the patient’s Spanish language, added a key step toward a possible diagnosis of schizophrenia.  The patient received several doses of haloperidol a few hours after presenting to the emergency room. In a brief mental status examination shortly afterward, her affect was described as flat, thus locking in the admission diagnosis of schizophrenia. As will be discussed later, the evaluation of key mental health status items, such as affect, thought process, speech, and hallucinations and delusions, are especially sensitive to culture and learning, and thus very vulnerable to distortions when evaluating a patient through the language and cultural barrier.


The Diagnostic Assessment Examination

The diagnostic assessment of patients across the language barrier is full of opportunities for misunderstanding, over- and underestimation of psychopathology, and consequent misdiagnosis. Marcos and colleagues9 found that schizophrenic patients of Hispanic origin exhibited higher rates of psychopathology in interviews conducted in English than in interviews held in their native Spanish.

Beyond the language barrier, specific group stressors suffered by certain minority groups may add additional confusion. For example, cross-cultural clinicians working with refugees warn the culturally naïve evaluator not to mislabel as Axis I psychopathology the sometimes vivid and highly emotional narratives of Southeast Asian and other refugees describing having witnessed or suffered terrible atrocities in their countries of origin or in the process of immigration. Fortunately, clinicians practicing today across language and cultural barriers have access to the findings of numerous studies that provide guidance for accurate evaluation and diagnosis and will allow them to correct many distortions and provide culturally syntonic care.10


Mental Status Examination

The mental status examination, the key component of a psychiatric diagnostic interview, is subject to many distortions when conducted across a language and cultural barrier. The central process of the mental status examination requires observation and interpretation of the patient’s appearance, behavior, language, and mental activity, both spontaneous and as elicited by the clinician’s questions. In interpreting the patient’s appearance, behavior, language, and thought content, the clinician must guard against what has been called “the category fallacy,” which is the effort to fit all conditions, whatever their cultural context, into the Western diagnostic framework, without regard to validating that diagnostic framework in the local culture. Patient responses to specific mental status items are affected by the patient’s culture of origin, educational level, literacy, language proficiency, and level of acculturation. Investigators consider the following items of the mental status examination to be more sensitive to cross-cultural misinterpretation.

Appearance and Behavior
The mental status sections of psychiatric case reports when describing patient’s appearance and behavior are often replete with such expressions as “normal,” “attractive,” and “appropriate” and other terms subject to significant cultural variation. Appearance and behavior must be carefully evaluated by the clinician, with the patient’s own development and culturally determined normative framework as a referent.

Relationship to the Evaluator
The assessment of a patient’s attitude and relationship to the clinician, who is performing a psychiatric evaluation, is affected by many psychosocial variables, including whether the interview is voluntary and the relative emergency of the clinical situation. Key factors of such as assessment (eg, maintenance or avoidance of eye contact, personal deference, reserve, physical proximity, physical contact) are subject to cultural prescriptions that the clinician should strive to decode.

Motor Behavior
The assessment of motor activity is considered a fundamental part of the mental status assessment. Motor activity while producing speech is an activity which is also culturally mediated. In a prior publication, Marcos and Trujillo11 noted that patients who communicate in a nondominant language may use extra nonverbal activity to facilitate verbalization across the language barrier. This extra activity needs to be carefully evaluated, lest those which are used to facilitate verbalizations be attributed to tension, hyperactivity, or other forms of motor psychopathology.

Speech and Thought

Patients communicating in a language over which they have a poor command often exhibit a high frequency of speech disturbances such as omissions, sentence incompleteness, and long pauses. These must be carefully distinguished from the impact of anxiety, depression, or emotional withdrawal.

In evaluating the range, responsiveness, and quality of a patient’s affect, clinicians working across the language barrier must recognize that both the spontaneous and the elicited expressions of affect are deeply patterned by cultural norms and expectations. Culturally sanctioned impassiveness should not be misinterpreted as poverty of affect any more than the ebullience often attributed to people of Mediterranean origin should be evaluated as excessively intense affect. Clinicians need to be equally sensitive to the significance of linguistic factors that may cloud the interpretation of affect.

