Arline Kaplan

Recent large-scale registry and brain imaging studies are exploring the validity of this ancient observation, which linked creativity/genius and psychopathology. The results are mixed. Since the terms “genius” and “creativity” have different definitions, 

 asked neuropsychologist and creativity expert Rex Jung, PhD, Assistant Professor in the Department of Neurosurgery, University of New Mexico, to clarify how the terms are being used in scientific studies.

According to Jung, the best definition of creativity is found in a 1953 article

: creativity is defined as the production of something novel and useful. “This dynamic tension between novelty and usefulness likely has important neural correlates that we are attempting to explore with neuroimaging techniques,” said Jung.

“Genius,” he added, “is achievement at the far margins of human expression (eg, creative, intellectual, leadership). It involves production of extraordinary accomplishment and creative capacity that is exceedingly novel and breathtakingly useful. This capacity is, by definition, rare in spite of the tendency to sprinkle the term liberally throughout our daily endeavors. It is hypothesized to occur at the exceedingly rare rate of 1 per 1 million individuals, which implies that there are fewer than 7000 geniuses on the entire planet.”

The idea that creativity and psychopathology are inextricably linked is widespread but highly controversial. R. Keith Sawyer, PhD, Morgan Distinguished Professor in Educational Innovations at the University of North Carolina at Chapel Hill, cited several studies that examined creative individuals.

 “None of these studies found an elevated degree of mental illness in creative people.”

Simon Kyaga, MD, a senior consultant in psychiatry and PhD student in the Department for Medical Epidemiology and Biostatistics at the Karolinska Institute in Stockholm, contends that early studies by Andreasen,

 which focused on schizophrenia and bipolar disorder, have provided limited empirical evidence for the relationship between creativity and psychopathology. The problem may be that many earlier studies have been small and/or were done retrospectively.

Kyaga has been lead investigator on 2 Swedish studies on the association between creativity and psychopathology. “The main strengths of our studies are that they involve a lot of people, and while the analysis is retrospective, the collection of data is prospective.”

The researchers undertook a nested case-control study using longitudinal Swedish total population registries.

 Individuals who had received inpatient treatment for schizophrenia, bipolar disorder, and unipolar disorder and their relatives without the disorders were compared with controls. As a proxy for creativity, the researchers used occupational codes and census information. Artistic and scientific occupations were defined as “creative” and included university teachers, authors, visual artists, photographers, composers and musicians, designers, and performing artists.

The researchers found an increase in creative occupations among individuals with bipolar disorder and among relatives of patients with schizophrenia and bipolar disorder. No association was found for unipolar depression.

The second study involved 1.2 million patients and their relatives without psychiatric diagnoses compared with controls.

 The earlier study was expanded by adding other psychiatric disorders and including discharge diagnoses for inpatient treatment between 1973 and 2009 as well as some outpatient episodes from 2001 to 2009.

With the exception of bipolar disorder, no association between psychopathology and overall creativity was found. On the contrary, creative professionals had a reduced likelihood of having schizophrenia, schizoaffective disorder, unipolar depression, anxiety disorders, alcohol or drug abuse, autism, or ADHD. However, the team observed that the siblings of patients with autism and first-degree relatives of patients with schizophrenia, bipolar disorder, and anorexia nervosa were over-represented in the creative professions.

“I would say our findings on autism are a bit shaky, although there is some literature suggesting an association between scientific occupations and autism,” Kyaga said. “There is no literature suggesting an association between anorexia and creativity, and I have to say we really didn’t know what to do with that.”

Aware that findings from earlier studies suggest a higher prevalence of psychopathology among professional authors, Kyaga and colleagues looked at that group separately. They found that authors suffered from schizophrenia and bipolar disorder more than twice as often as controls. In addition, compared with controls, authors were more likely to have unipolar depression, anxiety disorders, and alcohol or drug abuse disorders, and to commit suicide.

The study of creativity is a “growth industry” for cognitive neuroscientists, according to Jung. For example, Fink and colleagues

 from the University of Graz in Austria, investigated functional patterns of brain activity using functional MRI (fMRI) during creative cognition in groups with low versus high psychometrically determined schizotypy. They found an association between the originality component of creativity and reduced deactivation of right parietal brain regions and the precuneus during creative cognition, congruent with the idea that people who are more creative may include many more events/stimuli in their mental processes than do less creative people. Similarly, the high-schizotypy group showed weaker deactivation of the right precuneus during creative cognition.

