Skip Ribbon Commands
Skip to main content

PsychsTalk: The Experts Blog About Mental Health

:

Quick Launch

Home
Estrogen for Depressed Menopausal Women

The phases of a woman’s life are demarcated by points of transition in her reproductive cycle. Global shifts in the hormonal milieu accomplish the transitions from child to woman, woman to mother, and mother to elder.

The major hormones of the female reproductive cycle include estrogens (estrone, estradiol and estriol), progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The effects of these reproductive hormones on a woman’s mood are most prominent not at points of lowest or highest expression but rather at times of rapid change in serum concentration.1

The transition to menopause is accomplished over many years, beginning with gradual increases in the levels of FSH and LH while the woman maintains regular cycling. During perimenopause, menstrual cycles become intermittent, and, in the 6 months around the time of the final menstrual period, estrogen levels markedly decrease. A corresponding decline in FSH and LH quickly follows, ultimately resulting in stably low levels of all reproductive hormones in the postmenopausal period.2

An increase in risk for depressive symptoms occurs during the menopausal transition. Common symptoms of perimenopause like insomnia and vasomotor symptoms may be important contributors to low mood.3 The cessation of menstruation is not itself depressogenic, as depressive symptoms are reduced after the completion of menopause.4

Transdermal estradiol has been found effective for perimenopausal depression in randomized controlled trials.5 But, in accordance with the hypothesis that it is the rapid alteration in estrogen levels rather than low serum estrogen itself that predisposes perimenopausal women to depressive symptoms, treatment with estradiol alone appears less effective for depressed women who have completed menopause.6 However, estradiol treatment in postmenopausal women has been found to enhance7 or accelerate8 the effect of antidepressant treatment, resulting in improved global well-being and quality of life over and above that obtained with the antidepressant alone.9 Thus, combination of estrogen with an antidepressant can be an effective strategy that in some cases is greater than the sum of its parts.

Estrogen treatment has a positive effect on physiological symptoms associated with menopause.10 To some degree, the positive effect of estrogen on mood in perimenopausal women may be mediated by mitigation of physiological symptoms,3 but the extent of the interrelationship is not yet clear.

Potential adverse effects of estrogen replacement therapy in older women include increases in risk for the development of coronary heart disease, pulmonary embolism, and breast cancer.11 Combined treatment with estrogen and a progestin does not appear to mitigate these effects and may in fact increase breast cancer risk relative to use of estrogen alone.12

Thus, extended periods of hormone replacement therapy for postmenopausal women are not recommended and indeed are not indicated given the lack of effect of estrogen for depression after menopause. However, estrogen replacement therapy can be a reasonable short-term treatment for managing depressive as well as physiological symptoms associated with perimenopause. We suggest a treatment period of no longer than 6 months to cover the period of adjustment to the lower estrogen state while avoiding the multiple adverse effects associated with long-term use of hormone replacement therapy.

Financial disclosure: Dr Robakis has received grant/research support from NIMH. Dr Rasgon has received grant/research support and/or honoraria from and/or is a consultant for Magceutics, American Diabetes Association, Corcept, Shire, Sunovion, and Takeda.

References

1. Deecher D, Andree TH, Sloan D, et al. From menarche to menopause: exploring the underlying biology of depression in women experiencing hormonal changes. Psychoneuroendocrinology. 2008;33(1):3–17. PubMed

2. Rannevik G, Jeppsson S, Johnell O, et al. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas. 1995;21(2):103–113. PubMed

3. Avis NE, Crawford S, Stellato R, et al. Longitudinal study of hormone levels and depression among women transitioning through menopause. Climacteric. 2001;4(3):243–249. PubMed

4. Freeman EW, Sammel MD, Liu L, et al. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry, 2004;61(1), 62–70. PubMed

5. Soares CN, Almeida OP, Joffe H, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58(6):529–534. PubMed

6. Morrison MF, Kallan MJ, Ten Have T, et al. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry. 2004;55(4):406–412. PubMed

7. Schneider LS, Small GW, Hamilton SH, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Am J Geriatr Psychiatry. 1997;5(2):97–106. PubMed

8. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3–4):338–343. PubMed

9. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9(4):393–399. PubMed

10. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Internal Med. 2006;145(12), 869–879. PubMed

11. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333. PubMed

12. Bakken K, Fournier A, Lund E, et al. Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2011;128(1):144–156. PubMed

Depression, Addiction, Suicide, and Robin Williams

The recent death of Robin Williams has brought up questions about the links between addiction and depression, or dual diagnosis. The Epidemiologic Catchment Area study conducted by the National Institute of Mental Health reported that nearly a third of individuals with depression also have a comorbid substance disorder at some point.1 The daughter of former US Senator George McGovern, who was treated for depression, froze to death after having been drunk and passed out in the cold.2