When a mental status evaluation is performed across language and cultural barriers, certain linguistic problems may be misinterpreted as surplus psychopathology, and clinicians should guard against this error by repeating key questions, introducing redundancies to facilitate communication, and identifying paralinguistic cues that may cloud their evaluation of mood and expression. When in doubt they should use trained translators, cultural consultants, or structured, validated interviews as aids in the diagnostic process.


Cultural Formulation

The incorporation of cultural content into the DSM-IV represents a major achievement as it may encourage clinical practices that will result in improving the diagnosis and treatment of minority patients. Additionally the clinical cultural knowledge accrued may increase our knowledge of models of psychopathology. Clinicians using the framework proposed in the DSM-IV have three options to improve the diagnostic process when working with patients belonging to a culture different than their own. First, the clinician is invited to consider cultural variations and specifiers as they apply to almost 100 diagnostic categories. Second, the clinician is presented with a guideline to the completion of a cultural formulation which encourages the systematic exploration of the patient’s cultural identity, the perceived causes or explanatory models used by the patient and his or her reference group, and the cultural factors that shape the therapeutic relationship. Third, clinicians are offered a glossary of culture-bound syndromes which may be used to perform a differential diagnosis or to complement, in some cases, the diagnoses made possible by the DSM-IV.

The development of a cultural formulation is probably the jewel in the crown of cultural offerings of the DSM-IV. Just like the psychodynamic formulation is central to the therapeutic process of psychodynamic psychotherapy, the cultural formulation can inform and enrich the clinician’s view of the patient’s problems and guide their treatment.

As described in the DSM-IV-TR, the suggested outline for a cultural formulation contains elements  found in Table 5.




Cultural Identity

The DSM-IV recommends that in assessing an individual’s cultural identity, the clinician should “note the individual’s ethnic or cultural reference group. For immigrants and ethnic minorities, they should assess the degree of involvement with both culture of origin and host culture.”12

To these factors one must add migration history, which is commonly left out of the clinical evaluation of cross-cultural patients. Culturally uninformed clinicians often treat their immigrant patients as if their lives began when they arrived in the US, and their clinical narratives often lack key data from the patients’ preimmigration experience. Careful attention must be paid to the traumas and losses encountered by refugees in their country of origin, often including exposure (as witness or victims) to physical or emotional torture, or both. The process of acculturation is once again key to understanding the psychological distress and psychopathology of immigrants. Rogler13 has identified three major sources of stress in the migration experience. First, insertion into the host society, frequently at lower occupational and social levels. Second, disruption of primary interpersonal networks. Last,  the stress-inducing acculturation process. The clinician can assess the degree of acculturation and the nature of the acculturation process through many indirect means. Age at immigration, number of years in the US, occupational status, language proficiency, and participation in the host culture social networks, give the clinician some idea of the rate and ease of acculturation for a given patient.

Families can also be classified by degree of acculturation. From this perspective immigrant families may be described along a continuum of acculturation as traditional, transitional bicultural, and Americanized. Each of these family structures presents different assets and vulnerabilities in relation to the immigrant experience.

Clinicians need to understand that cultural identity is a very fluid and dynamic construct. Each person develops their own sense of identity by selecting from a rich tapestry of belief systems and behavioral models available in the context of their native and adoptive cultures. As such, any label including Hispanic, African American, and the like, should only support additional lines of inquiry to understand the nuances of the cultural identity of their patients. Beyond these differences, additional refinements and complexities are added as generations of immigrants develop. The loyalties and cultural conflicts of the original immigrant are not the same as those of the first or second generations of their successors.


Overall Cultural Assessment

The cultural formulation must be focused on providing a culturally informed explanation for the patient’s actual symptoms and dysfunctions. By thus anchoring the formulation on clinical facts, the clinician ensures its relevance to the patient’s presenting problems and to the process of care. Here, experience will teach the clinician to select succinct and potent explanations while separating what is clinically meaningful from the many interesting but not clinically relevant cultural facts which could easily be collected in any clinical encounter. The place for such synthesis is the last item of the cultural formulation guide, ie, overall cultural diagnosis.



