Amy’s 5 years in New York City had been a success. She completed college and earned an internship in a prestigious publishing house before the economy collapsed. Her bachelor of arts degree with honors brought no job prospects, however, because no one was hiring. Fortunately, her recent mental health “report card” was as good as her college transcript.

She had bipolar disorder that was largely quiescent, so much so that it was barely on the radar as graduation rolled by. She kept appointments, always remembered her medications, and never needed hospitalizations, unlike family members whose severe symptoms reportedly worsened with alcohol overuse. Only 2 challenges remained: she needed a job and an income, and she wanted to tame her trichotillomania (TTM). Her TTM worsened under stress and never fully responded to behavioral techniques, such as habit reversal therapy recommended by experts.

Medications had little effect on her hair-pulling. Amy’s struggles were not surprising, considering the difficulty of treating TTM. A favorite symptom-substitution behavioral technique-plucking orthodontic rubber bands fitted to the fingertips-was no help. Nor was the hand-held rubber band ball sold by office supply stores. High doses of serotonin reuptake inhibitors or any dose of clomipramine or fluvoxamine brought more adverse effects than positive effects. Anticonvulsants that treated her bipolar disorder had no effect on her TTM, even though they kept her mood swings in check. Naltrexone helped a little but hurt her stomach a lot.

Drawing Venn diagrams to show how TTM symptoms overlap with OCD, impulse control disorder, anxiety, and even addiction explained her symptoms without offering relief. And Amy needed relief, especially if she returned to the family business while waiting out the financial storm. It was immaterial that there might be more than a chance association between bipolar disorder and TTM.

From experience, she knew that her TTM surged in response to her emotionally explosive family. Family dinners literally made her “pull her hair out,” as the saying goes. She had avoided visits home, until economic necessity left her little choice.

Superficially, Amy’s home sounded picture perfect. Flower gardens flourished, as often occurs in the South. Yet Amy insisted that the occupants of the picture-perfect house were far from perfect. She said that she came from a hybrid of Tennessee Williams and William Faulkner.

Her mention of gardens got me to thinking, not just about fragrant flowers but also about “symptom substitution,” an old-time favorite of behavioral psychologists. Which activities most resemble hair-pulling? Weeding, for one. I had heard anecdotal stories about persons with TTM who like to weed-while most people, dedicated gardeners included, dread this task. So, I suggested that Amy try weeding, adding disclaimers that I did not know of case-controlled studies to support this approach, but at least it might beautify the family’s flowerbeds.

Instead of laughing, Amy recollected her grandfather, the mild-mannered member of the clan who kept to himself. He tended his garden and avoided the arguments that consumed his siblings. Skeptical at first, she said that she would give it a try if for no other reason than to avoid more medication adverse effects or arguments with managed care companies about coverage.

Before moving home permanently, Amy returned for a weekend to attend her brother’s birthday celebration. She scheduled an extra appointment before she left, fearing that another family fight would send her reeling. Yet that did not happen this time around. On her return, she reported that she spent time weeding the garden and next to no time pulling out her hair.

Admittedly, retreating to the garden instead of sitting through suppertime shouting matches is a respite from stress, weeding or no weeding. She had a polite excuse to escape explosive sibs who lowered their lithium and upped their alcohol. Gardening with her grandfather, the most benign family member, also offered support. The “experiment” succeeded, perhaps for all the reasons mentioned above. With no time or money for case-controlled studies to “weed out” placebo effects or halo effects or other variables, we agreed to make do with what worked, especially since there seemed to be no downside to applying this approach while she transitioned treatment.

I subsequently found a surprising number of scholarly (and not so scholarly) reports on the subject. Amazon sells at least a dozen books about horticulture therapy. The history of medicine literature offers compelling centuries-old anecdotes. Benjamin Rush (1749-1813), the “Father of American Psychiatry,” signer of the Declaration of Independence, and namesake of Rush Medical College in Chicago, recommended “horticulture therapy” to his patients and to prison inmates.

 Rush wrote the first systematic textbook on mental diseases in America.

In addition to anecdotes, studies show that growing plants improves moods of nursing home and hospice residents. Of course, looking forward to just about anything improves mood, anywhere. Unfortunately, gardening does not guarantee 100% success, and grave disappointments may follow months of hard work.

Data documenting horticulture therapy’s benefits for persons with autism spectrum disorder are also impressive, but not entirely unexpected, since gardening employs non-verbal skills and circumvents direct human interaction. It seems that rehabilitation journals publish more articles on this subject than psychiatry journals.

Michigan State University and Kansas State University offered academic degrees in the field in the 1950s and 1960s. Interest in such approaches waxed and waned over the years but subsequently spread far beyond the Great Plains. At times, horticulture therapy was parodied for its place in “funny farms” and fossilized in the opening scene of Martin Scorsese’s 

 More recently, horticulture therapy became more urbane as the Bronx-based New York Botanical Gardens developed a “horticulture therapy” certificate program, as have several other botanical gardens across America. European horticulture programs have a much longer history.