With the DSM-5, we no longer make the distinction between substance abuse and substance dependency but place them together under the diagnosis of substance use disorder. It is interesting that alcohol and the various drugs of abuse all seem to cause activation of the brain’s reward circuits, especially the dopamine neurons located in the ventral tegmental area (VTA) with projections to the nucleus accumbens.3 Repeated activation leads to euphoria and an alteration in the reward mechanism, which is defined by the addict as “craving” when the drug is not present. This process is often referred to as sensitization. Eventually, with increased tolerance, the individual feels sick most of the time and will use the drug to feel “normal.” Given sufficient consequences for alcohol or drug use, the person with an addiction will seek help through rehab and/or a 12-Step program and may achieve a period of sobriety. Unfortunately, even one drink can again sensitize the neural circuits to want more and more. Last September, in an interview with Jon Stewart, Williams described the loss of 20 years of sobriety: “The moment I had the first sip…it was like…rahh…all of a sudden it was like, welcome back a**hole.”

Depression is one of the most common forms of mental illness, affecting about 15% of the population.4 A number of different brain areas are affected, which create different symptoms. The frontal cortex may be involved with disturbances of cognition,5 the hippocampus with feelings of suicidality,6 and the VTA and nucleus accumbens may mediate anhedonia and decreased motivation.7 The fact is that addiction and depression seem to share common neural substrates.8

An additional factor in Robin Williams’ death is the news from Mrs Williams that her husband had early Parkinson’s disease. Each illness—depression and Parkinson’s—can worsen the other, with increases in problems with concentration as well as movement problems and anxiety.9 In Parkinson’s disease, the dopamine-producing brain cells die, which we know are linked to reward and pleasure. In the 1990 movie Awakenings, Robin Williams portrayed a physician at a hospital in the Bronx caring for patients suffering from catatonia caused by an encephalitis epidemic. After attending a lecture, Dr Sayer (Robin Williams) believes the Parkinson’s drug L-Dopa may help, and he gives it to patient Leonard Lowe (Robert DeNiro). Leonard “awakens,” falls in love, and desires freedom, but then he develops facial and body tics. The tics grow more prominent, Leonard starts to shuffle, spasms, and then cannot move. Leonard returns to catatonia.

In a 2010 interview with comedian Marc Maron, Williams spoke about contemplating suicide but said the big picture was far more positive than any of the troubles of the present. It is possible that, following the diagnosis of Parkinson’s, the big picture changed for Mr Williams. He may have made the decision to end his life now rather than face a living death of depression, dementia, and the catatonic-like rigidity of Parkinson’s disease.

Financial disclosure: Dr King had no relevant personal financial relationships to report.

References

1. 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(19):2511–2518. PubMed

2. McGovern G. Terry: My Daughter’s Life-and-Death Struggle With Alcoholism. New York, NY: Plume; 1997.

3. Gardner EL. Addiction and brain reward and antireward pathways. Adv Psychosom Med. 2011;30:22–60. PubMed

4. Bromet E, Andrade LH, Hwang I, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90. PubMed

5. Clark L, Chamberlain SR, Sahakian BJ. Neurocognitive mechanisms in depression: implications for treatment. Annu Rev Neurosci. 2009;32:57–74. PubMed

6. Labonté B, Suderman M, Maussion G, et al. Genome-wide methylation changes in the brains of suicide completers. Am J Psychiatry. 2013;170(5):511–520. PubMed

7. Kroemer NB, Guevara A, Teodorescu IC, et al. Balancing reward and work: anticipatory brain activation in NAcc and VTA predict effort differentially [published online ahead of print August 6, 2014]. Neuroimage. PubMed

8. Peña CJ, Bagot RC, Labonté B, et al. Epigenetic signaling in psychiatric disorders [published online ahead of print April 5, 2014]. J Mol Biol. PubMed

9. Raskind MA. Diagnosis and treatment of depression comorbid with neurologic disorders. Am J Med. 2008;121(11 suppl 2):S28–S37. PubMed

A Clinically Useful Self-Report Measure of the DSM-5 MDD Anxious Distress Specifier

During the past 20 years, the clinical significance of co-existing anxiety disorders and anxiety symptoms in patients with major depressive disorder (MDD) has been increasingly recognized. The prevalence is high, with the majority of depressed patients having either symptoms of anxiety or a comorbid anxiety disorder. Anxiety in patients with MDD predicts greater morbidity than in those without anxiety. Co-occurring anxiety has been associated with increased suicidality, greater impairment in functioning, worse health-related quality of life, poorer longitudinal course, greater number of depressive episodes, and poorer response to treatment in controlled efficacy studies and uncontrolled effectiveness studies. Clinicians indicated that anxiety was the symptom that most commonly influenced their choice of antidepressant for patients with MDD.

