Generation A(dderall)

October 17, 2013

By Michael Weinstock

Faculty Peer Reviewed

Neurocognitive enhancement with mixed amphetamine salts (MAS) has grown commonplace in academic settings. Over 34% of college students at a large public university reported using MAS as a study aid at least once in their life [1]. Other researchers have found prevalence rates ranging from 13.7% lifetime use at another large public university to 55% lifetime use among fraternity members at a large public university [2,3]. Abuse and misuse of stimulants does not stop after four years of college, nor does it spare the medical profession; in a survey completed by 388 medical students, 10.1% reported using prescription stimulants for nonmedical and nonrecreational reasons (academic enhancement) [4].

MAS such as Adderall (Shire; St. Helier, Jersey) have been approved by the Food and Drug Administration (FDA) for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy; however, over the past decade, more and more college- and graduate school-aged people have begun obtaining MAS illegally and consuming it for purposes other than treatment of ADHD or recreation, namely neurocognitive enhancement. How effective is amphetamine at enhancing cognition? Is the benefit outweighed by the potential for addiction and cardiac toxicity? For the purposes of this discussion, MAS will only refer to the prescription forms of amphetamine (Adderall) and dextroamphetamine (Dexedrine; Amedra, Horsham, Pennsylvania) and their generic equivalents.

Mechanism of Action:

MAS work by increasing catecholamine activity in the prefrontal cortex. They block the reuptake of dopamine and norepinephrine from the synaptic cleft by partially inactivating the dopamine transporter (DAT). MAS also increase the rate at which these neurotransmitters are released from their presynaptic neurons [5]. This surge of dopamine and norepinephrine is responsible for revving up cortical activity and stimulating the sympathetic nervous system. Furthermore, MAS have the ability to block monoamine oxidase (MAO), which would normally break down neurotransmitters in the post-synaptic cleft. Some anti-depressant medications (eg, tranylcypromine and phenelzine) block MAO to increase the amount of serotonin, norepinephrine, and dopamine available. Prescription MAS such as those found in Adderall (amphetamine and dextroamphetamine mixed salts), differ from other similar compounds such as methamphetamine (meth), MDMA (3,4-methylenedioxy-N-methylamphetamine or Ecstasy), and cocaine in several important ways. Cocaine works by blocking DAT and preventing the reuptake of dopamine. Meth and MDMA work the same way that prescription MAS work. The distinction between prescription MAS and street meth, MDMA, and cocaine lies in their route of entry and onset of action. Oral consumption of unadulterated dextroamphetamine in pill form is less rewarding than cocaine, meth, or MDMA because of slower uptake into the brain [6].

Effectiveness as Cognitive Enhancer:

Users and abusers of amphetamines argue that their academic performance is enhanced by stimulants. How accurate is this claim? In a review of the available literature, Smith and Farah found that MAS enhance “consolidation of long-term declarative memory,” but have equivocal results regarding executive functioning and cognitive control (tasks and situations where the automatic, natural response is not the correct one) [7]. In a randomized controlled trial assessing the efficacy of MAS in enhancing neurocognitive performance, the placebo group outperformed the stimulant group when taking the math and verbal SAT [8]. Users who saw the most improvement on MAS had lower baseline levels of dopamine and norepinephrine as well as lower baseline grade-point averages.

Users of MAS claim an ability to focus intently on the minutiae of whatever task they are undertaking, whether they are writing a term paper or cleaning a room. Farah and colleagues undertook a preliminary study to determine if an increased focus on the details of a task would reduce the creative abilities of the user. Interestingly, they found that overall creativity was increased in users who took Adderall or other stimulants [9]. Researchers found that those study participants who were already performing above average creatively saw no rise in their creative performance and instead saw a marginal decline in creativity.

Cardiovascular Effects:

Stimulants may induce negative cardiovascular effects by increasing heart rate and blood pressure, causing vasospasm, and prolonging QT intervals [10]. However, the risk of serious sequelae from these abnormalities, such as myocardial infarction (MI) or cardiac arrhythmia, is unclear at this time. While some adult studies have found that there may be an increased risk of transient ischemic attack and sudden cardiac death (SCD), other studies have found a paradoxical decrease in risk of MI and SCD in users of prescribed stimulants [10]. The long-term effect of stimulants on individuals is not well known but needs to be clarified if long-term use of MAS for neurocognitive enhancement can be widely endorsed.


MAS create a surge of dopamine in the nucleus accumbens, ventral striatum, and other areas of the brain. This leads to the feelings of euphoria and pleasure [7]. The FDA requires manufacturers of amphetamine-methamphetamine to place this boxed warning on the label: “Amphetamines have a high potential for abuse. Prolonged administration may lead to dependence. Misuse of amphetamines may cause sudden death and serious cardiovascular adverse reactions”[11]. Although MAS are not as addictive as cocaine or meth, physical and psychological dependence are possibly their greatest health risk. Many users of MAS claim a decrease in cognitive performance from baseline when they do not take MAS. Some other minor central nervous system effects of MAS use include emotional lability, insomnia, and headaches [11].

Should students and professionals take MAS to enhance their neurocognitive performance? Looking purely at the effects on cognition and the effects on the mind and body, a small amount of research suggests that a low dose of MAS can improve academic performance without significantly increasing the likelihood of cardiovascular events. In the short term, the greatest benefit was seen in people who scored below average on cognitive and creative tasks before administration of MAS; conversely, those performing above average in these tasks actually saw a decline in performance with the use of MAS. The widespread use of MAS for neurocognitive enhancement can lead to serious complications such as addiction and dependence. While it is controversial and still yet to be determined, the risks of adverse cardiovascular events due to the long-term therapeutic
use of MAS is a very real clinical concern.

Michael Weinstock is a 4th year medical student at NYU School of Medicine

Peer reviewed by Daniel Lugassy, MD, Emergency Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] DeSantis AD, Webb EM, Noar SM. Illicit use of prescription ADHD medications on a college campus: A multimethodological approach. J Am Coll Health. 2008;57(3):315-324.

[2] Hall KM, Irwin MM, Bowman KA, Frankenberger W, Jewett DC. Illicit use of prescribed stimulant medication among college students. J Am Coll Health. 2005;53(4):167-174.

[3] DeSantis A, Noar SM, Webb EM. Nonmedical ADHD stimulant use in fraternities. J Stud Alcohol. 2009;70(6):952-954.

[4] Tuttle JP, Scheurich NE, Ranseen J. Prevalence of ADHD diagnosis and non-medical stimulant use in medical students. Acad Psychiatr. 2010;34(3):220-223.

[5] Wilens TE. Mechanism of action of agents used in attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2006;67(Suppl. 8):32-38.

[6] Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present – a pharmacological and clinical perspective. J Psychopharmacol. 2013;27(6):479–496.

[7] Smith ME, Farah MJ. Are prescription stimulants “smart pills?” The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals. Psychol Bull. 2011;137(5):717-741.

[8] Ilieva I, Boland J, Farah MJ. Objective and subjective cognitive enhancing of mixed amphetamine salts in healthy people. Neuropharmacology. 2013;64:496-505.

[9] Farah MJ, Haimm C, Sankoorikal G, Chatterjee A. When we enhance cognition with Adderall, do we sacrifice creativity? A preliminary study. Psychopharmacology (Berl). 2009;202(1-3):541-547.