According to these researchers, the fact that originality and schizotypy show similar functional brain activity patterns during creative ideation (ie, reduced deactivation of the right precuneus) supports the contention that similar mental processes may be implicated in creativity and in psychosis risk.

The neuroimaging techniques Jung finds most helpful in assessing brain traits include structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (1H-MRS).

 Jung explained, “sMRI informs us mostly about the cortical mantle, including the volume of neuronal cell bodies. . . . DTI gives information regarding the fidelity of the myelin/axonal fibers connecting such processing nodes, while 1H-MRS gives us information regarding underlying biochemical fidelity of both neurons (via 

-acetylaspartate) and axons (via choline and myoinositol), as well as neurotransmitters including glutamate and glutamine.”

Asked about his team’s brain imaging studies, Jung said that funding by the John Templeton Foundation “has allowed us to explore all the major measures of creativity (eg, divergent thinking, creative achievement, insight, and openness) and correlate these with our various neuroimaging techniques in rather large cohorts of normal human subjects. If creativity exists, it should be detectable across the entire range of human endeavors.”

 His team has produced 3 reports highlighting the first biochemical, white matter, and structural correlates of creative cognition in human subjects.

Jung and his team are now focused on less studied scientific creativity (science, technology, engineering, math). “Our first results have been submitted and are consistent with our findings in a more general population: lower measures of brain fidelity, particularly within the frontal lobe, are predictive of higher performance on measures of creative capacity, creative personality and achievement. . . . This is different than what we found in terms of intelligence correlates, where higher measures of brain fidelity were invariably associated with higher intelligence. Creativity and intelligence are different constructs and manifest differently within networks of the brain.”

With respect to creativity and mental illness, their study on white matter integrity, creativity, and psychopathology provides some guidance. Jung and colleagues used DTI to examine whether white matter integrity, assessed by fractional anisotropy (FA), is related to 2 measures of creativity-divergent thinking and openness to experience. They found that a composite creativity index was inversely related to FA within the left inferior frontal white matter and openness was inversely related to FA within the right inferior frontal white matter.

Jung and his team recommend that measures of creative cognition and personality should be administered in tandem with DTI measures to patients with psychotic disorders and to their unaffected relatives to better understand the mechanisms underlying lower FA, creativity, and psychosis within frontal white matter.

 is using neuroimaging to examine the neural basis of the creative process. The psychological and neural basis of the creative process is being examined: half of the subjects represent the arts and the other half, the sciences. The subjects are being interviewed, given standard neurocognitive tests, and sMRI and fMRI brain scans are taken.

Jung believes that to his knowledge “no well-known creative output was produced in the thrall of overt psychosis, mania, or other mental state that could be pointed to as critical to the process. . . . Perhaps the time between overt episodes is a time worth discussing as critical to creative cognition for such individuals, and the possibility of medications dampening or hindering such innovation or output should be explored. The risk of severe mental illness would appear to outweigh any potential benefit at the current time.”

 Sawyer RK. Creativity and mental illness: is there a link? November 2, 2012. http://www.huffingtonpost.com/dr-r-keith-sawyer/creativity-and-mental-ill_b_2059806.html. Accessed March 4, 2014.

 Andreasen NC. Creativity and mental illness: prevalence rates in writers and their first-degree relatives. 

 Jamison KR. Mood disorders and patterns of creativity in British writers and artists. 

 Karlsson J. Genetic association of giftedness and creativity with schizophrenia. 

 Kyaga S, Lichtenstein P, Boman M, et al. Creativity and mental disorder: family study of 300,000 people with severe mental disorder. 

 Kyaga S, LandÃ©n M, Boman M, et al. Mental illness, suicide and creativity: 40-year prospective total population study. 

 Fink A, Weber B, Koschutnig K, et al. Creativity and schizotypy from the neuroscience perspective. 

 Jung RE, Mead BS, Carrasco J, Flores RA. The structure of creative cognition in the human brain. 

 Rex Jung. How are intelligence and creativity related to brain structure and function? http://www.rexjung.com. Accessed March 5, 2014.

 Jung RE, Gasparovic C, Chavez RS, et al. Biochemical support for the “threshold” theory of creativity: a magnetic resonance spectroscopy study. 

 Jung RE, Segall JM, Jeremy Bockholt H, et al. Neuroanatomy of creativity. 