Yet weeding is weeding and is only one part of gardening. Luckily, Amy felt that “uprooting” weeds was similar enough to “uprooting” her hair to make this “symptom substitution” technique work for her. It remains to be seen if insurers will be convinced enough to reimburse for horticulture therapy and if they will recognize the newly minted Horticulture Therapy certificates. I doubt that gardeners need much convincing about gardening’s benefits overall.

Dr. Packer is affiliated with Mt. Sinai Beth Israel and has a private practice in Soho, NYC. Her most recent book is 

 is in press and scheduled for release in the summer of 2017.

1. Grant JE, Chamberlain SR. Trichotillomania. 

2. Verinder Sharma V, Baczynski C. Trichotillomania and bipolar disorder. 

3. Relf D. Horticulture: a therapeutic tool. 

Horticulture as Therapy: Principles and Practice

5. SÃ¶derback I, SÃ¶derstrÃ¶m M, SchÃ¤lander E. Horticultural therapy: the ‘healing garden’ and gardening in rehabilitation measures at Danderyd hospital rehabilitation clinic. 

Articles

Her mention of gardens got me to thinking, not just about fragrant flowers but also about “symptom substitution,” an old-time favorite of behavioral psychologists. Which activities most resemble hair-pulling? Weeding, for one.

Taming Trichotillomania While Weeding the Garden

There’s a slight imbalance in our therapeutics for bipolar disorder. While patients spend most of their time in the depressed phase, the FDA-approved treatments for mania outnumber those for depression 4 to 1.

First, here are my biases. In addition to the FDA-approved options, I will consider any treatment with at least one randomized, controlled trial that supports its merits. I tend to favor those with large effect sizes (eg, pramipexole) or low risks (eg, omega-3 fatty acids). I also value treatments with long-term data, even when their short-term benefits are debatable (eg, lamotrigine, psychotherapy). This is, after all, a chronic condition.

The ideal treatment for bipolar depression would 

 in the short term and prevent new episodes in the years to come. Examples of these 

 include lamotrigine, lithium, a few atypical antipsychotics (olanzapine-fluoxetine combination, quetiapine, lurasidone, cariprazine), and possibly valproate.

Bipolar disorder may be chronic, but its episodes need not be.

How to choose among them? Collaborate. Adherence hovers around 50% in bipolar disorder, so it behooves us to ask patients about their hopes and fears in treatment. If fast results are desired, the atypical antipsychotics may be best. More often, patients value tolerability, in which case lamotrigine and lithium might come first. Practitioners often question lamotrigine’s efficacy and lithium’s tolerability, but new research suggests those reputations may be undeserved.

Next in line are medicines that can treat acute bipolar depression without destabilizing mood. These are best paired with a mood stabilizer, since they won’t prevent new episodes on their own. I have left antidepressants off this list because their mood-destabilizing potential has not escaped the eye of controlled 

 To be fair, all the options on this list probably have some mood-destabilizing potential, as this problem is notoriously difficult to detect in research (and in practice). The non-antidepressants that made the cut are 

, modafinil, armodafinil, thyroid augmentation, 

 (with more than 60% eicosapentaenoic acid), 

, L-methylfolate, pioglitazone, and celecoxib.

Pramipexole is noteworthy because it has a large effect size (0.77 - 1.1) and lacks detrimental effects on weight, sexuality, and cognition.

 Modafinil and armodafinil also share that side-effect profile, although the research on these agents is not as clearly positive as it is for pramipexole.

 In my experience, these novel stimulants rarely break through severe depression but often improve residual symptoms such as cognition and fatigue. For patients, however, that can make the difference between staying in bed and returning to work.

Thyroid augmentation is particularly useful in lithium-treated patients, in whom keeping the thyroid-stimulating hormone level close to 2.6 mIU/L lowers the risk of depressive relapse.

Among devices, ECT has long been known to surpass pharmacologic options for unipolar depression, and a recent 

 confirmed that effect in bipolar depression.

 Transcranial magnetic stimulation has a smaller effect size than ECT, but it appears to work equally well in unipolar and bipolar depression.

Light therapy has promising open-label studies and a positive controlled trial (when paired with 

) in bipolar depression. Although morning light has been associated with mania, the problem can be reduced by using the lightbox at noon and reducing its duration.

My top choices in this category are Social Rhythm Therapy (SRT), 

Cognitive Behavioral Therapy for Insomnia-Bipolar (CBT-ib)

The benefits of exercise compare favorably with those of antidepressants, and in one 

 exercise surpassed antidepressants in maintaining remission.

 The dose is relatively low: brisk walking, 45 minutes every other day. Though research is lacking in bipolar depression, from what we know about its mechanism (exercise raises levels of brain-derived neurotrophic factor [BDNF]), it is likely to work.

That raises a question: Can exercise trigger mania? I think not, unless the patient is exercising in place of sleep. BDNF levels are low in 

 Exercise also deepens sleep quality, which could improve manic states. If done at regular times, exercise might stabilize mood by setting the biological clock, which is the mechanism behind the next 2 therapies.