To acknowledge the clinical significance of anxious features in depressed patients, DSM-5 included criteria for an anxious distress specifier for MDD. With increased attention likely to be given to anxious depression because of the addition of this specifier, it is important that rating scales be developed that measure symptoms of both depression and anxiety. The development of new scales is particularly timely in the context of recent recommendations to measure outcome during routine clinical practice. Measurement-based care has been emphasized in official treatment guidelines for depression, as well as in DSM-5. Self-report questionnaires are a cost-effective option to implement measurement-based care because they require little time to administer and correlate highly with clinician ratings.

In a recent report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, my colleagues and I described a modification of a self-administered depression scale, the Clinically Useful Depression Outcome Scale (CUDOS), to include a 5-item subscale assessing the DSM-5 anxious distress specifier of MDD (CUDOS-A).

In a study of nearly 800 outpatients diagnosed with MDD, the CUDOS-A was found to be a reliable and valid measure of anxiety symptoms. The scale was more highly correlated with other self-report measures of anxiety than with measures of depression, substance use problems, eating disorders, and anger. The convergent and discriminant validity of the CUDOS-A was further supported by the finding that the measure was more highly correlated with clinician severity ratings of anxiety than of depression and irritability. In addition, CUDOS-A scores were significantly higher in depressed outpatients with anxiety disorders than in depressed outpatients without anxiety disorders. Consistent with other research on the high prevalence of anxiety in depressed patients, the majority of patients with MDD in our study met the DSM-5 anxious distress specifier on the CUDOS-A. Compared to patients who did not meet the DSM-5 specifier, the patients who did reported more functional impairment and poorer quality of life.

The CUDOS-A is the fourth in a series of “Clinically Useful” scales that were developed in the MIDAS project for use in clinical practice, with the other scales created to measure depression (CUDOS), anxiety (Clinically Useful Anxiety Outcome Scale [CUXOS]), and social anxiety (Clinically Useful Social Anxiety Disorder Outcome Scale). Each of the scales in the Clinically Useful series is intended to be brief, easily scored, and available to clinicians for personal use without cost. Each scale has the same rating instructions, which facilitates comparisons of symptom severity across varied symptom domains. The CUDOS and CUXOS are available for administration on the Internet on a free website that assists clinicians in monitoring the course of treatment (www.outcometracker.org).

Financial disclosure: Dr Zimmerman had no relevant personal financial relationships to report.

Why Become a Psychiatrist? The Id Speaks.

“I am not sure how you do it. I would never do this.” (Jolly good, then. I guess my job is safe for now, and so is the world…from you!)

“What is the point of wasting time on something you cannot cure?” (Ah, yes, and you just won the Nobel Prize for curing [insert illness name here]. What’s that? You can only manage it and not cure it? Interesting.)

There. I have finally blurted out the impure thoughts that have often crossed my mind during conversations with colleagues over the years. Years of simmering in a cauldron of narcissistic injury finally culminating in an eruption of bile, which, I suspect, I may have been stewing in all this while.

It comes as no surprise that a career in psychiatry is not particularly coveted by medical students worldwide,1 even though their clerkship experience may have positively influenced their attitudes toward the field.2 Stigma toward mental illness in general and stigmatization of students interested in psychiatry might serve as deterrents. A perceived lack of effectiveness of treatment and concerns about working with people with mental health issues may also turn students away from a career in the field.

Which begs the question, what makes me want to do it? Well, my interest in psychiatry could have something to do with fellow physicians who contemplated giving up their careers as their depression took root, the accomplished professor who was no longer able to do what she did best, the brilliant lawyer reduced to a shadow of herself, who were able to return to productive lives with the appropriate treatment. It may have to do with the medical student contemplating self-harm, who ultimately made it into a competitive residency program after receiving help. Or perhaps the manic lady who ranted for 45 minutes, only to capitulate and take her mood stabilizer “because you are the only one who has ever listened to me for this long.” The overwhelmed caregiver, the wife desperate to get her husband back, the son who lost his father to suicide, the anxious parents wanting their child to just be able to sit still for a while, and the wounded warrior unable to find solace even in the relative safety of his home. Their despair turning to hope as their treatment bore fruit. Their transformation, priceless.

Do any of these people sound like someone you might know? These people could easily be (and perhaps are) our loved ones, colleagues, and neighbors. And that is why a career in psychiatry matters. That is why, no matter how bad my workday might be, at the end of it, there is at least one person whose life is better for what I may have done for them. This is why I do what I do. Because it is worth it!