 Jung RE, Grazioplene R, Caprihan A, et al. White matter integrity, creativity, and psychopathology: disentangling constructs with diffusion tensor imaging. 

 Meet Dr Nancy Andreasen. http://www. nancyandreasen.com. Accessed March 5, 2014.

Articles

Since the terms “genius” and “creativity” have different definitions, Psychiatric Times asked a neuropsychologist and creativity expert to clarify how the terms are being used in scientific studies.

Creativity and Mental Illness

A recent systematic review and meta-analysis that compared benzodiazepines with antidepressants for anxiety disorders has triggered a debate among clinicians about first-line treatments, efficacy for specific disorders, and adverse effects.

 gathered data through 2012 on published, controlled, and direct comparisons between benzodiazepines and antidepressants for anxiety disorders but were hindered, they said, by a “paucity of studies.”

Their review encompassed 22 studies, 18 of which compared TCAs, such as amitriptyline, clomipramine, or imipramine, with benzodiazepines. Of the remaining studies, 3 compared SSRIs or SNRIs with benzodiazepines and 1 compared the MAOI phenelzine with benzodiazepines. Eleven studies in the meta-analysis compared a ben-zodiazepine with a TCA for the treatment of panic disorder with or without agoraphobia.

While there has been a shift in recent years toward using such newer antidepressants as SSRIs and SNRIs as first-line treatments for anxiety disorders instead of benzodiazepines, Giovanni Andrea Fava, MD, Clinical Professor of Psychiatry at the State University of New York at Buffalo and one of the review’s coauthors, questioned whether the shift is warranted. “There is no evidence to suggest that antidepressant drugs are more effective than benzodiazepines in anxiety disorders,” he said. “Certainly, benzodiazepines have fewer side effects.”

In their review, the authors cited results for various anxiety disorders. “In mixed anxiety, GAD [generalized anxiety disorder], and social phobia, a superior efficacy of TCAs did not clearly emerge,” they said. They acknowledged that studies “with mixed anxiety were difficult to evaluate because of the heterogeneous features of the samples and the confounding effects of depressive symptoms.” The meta-analysis of treatments for panic disorder showed “less efficacy” and tolerability of TCAs than benzodiazepines, according to the review authors.

In trials that compared benzodiazepines with the newer antidepressants, the benzodiazepines “resulted in comparable or greater improvements and fewer adverse events in patients suffering from GAD or panic disorder,” Offidani and colleagues added. Hackett and colleagues

 compared diazepam and venlafaxine extended-release in 540 patients with GAD. Results showed no significant differences in response rates between groups, but discontinuations and adverse effects were more frequent in patients treated with venlafaxine.

 compared lorazepam, paroxetine, and placebo for treatment of patients with GAD. “Both active treatments were effective in reducing anxiety-related psychiatric symptoms, while somatic features improved significantly only in patients taking lorazepam.”

 conducted a randomized, open-label, naturalistic 8-week study to compare the efficacy and safety of treatment with clonazepam and paroxetine in patients with panic disorder with or without agoraphobia. Clonazepam resulted in fewer weekly panic attacks at week 4 and greater clinical improvements at week 8. Anxiety severity was significantly reduced with clonazepam at weeks 1 and 2, with no difference in panic disorder severity. Patients treated with clonazepam had fewer adverse events than patients treated with paroxetine. The most common adverse effects were drowsiness/fatigue (57%), memory/concentration difficulties (24%), and sexual dysfunction (11%) in the clonazepam group and drowsiness/fatigue (81%), sexual dysfunction (70%), and nausea/vomiting (61%) in the paroxetine group.

Offidani and colleagues also cited a long-term follow-up study by Nardi and colleagues

 that compared the efficacy and safety of clonazepam and paroxetine over 3 years of treatment. Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression of Improvement rating than treatment with paroxetine. Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine (28.9% vs 70.6%; P < .001).

On the basis of their systematic review and meta-analysis, Offidani and colleagues concluded that the change in the prescribing pattern that favors newer antidepressants over benzodiazepines in the treatment of anxiety disorders “has occurred without supporting evidence.”

Fava, who is also Professor of Clinical Psychology at the University of Bologna in Italy, believes the shift to the newer antidepressants was for “purely commercial reasons.” He told 

, “The shift from benzodiazepines to antidepressants is one of the most spectacular achievements of propaganda in psychiatry. . . . The use of antipsychotics for anxiety disorders follows the same lines.”