[10] Westover AN, Halm EA. Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review. BMC Cardiovascular Disorders. 2012;12: 41.

[11] Food and Drug Administration. Adderall XR prescribing information. Reference ID 3324889. Updated June, 2013. Accessed August 14, 2013.


Morgellons: Real Disease or Delusion Turned Internet Meme?

October 3, 2012

By Robert Mazgaj

Faculty Peer Reviewed

Morgellons disease is an “unexplained dermopathy” characterized by fibers emerging from skin lesions, and associated with various cutaneous sensations.[1] Inspired by a curious medical condition reported by a 17th century English physician, Morgellons was actually named in 2002 by Mary Leitao, a layperson, to describe the mysterious set of symptoms reportedly suffered by her then 2-year-old son.[2,3] Leitao then launched the not-for-profit Morgellons Research Foundation (MRF) along with a (no longer active) website,[3] MRF successfully petitioned members of Congress as well as the public to convince the Centers for Disease Control (CDC) to perform an epidemiologic study of Morgellons disease. In January 2012, the CDC published their findings from this investigation on the peer-reviewed online journal PLoS ONE.[1]

The CDC study enrolled members of Kaiser Permanent of Northern California (KPNC), a managed care consortium of about 3.2 million members.[1] For the purposes of the study, the CDC defined a case-patient as any patient who received care at KPNC between July 1, 2006 and June 30, 2008 and reported fibers or similar forms of solid material such as “threads, specks, dots, fuzzballs and granules” and at least one of the following:

1. A skin lesion such as a rash, wound, ulcer or nodule.

2. A disturbing skin symptom such as pruritus, feeling that something is crawling on top of or under the skin, or stinging, biting, or a pins and needles sensation.

The CDC identified a total of 115 case-patients, yielding a prevalence of 3.65 per 100,000 enrollees. These case-patients were mostly female (77%) and white (77%) and had a median age of approximately 55 years. More than half of all case-patients admitted to additional symptoms including fatigue of at least 6 months duration and musculoskeletal complaints. More than half of all case-patients also rated their general health status as fair or poor on a web-based survey. The case-patients reported using a variety of over-the-counter, prescription, and alternative therapies to relieve their dermatologic complaints, but no treatment was reported to be regularly effective.

Of the 115 identified case-patients, 41 received comprehensive evaluations, including clinical examinations by both internists and dermatologists; histopathologic, immunohistochemical, molecular, and chemical analysis of skin biopsies; molecular and spectral analysis of collected fibers and other material; neurocognitive and neuropsychiatric testing; extensive blood tests; chest radiographs; urinalysis and culture; and drug testing of collected hair samples. These clinical evaluations yielded the following results:

1. Skin lesions were most consistent with “arthropod bites or chronic excoriations.”

2. No parasites or mycobacteria were found in skin biopsies.

3. Collected fibers and other materials were mostly of textile origin.

4. Fifty-nine percent of case-patients had cognitive deficits.

5. Fifty percent tested positive for drugs, including amphetamines, barbiturates, benzodiazepines, opiates, cannabinoids, and propoxyphene.

6. All chest radiographs were normal.

Based on these results, the authors of the study concluded that, although Morgellons is associated with a significant reduction in quality of life, no causative medical condition or infectious agent was found in the case-patients. They likened this “unexplained dermopathy” to delusional infestation, a well-characterized psychiatric disorder responsive to antipsychotics.

One of the most intriguing facts gleaned from the study was that more than 75% of case-patients reported onset of their symptoms after 2002, the year in which Mary Leitao launched MRF and its website.[1] This finding begs the question of whether the Internet helped spread a delusion to individuals with pre-existing psychiatric morbidities. In fact, even before the CDC study’s results were released, several articles suggesting this very possibility were published. Although these suspicions may never be proven, they raise the provocative issue of the considerable influence of Internet memes on beliefs in modern society.[2] The term meme, first coined by the British evolutionary biologist Richard Dawkins in his 1976 book The Selfish Gene,[3] refers to an idea or concept that is essentially the cultural analogue of a gene. That is, a meme can be spread from generation to generation, change due to imperfect copying, and be selected for or against within a given culture. Examples of memes include musical pieces, religious beliefs and one-liners from movies.

A study published in Psychosomatics offered an explanation of how a meme such as Morgellons disease came to be rapidly accepted by a relatively large online community.[4] First, simply being able to attach a specific label to one’s own perceptual abnormalities provides significant, albeit temporary, relief of anxiety. Second, interacting with others supposedly suffering from the same ailment breaks one’s social isolation and provides a sense of legitimization and comfort.[4] This confers on the Morgellons meme a significant advantage in the marketplace of ideas that is the Internet over the competing meme of delusional parasitosis, a much more stigmatizing label. Thus, we see that the psychological appeal of an idea, and not necessarily its validity, can be more valuable to its success as an Internet meme. Finally, it becomes apparent that the conventional definition of a delusion as a fixed, false belief not held by one’s culture may be challenged by the rise of the Internet as an unprecedented platform for the exchange and acceptance of memes, and quite possibly, delusions as well [5].

By Robert Mazgaj, 2nd year medical student at NYU School of Medicine

Peer reviewed by Mitchell Charap, MD, Medicine (GIM Div), NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] Pearson ML, Selby JV, Katz KA, et al. Clinical, epidemiologic, histopathologic and molecular features of an unexplained dermopathy. PLoS ONE. 2012;7(1):e29908. Published January 25, 2012. Accessed January 27, 2012.

[2] Lustig A, Mackay S, Strauss J. Morgellons disease as Internet meme. Psychosomatics. 2009;50(1):90.

[3] Dawkins R. The Selfish Gene. Oxford, England: Oxford University Press; 1976.

[4] Freudenreich O, Kontos N, Tranulis C, Cather C. Morgellons disease, or antipsychotic-responsive delusional parasitosis, in an HIV patient: beliefs in the age of the Internet. Psychosomatics. 2010;51(6):453-457.

[5] Vila-Rodriguez F, Macewan BG. Delusional parasitosis facilitated by web-based dissemination. Am J Psychiatry. 2008;165(12):1612.

Mental Health Considerations for Gay and Lesbian Patients

July 27, 2011

By Benjamin Cox

Faculty Peer Reviewed

Gay men and lesbian women are members of a stigmatized minority group and evidence suggests that they may disproportionately utilize mental health services.[1] This increased use of mental health services may be related to the concept of minority stress: that stigma, prejudice, discrimination, and violence create a hostile and stressful social environment that can contribute to mental health problems.[2] Examples of external stressors that pose threats to mental health in gay and lesbian patients include verbal and physical violence, housing and job discrimination, lack of legal rights to protection in medical emergencies, and institutionalized discriminatory policies such as rejection of blood donations from gay men, anti-gay ballot initiatives, and lack of legal acknowledgment of same-sex couples’ relationships.  Some of these stressors can occur on a daily basis; whenever a gay man or lesbian woman meets a new person, he or she must choose whether or not to “come out” to that new person.  These situations can generate fear of rejection, hostility, or even violence. Even if a gay man or lesbian has not been a direct victim of violence, there is still significant stress generated by the perceived threat of physical danger evoked by hearing about murders and tortures of lesbian, gay, bisexual, and transgender (LGBT) individuals in the news.  These external stressors and negative societal attitudes may generate internal stressors such as self-image problems ranging from lack of self-confidence to overt self-hatred.[3,4]  Research shows that gay and lesbian persons have greater rates of depression, suicidal ideation and attempts, and substance abuse problems than their heterosexual counterparts [1,5-11], and that gay men—though not lesbians—have higher rates of body dissatisfaction and eating disorders.[12]  It is possible that the combination of these external and internal stressors is partly responsible.  In order to effectively treat their gay and lesbian patients, physicians must ask all patients about their sexual orientation and sexual practices and be aware of resources such as hotlines, shelters, substance abuse treatment programs, LGBT-experienced psychiatrists, and legal assistance.