PS: The author reports no financial conflicts, but (in the recent words of a colleague) a number of ongoing psychological conflicts may be apparent to readers!

Financial disclosure: Dr Joshi had no relevant personal financial relationships to report.

References

1. Lyons Z. Attitudes of medical students toward psychiatry and psychiatry as a career: a systematic review. Acad Psychiatry. 2013;37(3):150–157. PubMed

2. Lyons Z. Impact of the psychiatry clerkship on medical student attitudes towards psychiatry and to psychiatry as a career. Acad Psychiatry. 2014;38(1):35–42. PubMed

Cost-Effectiveness and Patient Choice of PTSD Therapy

Participation in a treatment begins with choice of treatment. In evaluating efficacy or effectiveness, though, we often do not pay attention to this act of choosing, nor do we give much thought to whether choice in and of itself may lead to lower economic costs or improved patient outcomes. Nowhere is choice more important than for mental health treatments. Mental disorders often have causes both inside and outside the body. Individuals may have strong opinions about treatments that target biology, cognition, or behavior. Because of this, they may experience some relief of their distress when they receive the treatment that they prefer. They may also adhere to treatment better and be more willing to persist with therapy during setbacks.

The gold standard in research, the randomized clinical trial, ignores these benefits of choice. In fact, by its nature, the traditional randomized clinical trial prohibits choice. An alternative to this approach is a doubly randomized preference trial. This type of trial randomizes participants to either their choice of treatment or further randomization to an assigned treatment. The benefit of this design is that it separates the effect of choice from the effect of treatment on outcome.

My colleagues and I evaluated cost-effectiveness in a prospective doubly randomized choice trial of 2 treatments for posttraumatic stress disorder (PTSD). Specifically, we studied the incremental cost of obtaining a unit health effect in quality-adjusted life-years. We chose to study the effect of choice, a psychological therapy (prolonged exposure), and a pharmacotherapy (sertraline). We administered each treatment for 10 weeks and tracked patients for 1 year. We collected information on direct and indirect medical costs as well as effectiveness. Results suggest that giving patients a choice between prolonged exposure therapy and sertraline is a cost-effective shared decision-making strategy. In the absence of choice, prolonged exposure is more cost-effective than sertraline.

The traditional restriction of choice in our research methods has affected the dialogue in evidence-based practice. Our concern has revolved around the question, “Which treatment has greater efficacy or effectiveness?” This question drives systematic reviews, meta-analyses, cost-effectiveness models, and, ultimately, guidelines of care. Yet, effective treatments are not discovered through rigid adherence to this narrow scientific question. They arise in the context of decisions made by patients about which treatment they choose to pursue. The notion of what constitutes an effective treatment may depend in part on patient preferences. Giving patients a choice of either sertraline or prolonged exposure therapy for chronic PTSD may yield a benefit of its own. In general, we need to further explore whether shared decision-making should play a greater role in mental health guidelines.

Financial disclosure: Dr Doctor is a consultant for Baxter Biosciences and Precision Health Economics and has received grant/research support from Baxter Biosciences.

Time to Move on Physical Activity as Usual Care for Mental Illness

Physical inactivity is estimated to cause 9% of premature mortality worldwide,1 but recognition of the benefits of being physically active is increasing. In addition to the cardiometabolic benefits of regular bodily movement, physical activity has repeatedly been shown to have antidepressant and anxiolytic qualities, both as monotherapy and as adjunctive therapy.2,3

For people experiencing mental conditions beyond depressive disorders and anxiety, little evidence on useful treatment strategies is available. However, support exists for the notion of addressing the limited participation in physical activity seen among people with serious mental illnesses like schizophrenia, because a sedentary lifestyle happens to be a key modifiable risk factor for the development of metabolic syndrome. A recent editorial4 in The British Journal of Psychiatry made an urgent call “for better clinical trial evidence to determine how best to increase levels of physical activity”(p239) in people with schizophrenia, while a subsequent letter5 made reference to mental health physiotherapists as professionals ready to lead the charge in delivering evidence-based interventions.

Our review6 of 39 studies with varying participant diagnoses, including major depressive disorder and schizophrenia, aimed to determine what effect physical activity has on symptoms of depression in people with a mental illness, while also determining the impact on symptoms of schizophrenia, anthropometry, aerobic capacity, and quality of life.

The key findings were unsurprising, revealing that indeed physical activity is effective in improving both the physical health and mental health of people experiencing mental illness. However, the effect sizes of methodologically stronger trials were smaller than those of studies of a poorer quality. We also found that the intervention protocols were often poorly described, failed to utilize clinicians with expertise in exercise prescription, and often failed to meet basic principles of exercise programming.