Regular rhythms of sleep and daytime activity are the focus of the 2 therapies I’ve highlighted: 

. These approaches are better at preventing relapses than resolving acute episodes.

 For example, patients saw little change in their mood after a 2-month course of CBT-ib, but 4 months after completing the therapy, they had an 8-fold improvement in days well.

 That’s a remarkable benefit, and the delay is just as important to emphasize. People are less likely to give up prematurely when they know what to expect.

The most important expectation to clarify for people with bipolar depression is this one: they should expect, and do deserve, a full recovery. Bipolar disorder may be chronic, but its episodes need not be.

This article was originally posted 5/10/17 and has since been updated.

Dr. Aiken is the Director of the Mood Treatment Center and an Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He does not accept honoraria from pharmaceutical companies but receives honoraria from W.W. Norton & Co. for 

1. Fountoulakis KN, Grunze H, Vieta E, et al. 

The International College of NeuroPsychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BD-2017), part 3: the clinical guidelines

2. Durgam S, Earley W, Lipschitz A, et al. 

An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression

The ‘disconnect’ between initial judgments of lamotrigine vs. its real-world effectiveness in managing bipolar disorder. A tale with wider ramifications

Handbook of Diagnosis and Treatment of Bipolar Disorders

 Washington, DC: American Psychiatric Publishing; 2009.

5. Viktorin A, Lichtenstein P, Thase ME, et al. 

The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer

6. Sublette ME, Ellis SP, Geant AL, Mann JJ. 

Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression

7. Nierenberg AA, Montana R, Kinrys G, et al. 

L-methylfolate for bipolar I depressive episodes: an open trial proof-of-concept registry

Pramipexole in psychiatry: a systematic review of the literature

Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies

10. Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. 

Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials

Light therapy in the treatment of patients with bipolar depression: a meta-analytic study

12. Babyak M, Blumenthal JA, Herman S, et al. 

Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months

13. de Sousa RT, van de Bilt MT, Diniz BS, et al. 

Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: a preliminary 4-week study

14. Oud M, Mayo-Wilson E, Braidwood R, et al. 

Psychological interventions for adults with bipolar disorder: systematic review and meta-analysis

15. Harvey AG, Soehner AM, Kaplan KA, et al. 

Treating insomnia improves mood state, sleep, and functioning in bipolar disorder: a pilot randomized controlled trial

Here: a plethora of treatment options, including mood-lifting stabilizers, non-antidepressants, psychotherapy, and lifestyle interventions.

What’s New in Bipolar Depression?

Genetic information is slowly working its way into psychiatric practice and our patients’ daily lives.

 Pharmacogenomic panels can be ordered by psychiatrists, and genetic testing is being sold to the general public without any involvement of physicians or genetic counselors. The practicing psychiatrist needs to be informed about both of these types of services.

When pharmacogenomic panels started to hit the market about 5 years ago, most general psychiatrists greeted this option with understandable skepticism. Now the use of these tests is growing, both in numbers of genes tested and in the number of psychiatrists utilizing them.

According to Daniel Dowd, PharmD, Vice President of Medical Affairs at Genomind, one of the two leading commercial pharmacogenomic services, close to 5000 clinicians are currently using Genomind’s panel, and the company has recently logged its 100,000th test. “What we’re actually seeing in practice is most psychiatrists are ordering this for the treatment-resistant patients with 2 or more treatment failures,” says Dr. Dowd. “But in the pediatric patient population, they’re more likely to order it for treatment-naive patients.”

John A. R. Grimaldi Jr, MD, Instructor at Harvard Medical School (HMS) and attending outpatient psychiatrist at Brigham and Women’s Hospital (BWH), says he has had many patients ask about these genetic panels, and 2 patients brought in genetic panels ordered by their previous psychiatrist. “There is a real need for guidance about the use of these ‘assays’,” says Dr. Grimaldi. “I can imagine that ‘genetic assays’ would be useful with treatment-resistant patients, if the assay were paid for by insurance and if there were an evidence base to support interpretation.”

As a new neuropsychiatry fellow, I started to use pharmacogenomic testing for some of my patients last year when I inherited and started to collect a patient caseload filled with very complicated people. Some had tried many different psychiatric medications with little effect, or with significant and sometimes surprising adverse effects.

My supervisor and mentor, Barry Fogel, MD, Professor of Psychiatry at HMS and staff neurologist and psychiatrist at BWH, had asked me if I had considered pharmacogenomic testing. I objected that I did not know anyone who had ever used this testing, and that I did not know how to order it or how much this would cost my patients. Dr. Fogel gently pointed out that these were not insurmountable barriers.

When I looked into the options for pharmacogenomic testing, I found multiple companies offering similar panels, some of which had booths at the American Psychiatric Association meeting in May 2017. The biggest and most well-established providers of pharmacogenomic testing are GeneSight and Genomind.