The Urban Men’s Health Study published in 2004 reported that homosexual men had a rate of depression that was 17.2% greater than adult men in general.[5] Another study by Cochran and Mays reported that, in addition to depression, homosexual men were also more likely to have panic attacks.[1]  A large UK-based survey of psychological well-being demonstrated that there was also an increased risk for depression and mental distress among lesbians.[6] Given these data, it is advisable for physicians to screen their gay and lesbian patients for depression and mental distress using the Patient Health Questionnaire-9 (PHQ-9) or other screening tool.

An analysis of the National Health and Nutrition Examination Survey III (NHANES III) by Cochran and Mays revealed that there was a significantly higher prevalence of suicidal ideation and suicide attempts among homosexual men than among their heterosexual counterparts.[1]  The National Lesbian Health Care Study found that more than half of their study sample had experienced thoughts of suicide at some time and 18% had attempted suicide.[8]  This compares to 33% and 4%, respectively, for women in the United States, as reported in the Epidemiologic Catchment Area Study.[13]  Therefore, it is critically important to screen all gay and lesbian patients for suicidal ideation and be familiar with institutional protocols for managing suicidal patients.

The Urban Men’s Health Study published in 2001 demonstrated that among urban gay men both recreational drug (52%) and alcohol use (85%) were highly prevalent, and that alcohol-related problems (12%) and frequent drug use (19%) were not uncommon.[9]  In a review of substance use in LGBT populations, Hughes and Eliason reported that, while rates of heavy drinking among lesbians and heterosexual women were comparable, lesbians reported more alcohol-related problems.[10]  Another survey, conducted at the Millennium March in Washington DC, asked lesbians about the use of recreational drugs within their circle of close friends. In this survey, 11.4% of participants reported monthly use, 5.9% reported weekly use, and 20.8% reported use 1-2 times a year.[11]  These data suggest that both gay and lesbian patients are at increased risk for alcohol and other substance abuse and therefore warrant appropriate screening.

Research conducted by Herzog et al. revealed that lesbians were significantly more satisfied with their body appearances than the heterosexual women in the study: 72% of heterosexual women wanted to lose weight, whereas 48% of homosexual women wanted to lose weight.[14]  In another study comparing homosexual and heterosexual men, Herzog demonstrated that gay men tended to be more dissatisfied with their bodies and had a greater desire to be thin.[15]  Notably, when the men in this study were asked to report their ideal body weight, nearly a quarter of the gay men selected an ideal weight that was underweight, while none of the heterosexual men did.  Based on the results of this study, gay men tend to be at a higher risk for body dissatisfaction, whereas lesbian women tend to have a lower risk.  This high prevalence of unrealistic body ideals in gay men correlates with a higher prevalence of eating disorders, as evidenced in a study by Feldman and Meyer.[12] As one might have predicted from the results of the body dissatisfaction studies, lesbians were not at an increased risk for eating disorders.[12]  It would therefore be appropriate to screen gay male patients for eating disorders.  The SCOFF questionnaire is a five-question survey that has been validated as an effective screening tool for anorexia nervosa and bulimia nervosa in men and women, with 100% sensitivity and 87.5% specificity.[16]

Many gay and lesbian patients confront a variety of internal and external stressors that pose significant threats to their mental wellbeing.  Research shows that these men and women are at increased risk for certain mental disorders and their sequelae.  Recommendations for effective care include asking all patients about their sexual orientation and sexual practices; screening gay and lesbian patients for depression, suicidal ideation, and alcohol and substance abuse; screening gay males for eating disorders; and being aware of resources for gay and lesbian patients such as hotlines, shelters, substance abuse treatment programs, LGBT-experienced psychiatrists, and legal assistance.  The Healthy People 2010 Companion Document for LGBT Health ( contains listings of national resources as well as resources in each state.

Commentary by Dr. Victor Rodack

Patients who identify themselves as gay or lesbian are often sensitive to discomfort their presumed life-styles arouse in treating physicians; it would be helpful for primary care doctors to be able to explicitly ask about sexual behavior, including number of partners and venues frequented, without apprehension, surprise, or distaste. Gay men should be offered anal Papanicolaou testing. Throat cultures should be examined for gonococcal infection. This presumes that a rapport has been established in which the patient is comfortable enough to acknowledge his sexual behavior, regardless of how he self-identifies. An initial history should include questions about the patient’s comfort and acceptance of his own sexuality and sexual behavior. And as with all patients, referral to mental health resources should be suggested if there is any indication of dysfunction.

Benjamin Cox is a 4th year medical student at NYU Langone Medical Center

Peer reviewed by Victor Rodack, MD, Medicine, Psychiatry, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Cochran SD, Mays VM. Relation between psychiatric syndromes and behaviorally defined sexual orientation in a sample of the US population. Am J Epidemiol. 2000;151(5):516-523.

2. Meyer IH. Prejudice, social stress, and mental health in lesbian, gay, and bisexual populations: conceptual issues and research evidence. Psychol Bull. 2003;129(5):674–697.  http://

3. Meyer IH. Minority stress and mental health in gay men. J Health Soc Behav. 1995;36(1):38-56.

4. Shidlo A. Internalized homophobia: conceptual and empirical issues in measurement. In: Greene B,  Herek G, eds. Psychological Perspectives on Lesbian and Gay Issues: Vol. 1. Lesbian and Gay Psychology: Theory, Research, and Clinical Applications. Thousand Oaks, CA: Sage Publications, 1994.

5. Mills TC, Paul J, Stall R, et al. Distress and depression in men who have sex with men: The Urban Men’s Health Study. Am J Psychiatry. 2004;161(2):278-285. http://

6. Warner J, McKeown E, Griffin M, et al. Rates and predictors of mental illness in gay men, lesbians and bisexual men and women: Results from a survey based in England and Wales. Br J Psychiatry. 2004;185:479-485.

7. Cochran SD, Mays VM. Lifetime prevalence of suicide symptoms and affective disorders among men reporting same-sex sexual partners: Results from the NHANES III. Am J Public Health. 2000;90(4):573–578.

8. Bradford J, Ryan C, Rothblum ED. National Lesbian Health Care Survey: implications for mental health care. J Consult Clin Psychol. 1994;62(2):228-242.

9. Stall R, Paul JP, Greenwood G, et al. Alcohol use, drug use and alcohol-related problems among men who have sex with men: the Urban Men’s Health Study. Addiction. 2001;96(11):1589–1601.