Much knowledge has accrued about the applications of standard, psychoanalytically based, psychotherapy to populations and ethnic backgrounds other than Caucasians of Western origin. To the repeated observation that ethnic communities are accepted for psychotherapy treatment at lower rates and drop out earlier than their mainstream counterparts, researchers and clinicians have provided a bounty of adaptations ranging from preparations for psychotherapy to substantive framework modifications. The most daring step in this continuum is the development of culture-specific therapies empirically derived from culture-specific behavioral features. Szapocznick and colleagues,14 for example, developed and proposed a model of family therapy for Miami, Florida’s Cuban families guided by empirically derived values prevalent in that population, such as strong familial affliction and preference for hierarchical family structures.

Other therapies such as cognitive and cognitive-behavioral therapies may achieve some modicum of freedom from cultural bias, to the degree that cognitive therapists work with the specific pathogenic beliefs of the patient, whatever the cultural origin of such beliefs. Its application to minority populations suffering from anxiety and depressive disorders may be an area of promising cross-cultural research.

Just like in the practice of psychiatry with any population, the optimum approach to treatment includes the selection of interventions based on evidence. Tables 6 and 715 illustrate how the evidence (still scarce but growing) accumulated regarding the mental health of minorities can be used productively by clinicians, and systems of care, to craft relevant interventions.




All these therapeutic strategies need to be mediated by the ongoing assessment of the patient’s language competence, acculturation status, and voiced personal preference.


Ethnic Psychopharmacology

The treatment of psychiatric disorders with psychotropic medications has been one of the great success stories of biomedicine particularly in the second part of the 20th century. However, since most currently used psychotropic agents were developed and tested in Western populations, there is little knowledge of the effects of psychotropics across different ethnic groups to guide clinical practice. Thus, cross-cultural psychopharmacology is a relatively young field. Clinicians prescribing medications to patients belonging to different ethnic groups need to consider the following factors when deciding to prescribe psychotropics to their patients.

First, cultural factors include mediating beliefs and expectations about both the therapeutic and adverse effects of medications. Included here are religious beliefs and taboos that may affect parameters such as the timing of medication intake, acceptability of utilizing certain medications, duration of the episode of treatment, and other factors. In many cultures, the patient’s family may play a role in making medical decisions for the patient and should be involved in psychoeducation efforts.

Second, certain environmental factors that, when maintained over long periods, may lead to adaptations of metabolism and promote a differential response to treatment. Factors such as the use of tobacco, caffeine, preferred foods and food additives, over-the-counter medications, and herbal medicines are ethnically mediated and may affect the effectiveness and safety of psychotropic medications. For example, by promoting the induction of key hepatic enzymes, alcohol may lower the effective level of medications.

Third, biologic factors should be considered. Ethnicity is known to affect the bioavailability and effect of medications through three broad biologic mechanism; namely, pharmacokinetics, pharmacodynamics, and pharmacogenetics.

Potential ethnically mediated cytochrome P450 (CYP) variability should be specially noted. Pharmacokinetics studies the absorption, distribution, metabolism, and excretion of drugs in the human body. CYP plays a key role in the metabolism of psychotropics (and many other endogenous and exogenous chemical compounds) and is subject to genetically mediated variation in activity. Such genetic variation in activity permits the allocation of individuals to any of three groups; these include poor metabolizers, who have reduced (or non-existent) enzyme activity and metabolize certain drugs slowly achieving higher blood levels with equal doses; extensive metabolizers, who have normal amounts and normal enzymatic activity; and intermediate metabolizers, who have intermediate enzymatic activity. The percentages of poor and extensive metabolizers vary in different ethnic populations as reflected in Table 8.16



A fourth category, ultra-rapid metabolizers, have enhanced enzymatic activity and metabolize the drug rapidly, requiring higher dose to sustain therapeutic efficacy. Certain populations (Arabs and Ethiopians) have high prevalence of CYP 2D6 ultra-rapid metabolizers (20% to 30% versus 1% to 5% among Caucasians).