Critics of physical activity interventions in people with mental illness often cite studies with negative findings such as those of Chalder et al,7 in which a predominantly telephone-based intervention had little effect on mood in a sample of participants with depression. Such interventions are unlikely to be comparable to, for example, supervised exercise programs incorporating an individualized prescription and incorporating both resistance- and aerobic-based components provided by allied health clinicians (such as exercise physiologists and physiotherapists). Unfortunately, this criticism reflects the current conceptualization (and subsequent lack of funding) of the role of physical activity as a diversion strategy rather than as a clinically meaningful intervention requiring clinicians with unique expertise.

At what point do we decide that sufficient evidence exists for a cultural change within psychiatric care, whereby exercise physiologists or physical therapists (and indeed dietitians) are considered as standard members of the multidisciplinary mental health team? Such paradigm shifts are often limited by the bottom line. Rather than looking at the cost of delivering such interventions, we need to consider the cost of failing to do so.

Financial disclosure: Mr Rosenbaum had no relevant personal financial relationships to report.

References

1. Lee I-M, Shiroma EJ, Lobelo F, et al. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet. 2012;380(9838):219–229. PubMed

2. Cooney GM, Dwan K, Greig CA, et al. Exercise for depression. Cochrane Database Syst Rev. 2013;9:CD004366. PubMed

3. Jayakody K, Gunadasa S, Hosker C. Exercise for anxiety disorders: systematic review. Br J Sports Med. 2014;48(3):187–196. PubMed

4. McNamee L, Mead G, MacGillivray S, et al. Schizophrenia, poor physical health and physical activity: evidence-based interventions are required to reduce major health inequalities. Br J Psychiatry. 2013;203(3):239–241. PubMed

5. Stubbs B, Probst M, Soundy A, et al. Physiotherapists can help implement physical activity programmes in clinical practice. Br J Psychiatry. 2014;204(2):164. PubMed

6. Rosenbaum S, Tiedemann A, Sherrington C, et al. Physical activity interventions for people with mental illness: a systematic review and meta-analysis [published online ahead of print March 31, 2014]. J Clin Psychiatry. doi: 10.4088/JCP.13r08765. Abstract

7. Chalder M, Wiles NJ, Campbell J, et al. Facilitated physical activity as a treatment for depressed adults: randomised controlled trial. BMJ. 2012;344:e2758. PubMed

Reintegrating Psychiatry and Neurology Is Long Overdue: Part 2

In my previous blog entry, I explained why the splitting of neurology and psychiatry is no longer conceptually justified. At the practical level, there are numerous advantages and very few drawbacks to reuniting neurology and psychiatry into a single discipline of clinical brain disorders. Using the academic tripartite mission, I’ll describe the expected benefits.

Research. All clinical knowledge has to be discovered before it is taught and applied to patient care, so the positive impact on research must be highlighted first. Neurology and psychiatry have separately conducted their own studies with barely any collaboration with each other. Thus, there has been a dearth of testable hypotheses that integrate both the hardware (brain) and software (mind). A tragically high number of investigative opportunities were lost by failing to collaborate. Every neuroscience discovery has implications for ordinary brain functions as well as higher brain functions. By reuniting and integrating the 2 specialties into 1 department, disruptive translational neuroscience discoveries are more likely to emerge, substantively changing the current models of conceptualizing, diagnosing, and treating brain disorders.

Teaching and Training. The training for future clinical neuroscience practitioners must integrate the current neurologic and psychiatric training methods in order to assess and manage every patient with any brain disorder in a 360° approach. Every graduate of an integrated department would concurrently conduct neurologic-psychiatric history and examination and amalgamate the findings into a 360° diagnostic and treatment plan. Trainees would become adept at (1) recognizing and localizing the primary and secondary brain “lesions” that produce the patients’ physical and mental symptoms and (2) consistently looking at the consequences of a neurologic lesion on sensory and motor functions and concomitantly on cognitive behavior, thought, emotions, mood, and behavior. Here is one example of how the current un-integrated training overlooks important findings: patients with first-episode psychosis are rarely given a full neurologic exam by a psychiatry resident. Yet, researchers have consistently found that a substantial proportion of drug-naïve patients with first-episode psychosis have hypokinesia, dyskinesias, and dystonias. Because they are not documented in clinical settings, those movement disorders are attributed to iatrogenic effects of antipsychotics following the initiation of pharmacotherapy. Such undetected findings have neurobiological, diagnostic, and treatment implications. Trainees of an integrated program will develop a multidimensional view of the brain and all of its neuropsychiatric dysfunctions and their effects on patients’ functional outcomes.