10. Hughes T, Eliason M. Substance use and abuse in lesbian, gay, bisexual and transgender population. J Prim Prev. 2002;22(3):261–295.

11. K-Y Brand Liquid Community Health Survey. Conducted at the Millennium March, Washington, DC. April 29-30, 2000.

12. Feldman MB, Meyer IH. Eating disorders in diverse lesbian, gay, and bisexual populations. Int J Eat Disord. 2007;40(3):218-226.

13. Robins LN, Regier DA. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York, NY: Free Press, 1991.

14. Herzog DB, Newman KL, Yeh CJ, Warshaw M. Body image satisfaction in homosexual and heterosexual women. Int J Eat Disord. 1992;11(4):391–396.

15. Herzog DB, Newman KL, and Warshaw M. Body image dissatisfaction in homosexual and heterosexual males. J Nerv Ment Dis. 1991;179(6):356-359.

16. Morgan JF, Reid F, and Lacey JH. The SCOFF questionnaire: assessment of a new screening tool for eating disorders. BMJ. 1999;319(7223):1467-1468.

A Vaccine Against Nicotine—New Hope or Mere Hype?

February 18, 2011

By Carolan Hass, Class of 2012

Faculty Peer Reviewed

Cigarettes remain an anathema to many physicians.  Like so many unhealthy behaviors over which a clinician has little control, it can be frustrating to deal with a habit that can do so much harm to a patient, but which may be deeply entrenched in his daily life.  Although the percentage of current cigarette-smoking US adults has steadily decreased from 34.1% in 1978 to 19.8% in 2007 [1] there remains vast room for improvement.  A fifty-percent reduction in US smokers could save the country $96 billion a year.[2]  It is exciting that a new pharmacological agent will soon be available to help patients overcome what is possibly the most addictive drug on the planet.

Three companies are currently working on nicotine vaccines: Nabi Biopharmaceuticals in the US, Cytos AG in Switzerland, and Celtic Pharma in the UK.[3]  The American product NicVAX® will most likely be the soonest approved in the US and is the focus here.

The basic design of the vaccine depends on the production of an antibody response that generates immune complexes of nicotine-anti-nicotine immunoglobulin G so large that they cannot cross the blood-brain barrier.  The smoker has diminished stimulation of nicotinic receptors in the brain and decreased pleasure in response to smoking.[3]  The proof of concept was first demonstrated in animal studies.[4]  In one study, rats that had been vaccinated were compared with non-vaccinated controls.[5]  The groups were administered large doses of nicotine, then a final radio-labeled dose of nicotine.  Blood and brain levels of nicotine were compared in the two groups, with brain levels significantly reduced in the vaccinated group compared to the naïve group and serum concentrations of nicotine higher in the vaccinated group.

In a double-blinded phase II clinical trial for Nabi’s nicotine conjugate vaccine (NicVAX®), four serial vaccinations at doses of 0 (placebo), 50 µg, 100 µg and 200 µg were given to smokers who had no intent to quit.[6]  The outcomes were safety and immunogenicity.    Safety was assessed via physical examination, vital signs, electrocardiogram, blood and urine tests, recorded adverse events, and questionnaires on allergic reactions.  The trial indicated that nicotine vaccine is safe and well tolerated.  Antibody levels were assessed with ELISA and found to reach levels of >30 µg/mL in the 200 µg group.  This level had been demonstrated in independent studies to substantially change nicotine distribution in rats.[4]  The study recruitment size was small (n=68); however, in this trial there was no indication of compensatory smoking or increased nicotine withdrawal as measured by subjects’ self-reported daily smoking and cravings, carbon monoxide blood levels, and urinary nicotine metabolite levels.

In Phase IIb clinical trials, the study design was altered so that some groups received an increased dose of vaccine and more shots were administered.[7]  The trial was also double-blinded and placebo-controlled.  301 participants enrolled, all of whom smoked at least 15 cigarettes per day, with an average consumption of 24 cigarettes per day at enrollment.  At 6 months, the primary endpoint–continuous carbon-monoxide-confirmed abstinence from weeks 19-26–was found to be significantly higher only in the participants with the highest antibody responses to the vaccine (the top 30%).  24.6% in this group were abstinent compared to 12% in the placebo group (p=.024).  At 12 months, the subjects treated with the “optimal dose” of nicotine conjugate vaccine–five injections of 400 µg–had a 16% quit rate and remained abstinent versus 6% of the placebo group (p=.038).  The 400 µg group was the only group that had a statistically significant difference from the placebo group in 12-month sustained abstinence.

Double-blinded, placebo-controlled Phase III trials are currently underway with a primary outcome of smoking abstinence rate at 12 months.[7]  The results are expected in 2011 and 2012.  Participants must be current smokers who smoke at least 10 cigarettes per day and will receive 6 shots over 6 months.  Each trial is enrolling approximately 1000 participants.

While current evidence and statements from Nabi and other groups look promising, physicians must look keenly into the results of the phase III trials currently underway to see if the vaccines are truly effective, especially since the prior trials have had lower enrollment numbers. Le Houezec published a thoughtful commentary in Clinical Pharmacology and Therapeutics in 2005.[8]  While maintaining an optimistic tone, he judiciously pointed out factors that physicians will have to keep in mind, should the vaccine become available.  To summarize: 1) Patients have variable responses to vaccinations and some may need regular boosters.  2) Physicians should continue to monitor both studies and their patients using nicotine vaccine therapy for evidence of compensatory smoking: he notes that production of IgG in response to vaccination is capped at no more than 0.1-0.2 g/L and that this amount of IgG could be overcome by the amount of nicotine in ten cigarettes.  3) Patients should begin cessation at an appropriate time after vaccination, as antibody response may take months.  4) The vaccine would be best for smokers wishing to quit, ex-smokers wishing to avoid relapse, and adolescents hoping not to start.  The Phase III trials should be able to address some of these issues, particularly points 2 and 3. Other issues on the table will be cost and the availability of blood tests to see if patients are producing adequate antibody.  Nabi has created its own ELISA test to detect nicotine antibody, which will enter into the cost of the vaccine.[6]  Finally, the six injections being administered in the phase III trials require a burdensome time commitment. The cost-benefit ratio in terms of time, money, and success rates will undoubtedly affect the practicality of the vaccine.

If NicVAX® proves to be relatively inexpensive and safe and if Nabi can come up with a way to distribute it in fewer than six doses, it could become a mainstream element of tobacco cessation therapy.  It could potentially be applied to cessation of other tobacco products.  Based on current evidence and the willingness of the National Institute on Drug Abuse to grant Nabi millions of dollars to conduct these trials, the future looks promising.

Alas, the nicotine vaccine shall by no means act as a “magic pill.”  Patient education and participation remain crucial to success in smoking cessation.  Nevertheless, it may be a beneficial tool for physicians to help willing patients succeed in quitting.

Carolan Hass is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Ellie Grossman, MD, Assistant Professor of Medicine, Dir Bellevue,  Stop Smoking Program

Image courtesy of Wikimedia Commons


1. National Center for Health Statistics.  Health, United States, 2009: With Special Feature on Medical Technology. Hyattsville, MD. 2010.   Cigarette smoking among high school students and adults, United States, 1965-2007; Figure 6, p. 24. Accessed July 26, 2010.