In addition to these activity differences, clinicians need to take into account the fact that many psychotropics act themselves as inhibitors (or inducers) of the isoenzymes. The selective serotonin reuptake inhibitors (SSRIs), for example, inhibit the activity of CYP 2D6 and CYP 2C19, which may affect the therapeutic availability of the SSRI itself and/or co-administered medications. Inducers increase the synthesis of CYP enzymes and reduce the serum level of affected medications. The most common psychotropics which act as inducers are carbamazepine and other anticonvulsants, which increase the synthesis of CYP 3A4 and may reduce the bioavailability of other CYP 3A4 substrates such as benzodiazepines.

The same is true of herbs and dietary products. Chinese herbs such as ginseng and glycyrrhiza promote induction of CYP enzymes. Table 9 summarizes observed clinical effects in the administration of medications that maybe related to differences in CYP enzymatic activity. Table 10 summarizes existing knowledge regarding the effect, in different ethnic populations, of widely used psychotropics.



As ethnic psychopharmacology continues to make advances in the understanding of pharmacogenetics, pharmacodynamics, and pharmacokinetics, clinicians working with ethnically diverse populations should review the following factors while considering prescribing psychotropics.

Cultural Factors
First, clinicians should review patient (and family) history of use of psychotropic and other medications. Second, one should inquire about expectations of clinical effect and rate of recovery and about tolerance to known side effects. Third, the clinician should assess readiness for maintenance treatment when indicated. Fourth, the clinician should inquire about cultural or religious restrictions or the use of certain medications.

Environmental Factors
Clinicians should review the use of tobacco, alcohol, caffeine, over-the-counter medications, folk herbs, and other remedies.

Biologic Factors
If clinically possible, the clinician should start low and go slow. The clinician should assess family history (if available) of response and side-effects development. In the presence of non-response, psychotropic blood level should be evaluated and other CYP interactions should be considered. The clinician should evaluate for metabolic efficiency status (poor metabolizers, ultra-rapid metabolizers).


Cultural Competence

Though there are many definitions of cultural competence, the transformative work of Cross and colleagues17 offered an initial proposal-defining cultural competence as a set of behaviors, attitudes, and policies that come together in a system of care and among their clinicians as well as enable them to work efficiently in cross-cultural situations.

For the Office of Minority Health of the US Department of Health and Human Services, cultural competence involves having the capacity to function effectively as an individual and an organization within the context of the cultural beliefs, behaviors, and needs presented by consumers and their communities.

Cultural competence cannot be thought of as binary present or absent condition. It is best conceptualized as a continuum of beliefs, attitudes, skills and practices that start (at the low point) at a culturally blind position and end (at the high point) in a position that holds the belief that culture makes a difference, cultivates an open attitude to incorporate cultural knowledge, and develops skills in culturally syntonic diagnosis and treatment (Table 11).18




Cultural Consultation

Many approaches have been used to enhance the cultural responsiveness of psychiatric services working with multicultural populations. The scarcity of clinicians and researchers from minority populations limits the development of ethnographic mental health services or clinics in sufficient volume to reach large numbers of minority patients. The services of trained mental health interpreters and translators are very valuable but their engagement in the ongoing process of care is, by necessity, limited. To deal with these limitations Kirmayer and colleagues19 have proposed and evaluated a model of cultural consultation based on the principles and processes utilized in general psychiatry by the sub-specialty of consultation liaison. The cases seen by Kirmayer and colleagues19 broadly demonstrated the impact of cultural misunderstanding in the process of care. Issues such as incomplete assessments, incorrect diagnosis and treatments, and undeveloped treatment alliances were identified and, when possible, corrected by the team carrying through the consultation.