In an editorial citing the systematic review, Karl Rickels, MD,

 founder of the Mood and Anxiety Disorders Section at the University of Pennsylvania and Stuart and Emily B. H. Mudd Professor of Behavior and Reproduction in Psychiatry, called for more comparison studies and contended that “no evidence for the superiority of the newer antidepressants over benzodiazepines, in terms of both efficacy and safety, exists for either short-term or long-term treatment.”

Peter Roy-Byrne, MD, Professor of Psychiatry at the University of Washington and one of the contributors to the American Psychiatric Association’s Practice Guideline for the Treatment of Panic Disorder (2009), criticized the study by Offi-dani and colleagues as being of limited value for informing clinical practice today. “I think it is a flawed study, for the simple reason that it compares benzodiazepines with older antidepressants.”

The older antidepressants, he explained, have a greater adverse effect burden than the newer ones, so it is much easier to show some advantage for benzodiazepines in comparison studies. In addition, TCAs are now rarely used for anxiety disorders.

Fava and Roy-Byrne disagreed about using benzodiazepines as first-line treatment for anxiety disorders. “Benzodiazepines should be considered first-line pharmacological treatment for all anxiety disorders with the possible exception of obsessive-compulsive disorder,” said Fava, adding that drugs generally should not be the first-line treatment for anxiety disorders, because psychotherapy is very effective.

“I don’t think anybody anymore realistically thinks benzodiazepines should be used as first-line [pharmacological] treatments,” Roy-Byrne countered. He also questioned the practice of using benzodiazepines to help reduce anxiety during the initial weeks of treatment with antidepressants when anxiolytic effects have yet to occur.

 “In my experience, except in rare cases, using low doses of antidepressants and being in contact with patients frequently enough to answer their questions and provide them reassurance is usually sufficient to help them get used to the antidepressant over time. It introduces more logistic complications to put them on a benzodiazepine and then to take them off of it six or eight weeks later.”

The most common use of benzodiazepines, Roy-Byrne said, is in combination with antidepressants for individuals who have had suboptimal responses to antidepressants. He uses benzodiazepines as “second-line” treatments for patients with anxiety disorders, but continues them for the long term only if he sees substantial clinical improvement. “Most of the time it is not worthwhile to use them to just take the edge off symptomatic distress,” he said, noting that behavioral treatment might be a better alternative.

While he prescribes benzodiazepines for anxiety disorders in some of his patients, Roy-Byrne said GAD is “the absolute worst anxiety disorder” for which to use benzodiazepines, because GAD is a difficult diagnosis to make and is often comorbid with other disorders. “Using benzodiazepines for PTSD over the long term is also likely to produce more harm than good, though very short-term use in recently traumatized patients is a sound practice.” He said that it is better to use benzodiazepines for panic disorder and social anxiety disorder, “because they are easier to diagnose and less likely to be confused with other disorders, such as personality disorder or a subacute alcohol problem.”

Both Fava and Roy-Byrne were asked about the advantages and drawbacks of benzodiazepines for anxiety disorders. “Benzodiazepines are fast-acting and very well-tolerated drugs with few side effects and interactions with other medications. Their drawbacks are cognitive effects and dependence,” said Fava.

According to Roy-Byrne, the advantages of benzodiazepines “are that they are extremely potent and work very well. A disadvantage is that you can become physically dependent on them, although to be fair, there is also a withdrawal syndrome with antidepressants.” Other disadvantages include cognitive and psychomotor impairments, abuse potential, and most importantly, the possibility, not yet conclusively demonstrated, of a reduced response to CBT. Benzodiazepines tend to be anti-CBT treatments.

“Whereas CBT is very good for anxiety because it toughens you up, improves your coping ability, and lets you become more resilient to stress, benzodiazepines do the exact opposite,” he said. “It has not been extensively investigated, but it is probably true that benzodiazepines may sometimes interfere with CBT programs. CBT requires some anxiety that individuals need to experience upon exposure to desensitize themselves over time. But if they take a potent anti-anxiety drug, they just won’t be anxious.”

“I agree that in some investigations, notably the London-Toronto study [by Nardi and colleagues

], use of benzodiazepines decreased the efficacy of CBT,” said Fava. The same effect is seen with antidepressants in panic disorder and social phobia.

 Furthermore, “long-term outcome studies of panic disorder treated by behavioral methods disclosed a detrimental effect of antidepressants and not benzodiazepines.”

 Antidepressants also entail the risk of a switch into an undiagnosed bipolar course, particularly in younger patients.