2. CDC. Smoking-attributed mortality, years of potential life lost, and productivity losses–United States, 2000-2004.  MMWR. 2008;57(45):1226-1228. Accessed July 26, 2010.

3. Cerny EH, Cerny T. Vaccines against nicotine.  Hum Vaccin. 2009;5(4);200-205.

4. Pentel PR, Malin D, Ennifar S, et al. A nicotine conjugate vaccine reduces nicotine redistribution to brain and attenuates its behavioral and cardiovascular effects in rats.  Pharmacol Biochem Behav. 2000;65(1):191-198.

5. Cerny EH, Lévy R, Mauel J, et al. Preclinical development of a vaccine “against smoking.” Onkologie. 2002; 25(5):406–11.

6. Hatsukami DK, Rennard S, Jorenby D, et al.  Safety and immunogenicity of a nicotine conjugate vaccine in current smokers.  Clin Pharmacol Ther. 2005:78(5);456-467.

7. Clinical Trials. NicVAX (Nicotine Conjugate Vaccine). Nabi Biopharmaceuticals website. Accessed July 27, 2010.

8. Le Houezec J.  Why a nicotine vaccine? Clin Pharmacol Ther. 2005; 78(5):453-455.

Motivational Interviewing: Can You Really Change Behaviors?

April 27, 2010

Emily Stamell

Faculty peer reviewed

As a well-trained fourth year medical student, I inquire about smoking habits as part of almost all my patient encounters. Yet, I do not recall properly counseling a patient on smoking cessation aside from the one liner “You know you should quit, right?” During first and second year of medical school we are taught the stages of change model, which is just as obscure two years later as cell signaling pathways. I was recently introduced to what seemed like an innovative way to address smoking cessation, but it actually dates back to the last century and has been used to modify numerous risk behaviors including condom use,(1) smoking,(2) exercise,(3) and weight reduction.(4)

Motivational interviewing was first described by Miller in 1983 and defined by Rollnick and Miller in 1995 as “a directive, client-centered counseling style for helping clients explore and resolve ambivalence about behavior change.”(6) This method is founded on the patient’s readiness and confidence to change. Rollnick et al. proposed a three-phase intervention method based on motivational interviewing in 1997 that individualizes and encourages patient involvement in smoking cessation counseling.(5) This review includes a description of the three phases of motivational interviewing, using smoking cessation as the paradigm, as well as a review of evidence for and against this method.

Phase I: Quick assessment

The intervention begins with developing rapport with the patient though an open-ended question: “Can you tell me a bit about your smoking?” This initial assessment should include a disclaimer statement, such as “You may well be a little fed up with people lecturing you about smoking. I’m not going to do that, but it would help me if I could understand how you really feel about your smoking.” The physician subsequently evaluates the patient’s motivation to quit: “If, on a scale of 1 to 10, 1 is not at all motivated to give up smoking and 10 is 100% motivated to give up, what number would you give yourself at the moment?” Finally, you evaluate confidence in ability to quit: “If you were to decide to give up smoking now, how confident are you that you would succeed? If, on a scale of 1 to 10, 1 means that you are not at all confident and 10 means that you are 100% confident you could give up and remain a non-smoker, what number would you give yourself now?”

Phase II: Patient identifies problems and solutions

Following the quick assessment, the patient and physician attempt to identify problems in motivation or confidence level. Useful questions include “Why are you at (chosen number) and not at 1?” or “What would need to happen for you to get from (chosen number) to (higher number)?” or “How can I help you get from (chosen number) to (higher number)?” The physician is encouraged to offer ideas if the patient is unsure, as well as identify inconsistencies in the patient’s beliefs that create ambivalence toward smoking.

Although they are evaluated as two distinct arms, solutions to a low motivational score should be addressed prior to a low confidence score. Solutions to improve a motivational score can be identified by discussing pros and cons of smoking or providing non-judgmental information about personal risk. Conversely, if the patient is already highly motivated but lacks confidence, then phase II should include brainstorming on solutions to increase confidence, such as selecting a general problem area (e.g. tobacco withdrawal, weight gain, social situations, mood states, or stress) and encouraging the patient to individualize a practical plan. The physician can supplement with other ideas, but should not immediately offer a single, simple solution. In the end, the patient chooses the best option for him or herself.

Phase III: Target and follow up

The final phase will depend on the direction of phase II, but should reinforce the value of small gains and openness. The patient and physician should come up with a reasonable target, such as decreasing the number of cigarettes or improving other lifestyle factors that may influence smoking. Sometimes the patient may not be ready to set a target and the physician should reinforce that (s)he is available in the future whenever the patient is ready. Finally, the physician should find out how (s)he can assist in attaining the target, i.e. frequent follow-up visits, telephone calls, or nicotine replacement.

A review of the literature revealed a number of studies evaluating the efficacy of motivational interviewing. One of the first studies by Colby et al. randomized 40 adolescents in a hospital setting to either brief advice or motivational interview and found that, although there was no difference in smoking cessation at 3-month follow-up, there was a significant decrease in smoking dependence and number of days smoked in the motivational interview group.(2) More recently, Soria et al.’s randomized controlled trial of 200 smokers concluded that smoking cessation after both 6 and 12 months in the motivational interviewing group was 5.2 times higher compared to anti-smoking advice. Although motivational interviewing was first described by Rollnick et al. for smoking cessation, it has been found to be less effective for smoking cessation as a first-line method and more successful with resistant patients and increases the likelihood of future quit attempts.(8)

Since motivational interviewing has been described for a number of risk behaviors, I recently tried out the adaptability of this technique on a 68 year-old obese male. The patient had motivation to lose weight of 7/10, but confidence to succeed of 3/10. His low confidence was primarily due to the amount of weight he believed he had to lose in order to make an overall difference. Together we decided to set a reasonable goal for this month of cutting out regular Coca-Cola. Motivational interviewing individualized the patient’s care, prevented me from having preconceptions on why the patient did not try to lose weight, and was applicable to a behavior not originally described in the three phases.

Emily Stamell is a 4th year medical student at NYU School of Medicine.

Peer reviewed by Antoinette Schoenthaler, EdD.


1. Carey MP, Maisto SA, Kalichman SC, Forsyth AD, Wright EM, Johnson BT. Enhancing motivation to reduce the risk of HIV infection for economically disadvantaged urban women. J Consult Clin Psychol. 1997;65(4):531-541.

2. Colby SM, Monti PM, Barnett NP, et al. Brief motivational interviewing in a hospital setting for adolescent smoking: a preliminary study. J Consult Clin Psychol. 1998;66(3):574-578.

3. Harland J, White M, Drinkwater C, Chinn D, Farr L, and Howel D. The Newcastle exercise project: a randomised controlled trial of methods to promote physical activity in primary care. BMJ. 1999;319(7213):828-832.

4. Rollnick S. Behaviour change in practice: targeting individuals. Int J Obes Relat Metab Disord. 1996;20 Suppl 1:S22-26. Review.

5. Rollnick S, Butler CC, and Stott N. Helping smokers make decisions: the enhancement of brief intervention for general medical practice. Patient Educ Couns. 1997;31(3):191-203.