As ongoing migrations enhanced by the forces of globalization continues, clinicians practicing psychiatry in most areas of the US and especially in urban centers can expect rising numbers of minority patients seeking their help. Additionally, policy makers and regulators are responding to the Surgeon General’s call to address the health and mental health adverse disparities found among minority populations by developing requirements for the assessment of non-English-speaking patients and standards for cultural competence. On the bright side, much clinical and health services research has accumulated evidence to support the provision of culturally competent mental health services.

Such research has illuminated differences in onset, prevalence, course, and outcome among different ethnic groups, and has alerted clinicians to the presence of systematic diagnostic distortions that may occur when evaluating patients belonging to different ethnicities.

Fortunately, these findings also teach clinicians methods to be alert to, and to compensate for, such possible distortions. Paying special attention to certain elements of the mental status examination can enhance the diagnostic accuracy by correcting potential distortions in evaluating items such as appearance and behavior, speech and language, and affect and mood. Knowledge of the patient’s original ethnic group’s normal “idioms of distress” can also help the clinician to accurately evaluate the patient’s culturally expressed presenting complaint.

When it comes to treatment, an emerging body of knowledge will also help the clinician establish a therapeutic alliance inclusive of the patient’s culturally mediated explanations of their own illness, and will facilitate an accurate assessment of the meaning and severity of symptoms in relation to the patient’s cultural norms. Finally, the clinical evidence accumulated by the discipline of ethnopharmacology can also guide the clinician’s interventions when they decide to provide psychotropics to treat their patient’s disorders. PP



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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.


This issue of  Primary Psychiatry covers a broad range of topics. Anton A. Subuh Surja, MD, and colleagues address the prevalent stigmatization of depressed people who also abuse alcohol. They note that depression comorbid with alcohol abuse is common. As a consequence of this stigma, these dual-diagnoses patients receive inadequate assessment and treatment, which in turn compromises prognosis and leads to relapse. The authors note that alcohol and other substance abusers tend to engender negative feelings from healthcare professionals. Underlying mood disorders, if undiagnosed and unmanaged, can result in suicide. Thus, there is a need to teach better attitudes that improve outcomes and foster professionalism. Among many points made in the article, the authors note that when depression and its associated symptoms are present, treatment of depression is mandatory. Patients may require altered doses of psychotropic medication since alcohol induces hepatic enzymes and can result in liver dysfunction. Interventions for social, occupational, or legal disruptions may be needed. Substance abuse therapies must always be made available.

Ian A. Cook, MD, describes how “advances in understanding the machinery of the brain and how it is altered in disorders of the mind” may soon lead to the identification of clinical biomarkers that can be used to make a diagnosis and predict prognosis or response to treatment. He provides illustrative examples drawn from studies of physiologic measures in mood disorders, and reviews pragmatic aspects of evaluating biomarker technologies that may lead to the development and possible adoption of these techniques.


Surprisingly, according to Leslie S. Zun, MD, MBA, and LaVonne Downey, PhD, there is no agreed upon medical clearance process for patients who present to an emergency department with psychiatric patients. They note that there is often a difference of opinion regarding the need for testing these psychiatric patients. The authors describe and present the results of a study designed to validate a protocol for the medical clearance of patients with behavioral complaints. A checklist based on the protocol for patients presenting with psychiatric complaints was applied to a prospective 401 patients who met criteria. The study found the protocol for medical clearance of psychiatric patients to be valid as compared to the usual medical clearance evaluation performed in the emergency department.


Also in this issue is the second of a two-part adaptation of a reference guide by Jeffrey L. Cummings, MD, focusing on the treatment of Alzheimer’s disease and other dementias. Included in this month’s educational review is the expansion of diagnostic approaches to include more mild syndromes, such as mild cognitive impairment, as information is needed to manage patients using the latest advances. The presentations and discussions in these articles are deliberately concise and full of tables that should facilitate diagnostic and treatment decisions.