GeneSight currently offers 4 panels: psychotropic, analgesic, ADHD, and methylene tetrahydrofolate reductase (MTHFR). The GeneSight website states that its “Psychotropic laboratory developed test analyzes how patients’ genes may affect his/her metabolism and response to FDA-approved medicines . . . .”

The psychotropic panel looks at genes for liver enzymes that are responsible for the metabolism of most neuropsychiatric medications. It tests for various gene alleles and classifies the possible phenotypes as ultra-rapid, extensive, intermediate, or poor metabolizers. The panel also tests for a few genes not related to hepatic metabolism of psychotropic drugs, which are receptor polymorphisms with potential pharmacodynamic implications.

Genomind has one panel, the “Genecept Assay.” The assay includes genes encoding the serotonin transporter, calcium channel, sodium channel, serotonin receptor 2C, melanocortin 4 receptor, dopamine 2 receptor, catechol-O-methyltransferase, alpha-2A adrenergic receptor, MTHFR, brain-derived neurotrophic factor, Î¼-opioid receptor, and glutamate receptor, as well as a number of the hepatic cytochromes. According to Dr. Dowd, Genomind has received the most positive feedback from clinicians regarding the serotonin transporter gene (

) and the 2 weight-gain–related genes on the panel (

). Dr. Dowd asserts that certain serotonin transporter gene alleles identify people with lower response and remission rates and more adverse effects when treated for depression with SSRIs and that certain alleles of 

 imply a significantly higher risk of weight gain if the patient is treated with an atypical antipsychotic drug.

Shaun Purcell, PhD, Associate Professor of Psychiatry at HMS and a genetic epidemiologist who was involved in some of the studies to identify genes as risk factors for mental disorders, believes psychiatrists have ample cause to be cautious about using genetic testing. “To me, the evidence is underwhelming to say the least. It’s definitely concerning that these kinds of tests are being pushed prematurely.”

For the non-metabolic genes on the panel, Dr. Purcell says, “I’d question the basic assumptions and science behind the panel. As far as I’m aware, these genes are coming from studies of disease risk.” He adds, “It’s a different thing to have an association in the literature and to have it be clinically meaningful.”

Dr. Purcell continues: “The associations of major psychiatric illness with common variants in 

 are unambiguously sound. They say nothing about what implications these variants have, if any, for guiding treatment.” He adds, “There is a fundamental disconnect between what is being claimed and the extant evidence base for 

.” He also questions the premise that any of the other non-metabolic genes tested on the GeneSight and Genomind panels have clinical utility. “There’s no evidence that these variants are going to be clinically actionable in terms of guiding treatment.”

Dr. Fogel, who is generally in favor of clinicians considering pharmacogenomic testing for difficult-to-treat patients, agrees with Dr. Purcell that the clinical relevance of some of the genes on the panels is questionable. He says, “Will getting a gene associated with BDNF actually make more of a difference than getting a BDNF level? I don’t think so.” Regarding Genomind’s listed “treatment impacts” for the 

 genes, Dr. Fogel says, “A methylfolate supplement and exercise would usually be good for a patient no matter what their genotype.”

Of course, the evidence is different for each gene on the panels. For example, take the serotonin transporter gene, 

, which is heavily studied. The short form of the serotonin transporter-linked polymorphic region is associated with reduced activity of the serotonin transporter (low expression) and with higher levels of intrasynaptic serotonin. The long form (high expression) is associated with increased activity of the serotonin transporter and lower levels of intrasynaptic serotonin.

This variation has been associated with affective disorders and with pathological behaviors and personality traits related to anxiety, impulsivity, and stress.

 For example, those with a low-expression form of the 

 serotonin transporter gene have a bias to pay attention to both negative and positive affective pictures.

 This suggests that the serotonin transporter gene might be a plasticity gene rather than a vulnerability gene-the low-expressing form allowing people to tune in to the affective significance of their surroundings.

More relevant to pharmacogenetic testing is the question of whether variations in the serotonin transporter gene can guide prescribing. The literature on this is fairly robust, with 33 studies included in the most recent meta-analysis in 2012. Of 3 meta-analyses published between 2007 and 2012, 2 found that the long/long (

) genotype in Caucasians was associated with response to antidepressants, mostly SSRIs, and all 3 found that carrying the l allele was associated with remission.

 genotype predicts antidepressant response in Asians is less clear.

A 2016 pilot study of 35 patients showed that the 

 allele was associated with better response to desvenlafaxine.

 The genetic connection to treatment response may not only differ by ethnicity, but by age. A 2015 study of 234 patients with late-life depression showed that at least one 

 allele was associated with about a 2-fold probability of having a good SSRI response.

 Although the serotonin transporter gene has literature supporting its clinical relevance, there does not seem to be a clear, simple connection between genotype and treatment response.