Clinical Care. The salutary effects of integrating neurology and psychiatry on patient care are a genuine no-brainer. Every patient with a brain disorder (including mental symptoms) deserves a comprehensive 360° evaluation and management. Clinical and functional outcomes will be optimized with a neuropsychiatric approach. Another important benefit to psychiatric patients under the integrated model is the reduction in the stigma of mental illness. When the mind is recognized as a neurologic component of the brain, the ignorant discrimination toward psychiatric disorders will gradually disappear.

In medical schools, another important benefit of combining neurology and psychiatry is the improved fiscal integrity of the unified department. Neurology is associated with many well-reimbursed procedures (eg, EEG, EMG, lumbar puncture, botulinum toxin injections), while psychiatry is not. Thus, a combined department is more likely to have a healthier bottom line than a psychiatry department. In addition, due to economy of scale (eg, 1 chair instead of 2, 1 set of committees, 1 set of clinic receptionists and staff), the overhead is lower, and the faculty have more time to see patients, teach, mentor, or write research grant applications.

In conclusion, there are conceptual, academic, and practical benefits of reintegrating the 2 currently separate neuroscience disciplines of neurology and psychiatry. Reintegration is what Saint Louis University School of Medicine boldly initiated 7 years ago. This model should be given serious consideration by medical school deans and adopted by all medical schools, leaving behind the archaic, old-fashioned model of sequestering brain and mind disorders in separate departmental silos. Our patients with brain disorders deserve better because every “neurologic” disorder is associated with psychiatric sequelae and every “psychiatric” disorder has neurologic underpinnings. The remarkable neuroscience revolution will thrive further with an integrated model of brain disorders.

Financial disclosure: Dr Nasrallah is a consultant for Boehringer-Ingelheim, Genentech, Gruenthal, Janssen, Lundbeck, Merck, Otsuka, Roche, and Sunovion; has received grant/research support from Roche, Forest, and Otsuka; has received honoraria from Boehringer-Ingelheim, Forum, Genentech, Gruenthal, Janssen, Lundbeck, Merck, Otsuka, Roche, and Sunovion; and is a member of the speakers/advisory boards for Janssen, Otsuka, Genentech, Forum, Merck, and Sunovion.

Do We Frown Because We Are Depressed or Are We Depressed Because We Frown?

Smiling makes us feel better! In a TED talk, researcher Ron Gutman discussed the facts that people with bigger smiles tended to live longer lives, have happier marriages, and appear more competent to others.1 In addition, smiling can reduce stress levels by decreasing cortisol, and improve mood by increasing endorphins.1 Gutman’s talk received criticism as it was unclear whether the link between smiling and success was correlative or causative.2

According to evolutionary theorist Charles Darwin and philosopher/psychologist William James, the relationship is causative—we are happy because we smile, we are sorry because we cry, and we are angry because we clench our teeth, not the other way around.3,4 In other words, changes in facial expression create and enhance emotion and are not merely a consequence of that emotion.

If facial expression can influence emotional experience, then what would happen if depressed patients were no longer able to frown?

Three recent studies5–7 (with sample sizes of 30 to 85) set out to answer this question. Male and female participants with major depressive disorder were injected with botulinum toxin A (BTA) into the forehead region, causing a reduced ability to frown (ie, paralysis of the corrugator and procerus muscles, which control expressions of fear, anxiety, and anguish). In all 3 double-blind, placebo-controlled trials, BTA was associated with a statistically significant reduction in depressive symptoms compared with placebo. More interestingly, in our 24-week trial,7 the antidepressant effects of BTA continued even after the cosmetic effects had worn off.

If botulinum toxin in the frown muscles improves symptoms of depression, why?

Some may argue that looking aesthetically better leads to feeling better, but our study7 excluded those with concern about their frown lines. Others argue that the more pleasant and less depressed we look, the more inviting we are to others, leading to improved social interactions and, subsequently, improved mood. These arguments, however, do not explain why mood continues to improve even when the BTA is no longer cosmetically active.

A final argument is that BTA in the forehead alters peripheral feedback to the brain. A recent study8 showed that people who were given BTA in the frown muscles had reduced activity in the left amygdala on functional magnetic resonance imaging (fMRI) when mimicking angry facial expressions. In theory, paralysis of the forehead muscles reduces sensory information from the trigeminal tract to the brainstem, which then alters activity between the brainstem and left amygdala. These findings are important as hyperactivity in the left amygdala has been linked to anxiety, depression, posttraumatic stress disorder, and heightened fear responses.9 In one study,10 20 depressed patients exhibited exaggerated left amygdala activity when shown pictures of emotional faces, especially fearful faces. After antidepressant treatment, left amygdala hyperactivity returned to normal.