With regard to the newer antidepressants for anxiety disorders, Roy-Byrne said “they are well-tolerated and they work more slowly than benzodiazepines, so they don’t provide patients with a clear-cut signaling link between taking a pill and feeling an anti-anxiety affect.” There aren’t many drawbacks with the antidepressants, other than the sexual dysfunction associated with most of the agents.

The most common reason for using benzodiazepines is to add them to antidepressants when treating anxiety disorders that have not optimally responded to an initial antidepressant. According to Roy-Byrne, there is currently no published study comparing this strategy with switching the antidepressant, although a report of the study is in press, which may provide needed information in this debate.

Fava and Rickels call for further comparison studies, conducted, when possible, by non-industry sources. “A well-conducted comparison trial of a benzodiazepine and a newer antidepressant simply does not exist, neither for acute nor chronic treatment,” Rickels said.

In an editorial on whether benzodiazepines still have a role in treating patients with anxiety disorders, Baldwin and Talat

 said, “There is a persisting need for placebo-controlled combination studies in acute treatment; for placebo-controlled augmentation studies after non-response, for example, after unsuccessful treatment with a selective serotonin reuptake inhibitor or cognitive behavior therapy; and for well-designed relapse prevention studies.”

 Offidani E, Guidi J, Tomba E, Fava GA. Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. 

 Hackett D, Haudiquet V, Salinas E. A method for controlling for a high placebo response rate in a comparison of venlafaxine XR and diazepam in the short-term treatment of patients with generalised anxiety disorder. 

 Feltner DE, Harness J, Brock J, et al. Clinical evaluation of the Daily Assessment of Symptoms-Anxiety (DAS-A): a new instrument to assess the onset of symptomatic improvement in generalized anxiety disorder. 

 Nardi AE, ValenÃ§a AM, Freire RC, et al. Psychopharmacotherapy of panic disorder: 8-week randomized trial with clonazepam and paroxetine. 

 Nardi AE, Freire RC, Mochcovitch MD, et al. A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine [published correction appears in 

 Rickels K. Should benzodiazepines be replaced by antidepressants in the treatment of anxiety disorders? Fact or fiction.

 Goddard AW, Brouette T, Almai A. Early coadministration of clonazepam with sertraline for panic disorder. 

 Marks IM, Swinson RP, Basoglu M, et al. Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto. 

 Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: a randomized controlled trial [published corrections appear in 

 Haug TT, Blomhoff S, HellstrÃ¸m K, et al. Exposure therapy and sertraline in social phobia: 1-year follow-up of a randomised controlled trial. 

 Fava GA, Rafanelli C, Grandi S, et al. Long-term outcome of panic disorder with agoraphobia treated by exposure. 

 Baldwin DS, Talat B. Should benzodiazepines still have a role in treating patients with anxiety disorders? 

Benzodiazepines vs Antidepressants for Anxiety Disorders

 recently lamented the lack of novel new drugs to treat psychiatric disorders. He blamed big pharmaceutical companies for the “crisis in drug innovation.”

In calendar year 2012, the FDA’s Center for Drug Evaluation and Research approved 39 new molecular entities (NMEs)-the highest number approved in more than a decade. Yet no psychiatric drugs were approved, although florbetapir F18 (Amyvid), Abbott’s compound for imaging of Î²-amyloid plaque in the brain, did receive a go-ahead. Most of the FDA’s approvals were for rare or “orphan” diseases (13) and for cancer (11). Among NMEs approved so far in 2013, no psychiatric drugs are on the list.

“Even though 25% of Americans suffer from a diagnosable mental illness in any year, there are few signs of innovation from the major drug makers,” said Friedman, Professor of Clinical Psychiatry and Director of the Psychopharmacology Clinic at Weill Cornell Medical College.

“After a series of failed clinical trials in which novel antidepressants and antipsychotics did little or no better than placebos, the companies seem to have concluded that developing new psychiatric drugs is too risky and too expensive.” He noted that with rare exceptions, it is difficult to identify a truly novel psychotropic drug that has emerged in the past 30 years. “All of our current antidepressants, antipsychotics, and antianxiety drugs share the same molecular targets in the brain as their prototypes from the 1950s,” he said. The pharmaceutical industry is making a mistake, according to Friedman, “by running away from the brain just when things are getting interesting.” He cited the example of ketamine, an anesthetic agent that has been shown to have powerful antidepressant effects.