But what about the CYP liver enzyme gene variations? The relationship of these liver enzymes to drug metabolism is not in question. “We cannot say who is going to respond to what,” Dr. Fogel says. “But the drug metabolism is pretty well established, and there are genotypes that imply someone is going to be a slower or faster metabolizer of certain drugs. That may be relevant in clinical situations where getting to a therapeutic drug level or avoiding a drug interaction or an unintentional overdose is really going to be a problem for the patient.” He adds, “You have some very specific situations where you can say it really makes sense to have advance intelligence on what sort of metabolizer this person with this drug will be.”

For my patients, getting information about drug metabolism from the genetic panels helped me build a therapeutic alliance and/or choose which drug to try next when the first drug I prescribed was not effective. One patient’s results showed slow metabolism for every psychotropic she had ever tried. She found this validating, as she had experienced an unusual amount of adverse effects, and we were able to pick a new option from the short list of medications she metabolizes well. Another patient felt reassured when his panel indicated that his metabolism was normal for almost everything. Thereafter, he expressed fewer concerns about trying new medications. A third patient felt validated that her testing supported her intolerance of and lack of response to SSRIs, and she was more willing to try other classes of antidepressants.

John F. Sullivan, MD, Instructor at HMS and neuropsychiatrist at BWH, has ordered GeneSight panels for 3 of his patients who “would have dramatic adverse reactions to tiny doses of anything, regardless of the medication’s mechanism. One of these patients had panic attacks to his multivitamin.” Dr. Sullivan found the results of the genetic testing useful to demonstrate that the severe adverse reactions his patients had to a multitude of medications were not related to a biologic process.

Laura Safar, MD, also an Instructor at HMS and neuropsychiatrist at BWH, has ordered panels for several patients and found that the information helped her understand patients’ response to medication adverse effects. The panels either validated patient concerns or, in one of her cases, supported her impression that the patient’s high levels of adverse effects to very low doses of medications were due to anxiety

Do genetic panels change patient outcomes? The largest GeneSight study was conducted in 2013, when the company had only a 5-gene pharmacogenomics test. This open-label study compared 114 patients whose clinicians had access to the GeneSight report (“guided”) with 113 patients whose clinician could not see the report (“unguided”). After 8 weeks, the guided group had a 70% greater improvement in depression scores, as well as better remission rates. Participants in the unguided group who at baseline were prescribed a medication that was “most discordant with their genotype” experienced the least improvement.

Genomind did an unblinded study of its 10-gene panel in 2013, with 685 patients and a variety of diagnoses. The study showed that 91% of patients with 2 or more prior treatment failures had clinically measurable improvement, but the study was limited by having no treatment-as-usual comparison group.

It is fair to say that there is not a large body of evidence to prove that ordering genetic panels affects treatment decisions or the course of disease.

Jane Erb, MD, Assistant Professor at HMS and Clinical Director of the Brigham Depression Center, has not incorporated genetic testing into her practice because “as of a couple of years ago, the data were not convincing that the information improved outcomes.” She says, “I have seen a handful or two of patients who have had testing run by others, and I’ve reviewed the results, which did not seem to explain the patients’ medication responses.”

Gaston Baslet, MD, Assistant Professor at HMS and attending neuropsychiatrist at BWH, says genetic testing “needs to be put in context with many other clinical factors that are usually going to be the ones directing my decision, such as factors obtained from a detailed med history.” He adds, “I therefore don’t think that the amount of time and effort in getting these results would be contributing enough to my decision-making to justify their regular use. Of course, there are exceptions to every rule.”

Putting the genetic information into clinical context is very important. A study published in January 2017 showed that less-experienced psychiatrists tended to be more influenced by genetic information than older psychiatrists.

 The study presented 67 psychiatrists with patients’ pre- or post-treatment scores on the Positive and Negative Syndrome Scale for 2 hypothetical treatments for schizophrenia. Psychiatrists were also informed whether the patient possessed a genotype linked to hyper-responsiveness to one of the treatments, and they were asked to recommend one of these two treatments. Less-experienced psychiatrists were inclined to believe the genetic information more than the clinical report of how patients responded to different drugs in the past, and to recommend treatment based on the genotype. McMichael and colleagues concluded that “psychiatrists and other clinicians should be cautious about allowing a patient’s genetic information to carry unnecessary weight in their clinical decision-making.”

Barriers to adoption of pharmacogenomics include changes in workflow and the time and effort involved in signing up at the company’s website, ordering test kits, obtaining cheek swabs, and sending in the samples. However, for both GeneSight and Genomind panels, collecting the samples was easy-a quick cheek swab in the office-and results were back within 2 weeks. Cost is also a major concern. Both companies do their best to get insurance companies to pay and promise that the most a patient will ever be charged (even with no insurance coverage) is in the low $300s.

In the future, we should expect expansion of the use of pharmacogenomic testing. The industry is growing rapidly, and in the next year or two the panels are expected to have more variants. There may be information on the genetic panels that can help determine how likely a patient is to respond to ECT or transcranial magnetic stimulation, but so far these are relatively small studies and need to be replicated.

With GeneSight and Genomind, the business model is for physicians to order the panels. But, there are services that offer direct-to-consumer genetic testing, such as 23andMe.