Is botulinum toxin a viable treatment option for major depressive disorder?

Regardless of whether one subscribes to a more behavioral or biological mechanism of action, further trials are warranted to determine if BTA is indeed a viable therapeutic option for depression and if specific patient populations are more likely to respond (eg, a recent study11 showed that higher agitation scores are predictive of response). If larger trials can replicate the findings of the 3 small trials, BTA may become a novel treatment in the management of major depressive disorder.

Financial disclosure: Dr Magid received grant/research support from the Brain and Behavior Institute, Young Investigator Award, to fund this study. After completion and as a result of the study, Dr. Magid became a consultant for Allergan.

References

1. Gutman R. The hidden power of smiling. TED Talks. March 2011. http://www.ted.com/talks/ron_gutman_the_hidden_power_of_smiling.

2. Grohol J. Ron Gutman: smiling while confusing correlation with causation. http://psychcentral.com/blog/archives/2012/08/19/ron-gutman-smiling-while-confusing-correlation-with-causation/.

3. Darwin, C. The Expression of the Emotions in Man and Animals. London, England: John Murray; 1872.

4. James, William. The Principles of Psychology. New York, NY: Henry Holt & Co; 1890.

5. Wollmer MA, de Boer C, Kalak N, et al. Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res. 2012;46(5):574–581. PubMed

6. Finzi E, Rosenthal NE. Treatment of depression with onabotulinumtoxin A: a randomized, double-blind, placebo controlled trial [published online ahead of print December 16, 2013]. J Psychiatr Res. Abstract

7. Magid M, Reichenberg JS, Poth PE, et al. Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry [published online ahead of print May 13, 2014]. Abstract

8. Hennenlotter A, Dresel C, Castrop F, et al. The link between facial feedback and neural activity within central circuitries of emotion—new insights from botulinum toxin-induced denervation of frown muscles. Cereb Cortex. 2009;19(3):537–542. PubMed

9. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35(1):169–191. PubMed

10. Sheline YI, Barch DM, Donnelly JM, et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001;50(9):651–658. PubMed

11. Wollmer MA, Kalak N, Jung S, et al. Agitation predicts response of depression to botulinum toxin treatment in a randomized controlled trial. Front Psychiatry. 2014;5:36. PubMed

Reintegrating Psychiatry and Neurology Is Long Overdue: Part 1

For over a century, neurology and psychiatry were united in one discipline and one department in medical schools, representing a brain specialty. Neuropsychiatry dealt with all aspects of that divinely complex organ, from sensory, motor, vascular, or neoplastic to cognition, speech, thought, emotions, and behavior. Upon graduating from a unified neuropsychiatric department, some physicians focused on the physical brain disorders such as stroke, epilepsy, Parkinson’s, or multiple sclerosis, while others focused on the mental brain disorders such as psychosis, depression, anxiety, or pathological behaviors. This is not different from contemporary ophthalmology departments, where graduates of training programs subspecialize in disorders of the cornea, the lens, the retina, neuro-opthalmology, or ocular infectious diseases.

So why did the unified brain specialty split during the 1950s? Although multifactorial, a prominent reason was the rise of the theoretical, nonempirical psychoanalytic model that permeated and dominated psychiatric departments in that era. That was in stark contrast with the empirical, nontheoretical neurologic training and practice. The “organic vs. functional” dichotomy was accentuated, and the jargon of psychiatry alienated neurologists, who adhered to traditional medical terminology. This led to the “secession” of neurology that created separate journals and associations and a separate board exam. For the past 60 years, psychiatry and neurology retreated into their respective silos in all medical schools and rarely interacted clinically, an amazing paradox given that they dealt with the same organ! However, the alienation became so entrenched that cynics regarded psychiatry as brainless and neurology as mindless!

Fortunately, the neuroscience revolution came to the rescue and has elucidated the multiple links between brain and mind. The past 3 to 4 decades witnessed unprecedented advances in elucidating brain-behavior linkages and the neuroanatomic, neurochemical, neurophysiologic, and neurologic correlates of mental functions. Thanks to breakthroughs in structural and functional neuroimaging and accelerating advances in molecular neurogenetics, the medical foundations of psychiatry have become well established. The neuropsychiatrists of a century ago always assumed that the mind is a product of cortical activity, but they lacked the technological tools to demonstrate it.