Other experts have also sounded the alarm. Steven Hyman, MD, former head of the NIMH and now director of the Stanley Center for Psychiatric Research at the Broad Institute, wrote that in the past 3 years, “the global pharmaceutical industry has significantly decreased its investment in new treatments for depression, bipolar disorder, schizophrenia, and other psychiatric disorders.”

 For example, GlaxoSmithKline has closed its psychiatric laboratories entirely, Pfizer has decreased the size of its research programs, and Astra Zeneca has stopped its internal research.

The high cost and time involved in researching and developing psychotherapeutic drugs have thwarted the search for better drugs that can alter the disease process. Robert H. Lenox, MD, Professor of Pharmacology and Clinical Neuroscience at the University of New England College of Osteopathic Medicine, recently warned that drug discovery and development “is time and resource intensive.” The cost to develop a drug (including the cost of failures) is upwards of $1.5 to $2 billion. The Pharmaceutical Research and Manufacturers of America estimates that, on average, it takes about 10 to 15 years for a new medicine to complete the journey from initial discovery to the marketplace.

During his distinguished psychiatrist lecture at the American Psychiatric Association’s annual meeting in San Francisco, Lenox noted that drug failures occur even in phase 3 clinical trials and the number of failures is particularly high for CNS disorders. The failure rate for drug candidates entering phase 3 can be as high as 40% to 50%, with two-thirds of the failures due to lack of efficacy.

Psychiatric diseases are chronic and recurrent and have a complex etiology. These disorders “are neurodevelopmental and particularly vulnerable to the environmental factors,” Lenox said. “While there may be some understanding of the physiological dysfunction leading to symptoms, and we have had some success in symptomatic treatments, such as psychosis, we have very little understanding of the underlying disease process. Furthermore, we have very few animal models that have the validity to predict clinical efficacy.”

Particularly frustrating to Lenox is that “there is a dearth of valid new targets and novel drug candidates. Pharmaceutical companies often compete on the same poorly validated targets, wasting time and resources in the absence of early stage sharing of lead compounds and data . . . this is unsustainable as a business model.”

“DMS-5 does not reflect progress in our understanding of the shared pathophysiology of many of these neurobehavioral disorders, limiting translation of drug discovery data from animal models to humans,” according to Lenox. “We need to be looking at dimensional diagnosis, which DSM-5 has attempted to do. . . . So rather than looking at treating schizophrenia, I’m looking at treating anhedonia, cognition, or episodic memory; I’m looking at domains of brain dysfunction rather than treating that particular diagnosis.”

The Research Domain Criteria (RDoC) project of the NIMH was launched to define basic dimensions of functioning. “It is increasingly evident that mental illness will be best understood as disorders of brain structure and function that implicate specific domains of cognition, emotion, and behavior. RDoC is an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioral science to the problem of mental illness.”

Lenox explained that despite the problems involved in developing psychiatric and related drugs, there are some CNS disorders whose pathophysiology is currently more apparent for the pharmaceutical industry to explore. These include addiction, fragile X syndrome/autism, pain, and disorders of circadian rhythm. Brain imaging studies in animals and humans have implicated discrete circuits that mediate the stages of the addiction, including ventral striatum, limbic, and prefrontal regions of the brain. Recent studies in autism, he added, reveal the promise of modifying the disease process as well as the phenotypic expression of developmental brain disorders in childhood and may augur similar opportunities for altering disease progression in such psychiatric illnesses as schizophrenia.

Many pharmaceutical companies are “repurposing old drugs for new conditions,” such as duloxetine (Cymbalta) for depression, generalized anxiety disorder, and pain, said Lenox. The pharmaceutical industry is also beginning to shift risk of failure to earlier phases of drug development with the incorporation of novel translational biomarkers.

Some companies are moving from “blockbuster” drugs to “niche-buster” drugs and are concentrating on rare and orphan diseases for which there are market challenges but also genetic mutations that provide new drug targets with biological validity. A more collaborative approach to drug development is unfolding, according to Lenox. Pharmaceutical companies, for instance, are forming partnerships with researchers in government, academia, and smaller companies to support early-stage research, speed drug discovery, and facilitate funding.

“We cannot afford to waste time,” warned Lenox. “There should be a paradigm shift with more efficacious validation of targets and compounds in preclinical discovery based on a better understanding of pathophysiology. To this end, emerging biotechnology offers the promise of identifying functional networks in the brain that will permit novel pharmacological targeting of discrete pathways driving brain dysfunction associated with psychiatric disease.”