6. Rollnick S, Miller WR. What is motivational interviewing? Behav Cogn Psychother. 1995;23(4):325-334.

7. Soria R, Legido A, Escolano C, Lopez Yeste A, Montoya J. A randomised controlled trial of motivational interviewing for smoking cessation. Br J Gen Pract 2006;56(131):768-774.

8. U.S. Department of Health and Human Services. Treating tobacco use and dependence: 2008 update. Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health, 2008.

Addiction 2.0 Part 2

September 4, 2008

alcohol.jpgCommentary by Joshua Lee MD, Ellie Grossman MD and Marc Gourevitch MD, NYU Division of General Internal Medicine

Please also see Part 1 of this series, posted last week

Alcohol treatment in primary care: evidence for effectiveness and neharmacotherapies

Brief interventions by primary care physicians to address unhealthy alcohol use have been shown in multiple studies and settings to promote reduced drinking and engagement in other treatment, although long-term impact on alcohol-related morbidity and mortality is not clear.(Saitz 2005) Standard brief intervention techniques are based on the 4 A’s: Ask (about drinking using validated screens); Advise (regarding a diagnosis of hazardous drinking, alcohol abuse, or alcohol dependence); Assist (with the patient’s motivation for change), and Arrange (follow-up with the physician or refer to a treatment program). Brief intervention is indeed intended to be brief – only 5-10 minutes of discussion with a patient per session has been shown to be an effective intervention (http:/

Pharmacotherapies for Alcohol. With the 2006 FDA approval of extended-release naltrexone (XR-NTX, Vivitrol), the physician has four FDA-labeled agents available for the treatment of alcohol dependence: disulfiram (Antabuse), oral naltrexone (ReVia, 1994), acamprosate (Campral, 2004), and extended-release naltrexone. The recent COMBINE study employed a complex 3×3 randomized factorial design to study oral naltrexone and acamprosate on their own and combined, with or without other treatment modalities.(Anton 2006) These researchers found that alcohol treatment delivered by a physician (medical management) on its own was as effective as cognitive behavioral therapy or motivation enhancement delivered as additional individual therapy. In addition, oral naltrexone pharmacotherapy in addition to medical management was more effective at reducing alcohol use than acamprosate or placebo. Separate efficacy trials have shown disulfiram, XR-NTX, and acamprosate are beneficial when compared to placebo (Kiefer F et al. 2003.; Garbutt 2005).

XR-NTX is the newest addition to the alcohol-dependence pharmacotherapy armamentarium.(Garbutt 2005) Its development was grounded in the experience that oral naltrexone is effective at reducing alcohol use, but only for patients who actually took the drug – a significant barrier for a disease rooted in daily behavior like alcohol dependence. XR-NTX is a depot formulation that is injected monthly into the gluteal region – thereby overcoming issues of daily medication adherence. However, use of this medication remains lower than anticipated due to its high cost (and incomplete coverage by public insurers) and its injection format. Unlike primary care practices, most office-based addiction psychiatrists may not be equipped to perform injections or comfortable with such an invasive procedure. XR-NTX prescribing has to date mostly occurred in specialty addiction centers and internal medicine and family practice office-based settings. To date in an on-going single-arm study of primary care-based pharmacotherapy of alcohol dependence at Bellevue Hospital, we have shown that offering XR-NTX to low-income and uninsured patients is feasible: interest and acceptance of XR-NTX therapy is high among eligible patients, and retention through a 3 month treatment phase is roughly 75% per month (25% per month discontinue treatment). This compares favorably to other outpatient medical or psychosocial alcohol treatment, the literature for which reports generally lower rates of short-term treatment retention. Self-reported alcohol use in those remaining in XR-NTX treatment has been substantially lower than at baseline, as expected.

Limitations and referrals
The primary care or office-based specialty physician ready and willing to offer frontline addiction treatment can look forward to many rewarding cases, as patients are often younger and in otherwise good health excepting problematic substance use. However, psychiatric comorbidities, polysubstance dependencies, and chaotic social circumstances including homelessness, unemployment, and insurance difficulties often appear as complications to straight-forward treatment and recovery. Even in the simplest cases, chronic difficulties with cravings and relapse are the rule. The office—based practitioner always needs to keep these realities and limitations in mind, with other referral sources and backup resources available when more help is required. Linkages to general psychiatric care and specialty addiction treatment resources are practical next steps when a case requires that primary psychiatric diagnoses be addressed, or more comprehensive addiction care, including inpatient detoxification, residential rehabilitation, or intensive outpatient care involving individual counseling and frequent structured group therapy, be considered.


Center for Substance Abuse Treatment. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction: A Treatment Improvement Protocol (TIP) Series 40. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004

Lee JD, Grossman E, DiRocco D, Gourevitch M. At-Home Buprenorphine/Naloxone Induction in Urban Primary Care. Association for Medical Education and Research in Substance Abuse (AMERSA) National Meeting (podium) Washington DC, Nov. 10, 2007; Society of General Internal Medicine Annual Meeting (poster) Pittsburgh PA, April 10, 2008; American Society of Addiction Medicine Annual Scientific and Medical Meeting (poster) Toronto, ON, April 11, 2008.

Anton RF et al, Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA, 295(17), 2006:2003-17.

Garbutt JC et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA, 293(13), 2005:1617-25.

Lee JD, Grossman E, DiRocco D, Truncali A, Rotrosen J, Hanley K, Stevens D, Gourevitch MN. Extended-release Naltrexone Injectable Suspension for Treatment of Alcohol Dependence in Urban Primary Care – A Feasibility Study: Preliminary Analysis. Society of General Internal Medicine Annual Meeting (poster) Pittsburgh PA, April 10, 2008; American Society of Addiction Medicine Annual Scientific and Medical Meeting (poster) Toronto, ON, April 11, 2008; College of Problems on Drug Dependence (poster) San Juan PR, June 18, 2008; Research Studies on Alcoholism (poster) Washington DC, July 2, 2008.

Kiefer F. et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind ,placebo-controlled study. Arch Gen Psychiatry 2003 Jan;60(1):92-9.Saitz R. Unhealthy alcohol use. N Engl J Med 2005;352:596-607.

Addiction 2.0 Part 1

August 27, 2008

bottles.jpgCommentary by Joshua Lee MD, Ellie Grossman MD and Marc Gourevitch MD, NYU Division of General Internal Medicine

Substance abuse remains a leading cause of disease and mortality in the US, yet it is rarely addressed in general practice settings. In the past, clinicians could point to a relative paucity of effective interventions by way of explaining their disengagement in the care of these medical disorders. In recent years, however, effective pharmacotherapies have emerged for two classes of substances that are particularly destructive when abused, as they commonly are: opioids (heroin and prescription narcotics) and alcohol. In this two-part entry, we will review the current state-of-the-art in strategies for addressing these conditions in the office-based practice setting. The great majority of affected patients do not seek dedicated substance abuse treatment programs yet do interact with physicians for other reasons. With the new tools available to them, office-based physicians now therefore have the opportunity to substantially increase access to effective treatment of opioid and alcohol abuse and dependence. Part 1 follows below. Part 2 will be posted next week.