Thus, from a conceptual perspective, the splitting of neurology and psychiatry is no longer justified. However, reunification, while urgently desirable, will be slow because practitioners on both sides, trained and inculcated with the model of brain-mind dualism, may be reluctant to merge, and many might remain entrenched in their “separateness.” Nevertheless, the shift to a modern, scientifically valid paradigm of integrating psychiatry and neurology has begun and will ultimately be widely adopted. A motivated cadre of neuropsychiatrists and behavioral neurologists must serve as leaders and catalysts to overcome the inertia of decades of alienation.

In my next blog entry, I’ll discuss the numerous practical advantages of reuniting neurology and psychiatry into a single discipline.

Financial disclosure: Dr Nasrallah is a consultant for Boehringer-Ingelheim, Genentech, Gruenthal, Janssen, Lundbeck, Merck, Otsuka, Roche, and Sunovion; has received grant/research support from Roche, Forest, and Otsuka; has received honoraria from Boehringer-Ingelheim, Forum, Genentech, Gruenthal, Janssen, Lundbeck, Merck, Otsuka, Roche, and Sunovion; and is a member of the speakers/advisory boards for Janssen, Otsuka, Genentech, Forum, Merck, and Sunovion.

Science, Rhetoric, and the End of Psychosis

Recently, I have been told that incivility in the debate about early intervention in psychosis alienates the undecided. Exaggerated claims of cures and prevention on one side and caustic criticisms on the other side combine to reinforce the folk-wisdom of avoiding the company of fanatics, or at least of not discussing religion, politics, or psychosis at dinner parties.

The less partisan position appears to be a mildly skeptical suspension of judgment. Seductive hope that schizophrenia is a preventable neurodegenerative process is balanced against inconclusive evidence, leading to the thought, “I am open to the possibilities, but I am not yet convinced.”

As a critic of early intervention analysis, I have often heard, “Yes, evidence is lacking, but if rhetoric attracts greater funding, even for a small subset of patients, where’s the harm in pretending?”

My answer generally involves grabbing a lapel and offering a passionate defense of the scientific method. Early intense intervention for psychosis has not led to miraculous cures, although outcomes are better while the support continues.1 Pretending that early intervention modifies the disease prevents the scientific accumulation of knowledge, where each step depends on the accuracy of previous steps. Funding driven by optimistic misrepresentations of early intervention means alternative treatments that may actually modify the disease attract less funding.

The problem is compounded by the distorting effects of politics. Early interventionists in Australia have attracted public funds to specialist units2 based on optimistic misinterpretations of data. Once large sums have been sunk into bricks and mortar based on poor quality evidence, it becomes less politically possible to change course even if alternatives that do change the course of schizophrenia are empirically justified.

It is easy for skeptics to convince themselves of the prevalence of bias in the early intervention literature. My recent article provides many examples,3 and two are particularly illuminating. Consider the 10-year follow-up of the early detection of psychosis experiment by Hegelstad and colleagues.4 How convincing is a study that changed its primary outcome at 1 year, from relapse to symptoms, when the initial primary outcome showed no difference, and then changed its primary outcome again at 10 years, from symptoms to a novel measure of recovery, when symptom measures favored the control group? Next, compare McGorry’s statement that the OPUS study demonstrates the “disease-modifying” effect of early intense intervention5 with the conclusion by OPUS authors that “no basic changes in illness were seen after 5 years from the start of the program.”1(p770)

These examples demonstrate the confirmatory bias that dominates early intervention research. Until this evidence is accurately interpreted, the early intervention crusade will serve only to obscure the true nature of psychotic illness and retard scientific progress toward a cure.

Financial disclosure: Dr Amos had no relevant personal financial relationships to report.

References

1.  Bertelsen M, Jeppesen P, Petersen L, et al. Five-year follow-up of a randomized multicenter trial of intensive early intervention vs standard treatment for patients with a first episode of psychotic illness: the OPUS trial. Arch Gen Psychiatry. 2008;65(7):762–771. PubMed

2.  Department of Health and Ageing. Major Expansion for headspace as EPPIC Moves Forward. May 23, 2013. Available at: http://www.agedcare.com.au/aged_care_news.php?title=major_expansion_for_andltemandgtheadspaceandlt_emandgt_as_eppic_moves_forward_463. Accessed March 24, 2014.

3.  Amos AJ. A review of spin and bias use in the early intervention in psychosis literature. Prim Care Companion CNS Disord. 2014;16(1):e1–7. Abstract

4.  Hegelstad WT, Larsen TK, Auestad B, et al. Long-term follow-up of the TIPS early detection in psychosis study: effects on 10-year outcome. Am J Psychiatry. 2012;169(4):374–380. PubMed.

5.  McGorry PD. Truth and reality in early intervention. Aust N Z JPsychiatry. 2012;46(4):313–316. PubMed

1 - 10Next