Last year, 23andMe was like fast food: fairly quick, kind of fun, and with little substance. It provided carrier status for 39 genetic diseases and not much else in the way of health information.

Before 2013, 23andMe used to provide a lot of clinical data, from carrier status for hereditary cancers to information about drug metabolism. Dr. Purcell comments that the original 23andMe genetic testing “included some patently bogus reports for psychiatric diseases including schizophrenia.”

In 2013, the FDA cracked down on the company for not getting proper approval to market what the FDA considered to be a medical device. 23andMe responded by significantly slimming down their panel. Now, they are building it back up. This year, 23andMe has a few new “Genetic Health Risk Reports”: the 

 genes for hereditary thrombophilia, and the 

 gene for alpha-1 antitrypsin deficiency. As a physician who treats dementia, I was surprised and dismayed to see that the 

 Alzheimer risk gene has returned to 23andMe after being removed in 2013. In general, though, health information is limited.

To get an idea of what these genetic tests provide, I decided to try 23andMe. What did I learn? I have fewer Neanderthal variants than 88% of customers. I am genetically more likely to have a “photic sneeze,” or sneeze in the sunlight (and I do). I am less likely to be a deep sleeper and am more likely to move in my sleep.

I was not surprised to find out that I am 63.2% British and Irish; a slow coffee metabolizer; unlikely to have a cleft chin, unibrow, dimples, or a widow’s peak (indeed, I don’t); and that my earlobes are likely to be detached (they are). I was very surprised to learn that I am more likely than others to be able to smell the asparagus metabolite in urine, though I can say with complete honesty that my curiosity about myself had never once strayed toward that question.

There is a way around the limitations of 23andMe: download your raw data, then upload it to another program to tease out the health information. The program I used is Promethease, which costs $5 to $10 depending on the source of the DNA. Promethease describes itself as “a literature retrieval system that builds a personal DNA report based on connecting a file of DNA genotypes to the scientific findings cited in SNPedia.”

The Promethease report is a far cry from the simplistic, jargon-free, and sparsely populated pages of the 23andMe website. For each gene variant, Promethease provides information about the frequency of that genotype in your population (eg, Caucasian), the location of the gene, and the number of papers published.

As with 23andMe, the information in Promethease was often amusing. For example, I have an allele that was associated with good memory in a Swiss cohort. I unfortunately do not have a gene associated with longevity in Japanese men. Some of the “genos” were helpful or enlightening: my single copy of the C677T allele of 

 puts me at some risk of having low vitamin B

 and folic acid. Of course, some were anxiety-provoking, like risk factors for cardiovascular disease, diabetes, and various inflammatory and neurological diseases.

Although I am of the general persuasion that knowledge is power, I find it reassuring that, even as a doctor with some (albeit limited) knowledge of genetics, it was not a simple process for me to find my own genetic risk factors. While some patients could certainly wade through their own Promethease data and glean appropriate or useful information, most people will likely not go beyond the information available on the 23andMe website.

Dr. Allen is a Clinical Fellow in Neuropsychiatry, Brigham and Women’s Hospital, Boston, MA. 

Dr. Allen reports no conflicts of interest concerning the subject matter of this article.

 Serretti A, Calati R, Mandelli L, et al. Serotonin transporter gene variants and behavior: a comprehensive review. 

 Fox E, Zougkou K, Ridgewell A, Garner K. The serotonin transporter gene alters sensitivity to attention bias modification: evidence for a plasticity gene. 

 Porcelli S, Fabbri C, Serretti A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. 

 Ng CH, Bousman C, Smith DJ, et al. A prospective study of serotonin and norepinephrine transporter genes and the response to desvenlafaxine over 8 weeks in major depressive disorder. 

 Seripa D, Pilotto A, Paroni G, et al. Role of the serotonin transporter gene locus in the response to SSRI treatment of major depressive disorder in late life. 

 Hall-Flavin DK, Winner JG, Allen JD, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. 

 Brennan FX, Gardner KR, Lombard J, et al. A naturalistic study of the effectiveness of pharmacogenetic testing to guide treatment in psychiatric patients with mood and anxiety disorders. 

 McMichael AJ, Boeri M, Rolison JJ, et al. The influence of genotype information on psychiatrists’ treatment recommendations: more experienced clinicians know better what to ignore. 

Have you considered using pharmacogenomic testing in your practice?

Weighing the Benefits of Genetic Information in Clinical Psychiatry

The latter part of the 20th century saw the psychiatric research community striving for their work to be accepted as quantitative and scientific. Since the birth of psychodynamic psychotherapy at the turn of the century, the field has struggled to move away from untested theories about the causes of mental illness toward an empirically validated scientific discipline. This struggle was epitomized elegantly in Paul Meehl’s classic “Why I Do Not Attend Case Conferences,” which spells out reasons why he felt psychiatric and psychodynamic case conferences at the time were not adequately rigorous (eg, “reward everything-gold and garbage alike”).