I. Office-based opioid treatment.

Buprenorphine, a partial mu opioid receptor agonist, was approved by the FDA in 2002 for the treatment of opioid dependence in office-based settings.(CSAT 2004) This development has ushered in a new treatment paradigm for opioid disorders – that of treating them pharmacologically in primary care practices, as distinct from traditional methadone maintenance treatment programs. Due to its ‘ceiling effect,’ it is virtually impossible to overdose on buprenorphine, making it safer than methadone, and resulting in the DEA classifying it as a Schedule III compound. In its most widely available form, buprenorphine is marketed as a compound mixture with naloxone (brand name ‘Suboxone’), to deter its misuse by injection. A physician need only complete a relatively brief training course in order to obtain a DEA waiver authorizing prescribing. Thereafter, physicians can now incorporate treatment of heroin or prescription opioid dependence into everyday practice. Buprenorphine can be used as a long-term maintenance medication (much like methadone maintenance), or in tapering doses to prevent and treat withdrawal symptoms when the opioid drug of abuse is discontinued.

Buprenorphine prescribing has grown slower than expected in New York City, in part because of concerns that actually beginning patients on the medication (“induction”) might be complicated medically and problematic in terms of office logistics. Because of its high affinity for the mu opioid receptor and its partial agonist activity, buprenorphine can actually precipitate withdrawal symptoms in patients under the influence of other opiates. Published prescribing guidelines therefore suggest that the first few doses of buprenorphine be taken by the patient in the physician’s office, with monitoring of the patient for several hours afterward to minimize the risk of buprenorphine-associated precipitated withdrawal on induction.(CSAT 2004) However, as one might imagine, such a process might pose a significant burden on the average primary-care office practice. Locally, the Bellevue Hospital Center Primary Care Buprenorphine Initiative has recently documented what many experienced buprenorphine providers already knew: that an at-home induction protocol, which minimizes clinic visit times by having the patient administer the first buprenorphine dose at home, is safe and feasible.(Lee 2008) Such induction approaches may shrink logistical barriers and encourage prescribing.

A second potential barrier to buprenorphine usage in New York City is the high out-of-pocket cost of the drug (roughly $15/day for an average 16mg maintenance dose). However, in New York State we are fortunate that Medicaid covers the cost of buprenorphine/naloxone (Suboxone) and buprenorphine (Subutex), making it more accessible to our public-hospital population.

Buprenorphine is not the ideal medication for every opioid-dependent patient. Patients who require very high doses of methadone to avoid withdrawal symptoms may not achieve comfort on buprenorphine. Some patients benefit from the daily structure of methadone maintenance, and the group meetings and other counseling that can occur on-site at these programs. Patients who are unable to reduce their illicit opioid use while on buprenorphine may be better served in the more treatment-intensive environment of methadone maintenance or other programs. Physicians prescribing buprenorphine should be aware of local methadone programs and other treatment resources (as well as Narcotics Anonymous) where patients can receive counseling and related psychosocial services. Directories of such resources locally are available from the authors.



Center for Substance Abuse Treatment. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction: A Treatment Improvement Protocol (TIP) Series 40. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004

Lee JD, Grossman E, DiRocco D, Gourevitch M. At-Home Buprenorphine/Naloxone Induction in Urban Primary Care. Association for Medical Education and Research in Substance Abuse (AMERSA) National Meeting (podium) Washington DC, Nov. 10, 2007; Society of General Internal Medicine Annual Meeting (poster) Pittsburgh PA, April 10, 2008; American Society of Addiction Medicine Annual Scientific and Medical Meeting (poster) Toronto, ON, April 11, 2008.

Approach to a Patient with ‘Treatment Refractory’ Depression in The Medical Setting: Part 2

May 29, 2008

bellevue.jpgCommentary by Brian Bronson, MD, Chief of Psychosomatic Medicine, VA New York Harbor, New York Campus

Summary: Symptoms of depression in the medical setting may not respond to usual pharmacologic antidepressant treatment for a number of reasons. These may include an incorrect psychiatric diagnosis; failure to consider underlying medical causes of the symptoms; or insufficient antidepressant medication trial due to poor patient adherence, insufficient dose or length of trial. There is no consensus as to the definition of ‘treatment refractory’ depression. However, when the above steps have not resulted in improved outcome, the clinician may either change to an alterative antidepressant, or add a second medication as adjuvant treatment if the patient had a partial response to the first medication. Failure to modify critically important environmental or psychosocial stressors may also impair a full treatment response. Part I of this discussion focused on making the correct diagnosis. Part II summarizes pharmacologic management concepts for treatment non responders.

Part II

Assuming the diagnosis of a major depressive episode or adjustment disorder with depressed mood is correct and is not the manifestation or another underlying disorder, the primary care practitioner has many options to approach the treatment non-responder.

A common cause of patient non-response or partial symptom response to antidepressant treatment is a failure to titrate the antidepressant medication to adequate doses. Starting doses recommended by the drug manufacturer are often not sufficient final doses. In outpatient, non-emergent settings, clinicians should titrate the dose up every 3-4 weeks until the patient demonstrates some symptom improvement, holding the initially effective dose for 6-10 weeks or as long as symptoms continue to improve before titrating up further. The goal of increasing dose titration should be a complete remission of symptoms; ie a return to baseline. Asking patients about missed doses should be a routine part of follow-up, given the high prevalence of partial adherence or complete self-cessation of antidepressant treatment by patients.

Patients with a major depressive episode that do not respond to the maximum approved or tolerated dose of medication after at least 8 weeks should be considered for an alternative or second add on medication. In practice, patients with a partial treatment response to an antidepressant medication are generally continued on that medication at that dose, and a second medication is added to treat residual symptoms. This approach is supported by empiric evidence.

Read more »

Approach to a Patient with ‘Treatment Refractory’ Depression in The Medical Setting: Part 1

May 15, 2008

bellevue.jpgCommentary by Brian Bronson, MD, Chief of Psychosomatic Medicine, VA New York Harbor, New York Campus 

Summary: Symptoms of depression in the medical setting may not respond to usual pharmacologic antidepressant treatment for a number of reasons. These may include an incorrect psychiatric diagnosis; failure to consider underlying medical causes of the symptoms; or insufficient antidepressant medication trial due to poor patient adherence, insufficient dose or length of trial. There is no consensus as to the definition of ‘treatment refractory’ depression. However, when the above steps have not resulted in improved outcome, the clinician may either change to an alterative antidepressant, or add a second medication as adjuvant treatment if the patient had a partial response to the first medication. Failure to modify critically important environmental or psychosocial stressors may also impair a full treatment response. Part I of this discussion focuses on making the correct diagnosis. Part II will summarize pharmacologic management concepts for treatment non responders.

Part I:

Review of symptoms and clarification of primary diagnosis is an important first step to treatment non-responders in medical settings. Depressive disorders in primary care medical settings are frequently missed, yet they are not uncommonly misdiagnosed or treated. While antidepressants have good empiric evidence in reducing symptoms of both Major Depressive Episodes and Adjustment Disorders with Depressed Mood, patients with a variety of other primary psychiatric diagnoses and primary medical diagnoses may appear depressed or complain of depressive symptoms such as insomnia or a low mood as epiphenomena. Insomnia in particular is a very non-specific symptom and frequent hallmark of emotional distress in general, and in clinical settings is over-attributed to primary depressive disorders, as is loss of appetite in medically ill populations.

Read more »

SSRIs: Do They Increase Rates of Suicide?