Also included in this issue is a Letter to the Editor from Robert Kauffman, MD, who addresses one of my recent editorials,1 and calls attention to recent peer-reviewed literature—three separate case reports of sustained persistence of sexual dysfunction and genital anesthesia after discontinuation of selective serotonin reuptake inhibitor (SSRI) treatment. He also references a Website2 of former SSRI users who have experienced this previously unrecognized adverse event. Dr. Kauffman describes a woman with persistent post-treatment orgasmic dysfunction and diminished genital sensation following sertraline administration and suggests that efforts be made to prevent long-term impairment of sexual functioning. PP






1.    Sussman N. Side effects of psychotropic medications: importance of postmarketing surveillance. Primary Psychiatry. 2007;14(9):14-15.
2.    Yahoo Health Groups. SSRIsex · Persistent SSRI sexual side effects. Available at: Accessed February 18, 2008.


Dr. Cummings is the Augustus S. Rose Professor of Neurology, professor of psychiatry and biobehavioral sciences, director of the Mary S. Easton Center for Alzheimer Research at the University of California, Los Angeles (UCLA), and director of the Deane F. Johnson Center for Neurotherapeutics at the David Geffen School of Medicine at UCLA.

Disclosures: Dr. Cummings has served as a consultant for Acadia, Adamas, Astellas, Avanir, CoMentis, Eisai, EnVivo, Forest, Janssen, Lundbeck, Medivation, Merck, Merz, Myriad, Neurochem, Novartis, Ono, Pfizer, Prana, Sanofi-Aventis and Takeda. Dr. Cummings owns the copyright of the Neuropsychiatric Inventory. Dr. Cummings has been supported by a National Institute on Aging Alzheimer Disease Center grant (P50 AG 10157), an Alzheimer’s Disease Research Center of California grant, the Sidell-Kagan Foundation, and the August Rose Chair of the University of California.

Acknowledgments: Dr. Cummings thanks his colleagues at the UCLA Alzheimer Disease Center and the patients and caregivers who have given meaning to his commitment to find more effective treatments for Alzheimer’s Disease. He also thanks his wife Kate (Xue) Cummings (Zhong) without whose enthusiasm, love, and support this project would have been impossible.

Please direct all correspondence to: Please direct all correspondence to: Jeffrey L. Cummings, MD, Alzheimer Disease Center, 10911 Weybrun Ave, #200, Los Angeles, CA 90095-7226; Tel: 310-794-3665; Fax: 310-794-3148; E-mail:


Focus Points

• Alzheimer’s disease is the most common cause of dementia in the elderly.
• Clinical features and diagnostic criteria help identify dementia and related syndromes.
• Antidementia therapies, management of behavioral symptoms, and family counseling assist in the treatment of dementia and related syndromes.



This educational review is the second of a two-part adaptation of an ultra-quick reference guide useful in the diagnosis and treatment of Alzheimer’s disease and other dementias (The Black Book of Alzheimer’s Disease. J.L. Cummings, MD, 2008, publication pending). The classification of dementia, the expansion of diagnostic approaches to include more mild syndromes such as mild cognitive impairment (MCI), and the rapid evolution of new therapies make it difficult to remain informed about all critical progress relevant to Alzheimer’s disease and related conditions. These two articles provide information needed to manage patients using contemporary advances in diagnosis and management. They will be updated annually in the form of a Black Book to ensure that the information remains current.

This educational review is not intended as a comprehensive reference. It provides critical information only. The first part provided references and Websites where more information can be found on each topic presented. This second part emphasizes criteria-based diagnosis and optimizing pharmacotherapy. The set of diagnostic criteria provided in this educational review is among the most comprehensive available. However, the presentations and discussions have been kept deliberately short, as the purpose is not to serve as a comprehensive review but to provide information critical to patient care embedded in enough context to make management decisions coherent and logical.

Alzheimer’s disease research is forging ahead rapidly toward new therapies and the possibility of disease-modifying interventions. The context of these therapies is provided in the pathophysiology section of the text and the forward-looking therapies are introduced in the antidementia therapy section.