Candace Pert, a psychoneuroimmunologist who helped discover the opiate receptor-the cellular binding site for endorphins in the brain-and whose research into brain biochemistry contributed to a new understanding of relations between the mind and body, said that she was pleased that psychology was “finally becoming scientific.”

, illustrates her perspective: “Most psychologists treat the mind as disembodied, a phenomenon with little or no connection to the physical body . . . But the body and mind are not separate, and we cannot treat one without the other.”

The advent of modern clinical neuroscience techniques over the past 3 decades-including non-invasive brain imaging and brain stimulation-along with a concerted effort by the psychiatric academic community, has firmly placed academic psychiatry within the so-called “hard sciences.” Indeed, coursework in research methods, empirically supported treatments, and neuroscience are standard in most, if not all, psychiatric research programs in this country. The result has been a new generation of psychiatric researchers who routinely investigate mental illnesses with modern clinical neuroscience tools.

Perhaps inevitably, one result of this shift is that a segment of the field has expressed that the pendulum has swung too far. To be clear, the transition of the field toward more quantitative and rigorous methods is met with near-universal applause. However, the ever-increasing reliance on measures of physiology has left some researchers pondering whether the field has drifted from its roots. This shift in priorities toward neuroscience-based research is no more evident than in the funding priorities of the National Institute of Mental Health (NIMH), which has a current budget of over $1.4 billion.

Although it is difficult to quantify precisely how much of NIMH’s funding supports brain-based research, understanding the biological basis of mental disorders is a high priority for NIMH. The research includes describing the molecules, cells, and neural circuits associated with complex behaviors and disorders as well as identifying the genomic factors associated with mental illnesses. Other federal funding agencies that support psychiatric research, including the National Institute on Drug Abuse and the National Institute on Child Health and Development, also emphasize research into the biological basis of mental illness.

The backlash against this prioritization includes various arguments: that a focus on biological processes does not allow for free will and human agency, that a “neurocentric” view of the mind obscures the factors that shape our behavior and identities and risks undermining selfhood and personal responsibility, and that explaining the mind will always be a personal vision, not a scientific fact.

In “There’s Such a Thing as Too Much Neuroscience,” 

 Op-Ed contributor Dr. John C. Markowitz, a professor of clinical psychiatry at Columbia University and a research psychiatrist at the New York State Psychiatric Institute, argued that diverting much of the NIMH budget away from clinical studies and into neuroscience research does little to help patients who are suffering from psychiatric illnesses.

 He highlights the shift in emphasis from DSM toward “research domain criteria” (RDoC). Rather than focusing on DSM diagnoses, RDoC focuses on unitary constructs related to mental disorders. He recognizes that RDoC emphasizes understanding these clinically relevant constructs at various levels of analysis, including genes, molecules, cells, brain circuits, physiology, and behavior. However, he laments that the fruits of such multi-level approaches will likely not be borne for a decade or more, and hopes that the newly appointed director of the NIMH, Dr. Joshua Gordon, will prioritize clinical studies to “re-establish that balance” between neuroscience and clinical research.

Any psychiatric researcher undoubtedly feels solidarity with Dr. Markowitz’s yearning for better treatments that will help patients today rather than in decades and for clinically oriented research that will hasten the development of new therapies. Indeed, it was clinically oriented research that yielded the state-of-the-art first-line psychotherapies for many psychiatric conditions, including the current gold-standard cognitive-behavioral therapies for depression and anxiety.

Dr. Thomas Insel, former director of the NIMH, stressed in his January 2013 TED Talk that other fields of medicine-including oncology, infectious diseases, and cardiology-have made remarkable progress developing treatments for previously incurable diseases using biological approaches. Sadly, this stands in sharp contrast to psychiatry, where the prevalence of most disorders has remained remarkably flat since reliable data were first available in the 1950s. In fact, the prevalence estimates of some disorders, such as autism, have increased, and the World Health Organization recently reported that psychiatric disorders currently account for 30% of disability from all medical causes worldwide. Clearly, the field must do more to decrease the suffering of patients with psychiatric illnesses.

The RDoC represents a paradigm shift in how research into psychiatric conditions is conceptualized. A hurdle presented by DSM is that its use of polythetic criterion sets is a barrier against the development of novel treatments. For example, according to DSM, a diagnosis of major depression is contingent on a patient having at least 5 of 9 depressive symptoms. This results in a diagnostic system in which 2 patients may have vastly different symptom constellations yet be classified with the same disorder. This introduces a high degree of heterogeneity into each disorder, and it is thus not surprising that a given antidepressant treatment, for example, is effective for only about 25% to 50% of patients with major depression.

A consequence of relying on DSM for clinical research is that many psychiatric treatments are minimally effective for many patients, and most patients must endure a painful process of trial-and-error over months or even years to find an effective treatment. The use of RDoC hopes to overcome this barrier by focusing on unitary constructs to minimize the heterogeneity in how patient symptoms are classified.