January 25, 2008

prozac.jpgCommentary by Arthur Sinkman MD, NYU Department of Psychiatry

Three years ago the FDA began requiring that all selective serotonin reuptake inhibitors (SSRIs) carry a black-box warning stating that their use in children and adolescents is associated with an increase in risk for suicidal thinking, feelings and behavior. Recently the FDA ordered that this warning be extended to include treatment for young adults aged 18 to 24.

The 2004 order had a dramatic impact on the treatment of depression in children. The use of SSRIs dropped precipitously, and the overall diagnosis and treatment of pediatric depression also decreased. Clearly physicians and families had been scared away from treating depression. A subsequent increase in the rate of pediatric suicide has been observed.

The FDA’s action was controversial from the start, with several well-conducted studies coming to the opposite conclusion: that SSRIs prevent suicide rather than cause it. The latest research in this burgeoning controversy is a recent group of studies published in the American Journal of Psychiatry.

The first report examined a very large series of cases from a pre-paid health plan and evaluated the rate of suicide attempts both before and after the initiation of treatment.(1) It was found that suicide attempts were highest in the month prior to the start of treatment, second highest in the month after treatment was begun and steadily decreased thereafter. The same pattern held for other treatment modalities, both pharmacologic and nonpharmacologic. The authors concluded that suicidality after starting medication was part of the pattern of the illness and not a direct result of the treatment.

Another study examined an enormous database of the treatment of depression of a quarter of a million veterans(2). It showed that the rate of suicide was much lower in the group that took SSRIs in comparison to those who did not take medication. The suicide rate was also lower in the SSRI group than in the group that took other types of antidepressants. In addition, this study also repeated the findings of the aforementioned study in that the incidence of suicide was higher before treatment than after.

The editorial accompanying the above reports concluded that “it is more likely that suicidal behavior leads to treatment than that treatment leads to suicidal behavior.”(3)It should be noted that these studies mainly focused on adults; thus, the relevance for the treatment of pediatric depression is less clear. However, the VA study did include young adults and its findings are relevant for the newest group of patients to be included in the black-box warning.

A follow-up report in the same journal added further ammunition to those opposed to the black-box warning.(4) It was done by the same research group responsible for the VA report. This study analyzed the prescription rates of SSRI antidepressants and the rates of suicide both before and after the black-box warning. Data from both the U.S. and the Netherlands was examined. A clear correlation between the decreased prescriptions and increased death by suicide was observed. It was also noted that various limitations in the meta-analysis that the FDA used as the basis for its warning exist. Most telling is that there were no completed suicides in this meta-analysis. Rather, there was an increase in the rate of suicide ideation and gestures.

What conclusions can be drawn? One is that withholding an effective treatment is a decision that may have devastating consequences. Although there is a question about the danger of antidepressants, the risks associated with not treating depression are well known and not open to question. The other conclusion is that the use of SSRIs may be far less dangerous than the FDA’s black-box warning implies. Nevertheless, some caution is indicated, particularly when treating children. Prudent behavior includes close follow-up after initiating treatment, considerations for referral for other treatments aside from medication, and evaluation for the presence of side effects, including akathisia, the unpleasant subjective sensation of inner restlessness. Akathisia is usually associated with the use of neuroleptics such as Haldoperidol, but it not infrequently occurs with SSRIs and is often missed. Akathisia can lead to great discomfort and possible suicidal thinking and behavior.


1. Simon GE and Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry. 2007;164:1029-1034.

2. Gibbons RD, Brown CH, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry. 2007;164:1044-1049.

3. Brent D. Antidepressants and suicidal behavior: cause or cure? Am J Psychiatry. 2007;164:989-991.

4. Gibbons RD, Brown CH, et al: Early evidence on the effects of the regulators’ suicidality warnings on the SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164:1356-1363.


FDA Warns of Possible Link Between Chantix Therapy and Mood Disturbances

December 14, 2007

chantix.jpgCommentary by Robert Leonard PharmD, Pharmacy Resident New York Harbor Healthcare System

On November 20, 2007 the FDA announced mounting evidence linking varenicline (Chantix®) therapy for smoking cessation with suicidal ideation and erratic and aggressive behavior. The announcement comes in response to post-marketing case reports submitted to the FDA by the makers of Chantix®, Pfizer Inc. Early review of the cases reveal new onset of depressed mood, suicidal thoughts, and changes in emotions or behaviors within days to weeks of starting Chantix® therapy. A direct causal relationship remains limited at this time due to the nature of smoking cessation and the emergence of withdrawal symptoms with or without treatment. Nicotine withdrawal alone has been associated with acute exacerbation of underlying psychiatric disorders. Further confounding the interpretation of these reports is the presence of co-morbid conditions often associated with tobacco use disorder that predispose patients to mood disorders such as alcohol dependence. However, despite these limitations, reported cases include mood disturbances in patients who have no prior history of psychiatric illness and in patients who continue to smoke.

Pfizer Inc. has also submitted case reports to the FDA describing drowsiness associated with Chantix ®that influences the ability to safely drive or operate machinery.

In light of these preliminary findings, the FDA has made three recommendations concerning the use of Chantix® for smoking cessation. The official recommendations reported in the press release by the FDA are as follows:

“Healthcare professionals should monitor patients taking Chantix for behavior and mood changes. Patients taking Chantix should contact their doctors if they experience behavior or mood changes. Patients should use caution when driving or operating machinery until they know how quitting smoking with Chantix may affect them.” (1)

The FDA, in conjunction with Pfizer Inc., will continue to review data concerning the safety of Chantix®, the potential association with mood disturbances and the impact on driving or operating machinery. Patients and healthcare providers are encouraged to report adverse affects with Chantix® to the FDA via the MedWatch Adverse Event Reporting program available online at

1. Food and Drug Administration. Early communication about an ongoing safety review varenicline (marketed as Chantix). Available at Accessed November 21, 2007.

Breaking News: FDA Issues New Warnings for Haldol

September 21, 2007

haldol.jpgCommentary by Helen Kourlas, PharmD

On September 17th 2007, the FDA issued an advisory warning healthcare professionals to avoid the use of higher than recommended doses of haloperidol, marketed as Haldol, Haldol Decanoate and Haldol Lactate. In addition to this warning, the FDA also emphasized that the injectable form of haloperidol is only approved to be administered as an intramuscular injection. Common off – label intravenous administration of haloperidol has led to numerous case reports of QT prolongation, Torsades de Piontes (TdP) and sudden death. Seventy three reports of TdP resulted because of haloperidol use, and 8 of the 11 fatal cases were linked to the intravenous administration of haloperidol at various doses. These cases occurred in the absence of predisposing factors, such as electrolyte imbalances, underlying cardiac abnormalities, or the use of medications that are known to prolong the QT interval. Additional cases have also demonstrated a dose-response relationship between the intravenous haloperidol dose and the development of TdP. These events have led the FDA to update the product labeling of haloperidol to include a warning statement alerting healthcare professionals to observe and monitor patients receiving higher than recommended doses of haloperidol as well as patients receiving haloperidol through intravenous administration. Currently, although intravenous administration of haloperidol is a relatively common off label use, this advisory serves as a reminder that injectable haldol is not FDA approved for intravenous administration.

Information for Healthcare Professionals. Haloperidol.