Clinical Features and Diagnostic Criteria for Dementias and Related Syndromes

Differential Diagnosis of Cognitive Impairment

The differential diagnosis of cognitive impairment include depression, delirium, MCI, and a variety of common and uncommon dementia syndromes (Figures 1–3).1,2 Distinctive mental status, neuropsychiatric, neurologic, and imaging manifestations assist in differential diagnosis. Data are collected to determine if patients meet diagnostic criteria for specific neurologic disorders. Research diagnostic criteria are provided here to assist the clinician in diagnosis and differential diagnosis.

Mild Cognitive Impairment

MCI refers to patients who have cognitive impairment greater than age- and education-matched healthy elderly but do not meet diagnostic criteria for Alzheimer’s disease or any dementia. The patient or family member is aware of cognitive decline, the patient does not have impaired activities of daily living, and the patient does not meet criteria for dementia. Most patients with MCI progress to a dementia syndrome within 3 years; however, some remain with MCI for long periods of time and some recover. The amnestic form of MCI (disproportionate memory impairment) is often the prodrome of dementia of the Alzheimer type. Patients with amnestic MCI progress to diagnosable dementia of the Alzheimer type at a rate of 12% to 15% annualy. Nonamnestic forms of MCI may presage Alzheimer type dementia or other types of dementia. Alzheimer’s disease progresses from an asymptomatic phase to MCI to Alzheimer type dementia as the burden of pathology increases (Figure 4).


Dementia Syndromes

Dementia syndromes comprise memory impairment, decline in at least one other cognitive domain, deterioration from a higher level of function, and sufficient cognitive impairment to interfere with activities of daily living. The disorder cannot be present exclusively during a delirium.

Specific diagnostic criteria assist in identifying individual types of dementia syndromes (Figures 5 and 6; Tables 1-27).3-19 Dementia of the Alzheimer type, vascular dementia, frontotemporal dementia, prion disorders (eg, Creutzfeldt-Jakob disease), and dementia with various types of parkinsonism are the major diagnostic categories to be identified.

































Antidementia Therapies

Current Treatment Approaches

Currently available antidementia therapies include cholinesterase inhibitors and the (NMDA) receptor antagonist, memantine. Tables 29–34 provide comprehensive prescribing and side-effect monitoring information.


Emerging Therapies

Alzheimer’s disease research has identified plausible targets for new symptomatic and disease-modifying treatment. Some of these agents are in advanced stages of clinical testing. The steps of the amyloid cascade comprise one set of pharmacologic targets, and neuroprotective approaches comprise an alternate treatment strategy (Figures 7–10; Tables 28-35).















Management of Behavioral Symptoms in Dementia

Behavioral changes and neuropsychiatric symptoms are among the most disabling manifestations of Alzheimer’s disease and other dementias. Behavioral disturbances are a great source of distress for patients and caregivers, decrease quality of life, may precipitate institutionalization, and increase the cost of care.


Nonpharmacologic Management

Nonpharmacologic approaches to management of neuropsychiatric symptoms may obviate the need for pharmacotherapy or may decrease the necessary dose or length of time required for pharmacologic intervention.


Pharmacologic Management

There are no medications approved by the FDA specifically for the treatment of behavioral symptoms in patients with dementia. There have been relatively few masked, placebo-controlled trials to provide evidence-based guidance for pharmacotherapy of neuropsychiatric symptoms in dementia (Figures 11 and 12; Tables 36–44; Figures 13–15; Tables 45 and 46).20-25























Family Counseling

Families provide most of the care to patients with Alzheimer’s disease and other dementias. Even after the patient is resident in a nursing home, families continue to visit often and provide some of the care. Caregiving is associated with increased medical illness, psychological stress, and substance (eg, alcohol, tranquilizers) use. Caregiver burden may lead to caregiver “burnout,” with an inability to continue to provide care. Optimal care of dementia patients requires developing an alliance with the family and referring family members to community resources.26-45

Practical strategies useful in working with families include educating families about the course of Alzheimer’s disease, what to expect over time, and how best to manage the patient and their own response; referring to the Alzheimer Association or other advocacy organizations to identify local resources for patients and families; monitoring the caregiver for “burnout” and recommending respite care or day care as needed; and providing culturally competent care recognizing the cultural individuality of patients and families. PP




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