There are 3 prevalent misconceptions about RDoC. First, the emphasis of RDoC on understanding neurobiological systems at multiple levels has led many to erroneously believe that because RDoC is “pro-neuroscience” it must be “anti-behavior.” Indeed, Dr. Markowitz suggests that a research proposal that focuses on a symptom is rarely funded by the NIMH compared with research on a “neurosignature,” a brain-based biomarker of disease etiology. It is critical to realize that RDoC stresses understanding a clinical phenomenon, such as anxiety, at multiple levels, from cells to brain circuits to behavior. RDoC does not under-value behavior; rather it stresses that behavior must be understood within the context of other relevant units of analysis. Behavior has not been jettisoned. In fact, it has been elevated to an equal footing with understanding complex molecular processes and brain systems.

Second, there is the mistaken belief that NIMH no longer values clinical trials. This is not the case: the NIMH has invested heavily in new clinical trials to speed the development of novel psychiatric treatments, including behavioral therapies, medications, and device-based techniques such as magnetic brain stimulation. What has changed, however, is that NIMH-funded clinical trials must now include measures that explain how a treatment works by assessing so-called “mechanistic targets.” These targets may be neuroscience-based (brain scans, for example), but may also be behavioral (appraisals of images of sad faces, for example). In other words, this new approach to clinical trials is not “anti-behavior” but is instead “pro-mechanism,” and such mechanisms may certainly incorporate behavioral measurements. This emphasis will help the field learn how and why certain treatments work to inform the development of new interventions.

Finally, there is the belief that the NIMH does not value psychosocial intervention research but instead favors device- or medication-based interventions. In fact, in December 2016, the NIMH released a specific request for applications to develop psychosocial therapeutics and preventive interventions for mental disorders, which represents a significant investment of research dollars specifically for psychosocial treatment development.

RDoC reflects what psychiatric research has taught us over the past 2 decades: psychiatric disorders are, in fact, brain disorders. These illnesses, without a doubt, have their roots in how the brain develops and functions. That does not imply that behavior is not relevant or that talk therapies are ineffective. Indeed, some of the most effective psychiatric interventions are cognitive and behavioral treatments that influence thinking and behavior patterns.

In the current era of brain imaging technologies that have begun to make substantial progress delineating brain systems implicated in psychiatric illnesses, to deny the brain bases of these illnesses is no longer tenable. Moreover, brain and behavior are inexorably linked and dynamically influence each other. This interaction between the brain and behavior implies that comprehensive progress cannot be made to relieve the suffering of patients without systematically addressing the brain basis of such conditions. To develop treatments for heart disease, we must study the heart, and likewise to develop treatments for brain disorders, we must study the brain (including its downstream output, behavior).

Although modern neuroscience research is still relatively young, breakthroughs have emerged that will likely yield new therapeutic approaches for the treatment of psychiatric disorders.

 We must invest in neuroscience-based research to develop innovative psychosocial and pharmacologic treatments that provide symptom relief by targeting relevant brain systems. Although it will be painful to wait for these treatments to arrive, we must continue to prioritize such efforts if we hope to have the success stories in psychiatry that have been achieved in other fields of medicine.

Dr. Dichter is Associate Professor, Department of Psychiatry and Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC.

 Meehl PE. Why I do not attend case conferences. In: Meehl PE, ed. 

. Minneapolis, MN: University of Minnesota Press; 1973:225-302.

 Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. 

Molecules of Emotion: The Science Behind Mind-Body Medicine

 Morse S. Determinism and the death of folk psychology: two challenges to responsibility from neuroscience. 

Brainwashed: The Seductive Appeal of Mindless Neuroscience

A Skeptic’s Guide to the Mind: What Neuroscience Can and Cannot Tell Us About Ourselves

. New York: St. Martin’s Griffin; 2014.

 Markowitz JC. There’s such a thing as too much neuroscience. 

https://www.nytimes.com/2016/10/15/opinion/theres-such-a-thing-as-too-much-neuroscience.html?_r=0

 Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. 

 Department of Health and Human Services. 

https://grants.nih.gov/grants/guide/rfa-files/RFA-MH-17-604.html

 Felipe RM, Ferrao YA. Transcranial magnetic stimulation for treatment of major depression during pregnancy: a review. 

Interaction between the brain and behavior implies that comprehensive progress cannot be made to relieve the suffering of patients without systematically addressing the brain basis of such conditions.

Vol 34 No 7

Taming Trichotillomania While Weeding the Garden

What’s New in Bipolar Depression?

Weighing the Benefits of Genetic Information in Clinical Psychiatry

Neuroscience Research for Psychiatry: The Brain and Behavior Link

Restless Legs Syndrome: Clinical Implications for Psychiatrists

Welcome to the Editorial Board, Dr. Miller!

Housestaff Haiku

Culture as a Factor in Adherence: Learning From Latino Experiences

Introduction: Problems of Poor Adherence

Harnessing Patients’ Own Motivation to Engage in Pharmacotherapy

Cannabis-Induced Psychosis: A Review

Integration Redux