He continued, “We also need safer, more rapid, and earlier evidence of proof of concept. . . . And we need intellectual property and patent statutes that provide reasonable protections but that do not constrain efficient, innovative drug discovery and development. What’s more, we need FDA regulatory reforms with strong leadership.”

As regards psychiatry, “We must have the neurobiology to support our understanding of pathophysiology and the clinical descriptors that represent the disease process to better facilitate future drug discovery.” Lenox advised companies to design drug discovery programs to “effectively complement and enhance nonpharmacological treatment interventions” as new psychiatric drugs are developed. “We have other ways of accessing the brain,” he said, citing cognitive remediation, cognitive behavioral therapies, transcranial magnetic stimulation and vagus nerve stimulation. “We need to design drugs that work with these modalities, because ultimately we want to help our patients more effectively.”

 Friedman RA. A dry pipeline for psychiatric drugs. 

. August 19, 2013. http://www.nytimes.com/2013/08/20/health/a-dry-pipeline-forpsychiatric-drugs.html?_r=0. Accessed September 8, 2013.

US Food and Drug Administration. 2012 Novel New Drugs Summary. January 2013. http://www.fda.gov/downloads/Drugs/DevelopmentApproval Process/DrugInnovation/UCM337830.pdf. Accessed September 9, 2013.

 New Drugs at FDA: CDER’s new molecular entities and new therapeutic biological products of 2013. http://www.fda.gov/drugs/developmentapproval process/druginnovation/default.htm. Accessed September 9, 2013.

 Hyman SE. Psychiatric drug development: diagnosing a crisis. 2013. http://www.dana.org/news/cerebrum/detail.aspx?id=41290. Accessed September 4, 2013.

 Insel TR, Lieberman JA. DSM-5 and RDoC: shared interests. May 13, 2013. http://www.nimh.nih.gov/news/science-news/2013/dsm-5-and-rdoc-shared-interests.shtml. Accessed September 10, 2013.

 Long G, Works J. Innovation in the biopharmaceutical pipeline: a multidimensional view. January, 2013. http://www.analysisgroup.com/uploadedFiles/Publishing/Articles/2012_Innovation_in_the_Biopharmaceutical_Pipeline.pdf. Accessed September 10, 2013.

Pharmaceutical Research and Manufacturers of America (PhRMA). Medicines in development: mental illnesses. 2012. http://phrma.org/sites/default/files/pdf/phrmamedsindevmentalillness2012.pdf. Accessed September 12, 2013.

 Pharmaceutical Research and Manufacturers of America (PhRMA). Medicines in development: older Americans. 2013. http://www.phrma.org/sites/default/files/pdf/oac2013_0.pdf. Accessed September 12, 2013.

Despite pharma's retreat and the many challenges in psychiatric drug development -- as detailed here -- the current psychiatric drug pipeline is not totally dry.

Psychiatric Drug Pipeline

Complementary use of mindful exercise, such as Tai Chi and yogic meditation (Kirtan Kriya), can improve clinical outcomes of mood disorders in older adults-as demonstrated in brain scans, biomarkers of cellular aging, and mental health rating scales.

This according to Helen Lavretsky, MD, MS, an expert in geriatric psychiatry and holistic medicine, who spoke on this topic at the recent the American Psychiatric Association’s annual meeting.

“Mind-body exercise, which includes yoga, Qi Gong, and Tai Chi, is used to improve psychological well-being, hypertension, cardiovascular disease, balance, pain, insulin resistance, depression, and anxiety,” she said.

Acknowledging that colleagues and others often ask her to differentiate between aerobic and mind-body exercise as regards individual responses, Lavretsky described an observational study she and others conducted at a local YMCA that clarified the distinctions.

The study involved 42 participants (mean age, 64.6 years; SD = 13.6 years).[[{"type":"media","view_mode":"media_crop","fid":"17459","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_4218398376391","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"977","media_crop_rotate":"0","media_crop_scale_h":"166","media_crop_scale_w":"160","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]] Twenty routinely participated in a yoga or Tai Chi class and 22 routinely participated in an aerobic exercise class for at least 60 minutes per week. Questionnaires profiling participants’ mood states, general health functioning, sleep, and pain levels were reviewed.

In general, Lavretsky said, participants in yoga or Tai Chi classes had significantly greater levels of vitality and lower levels of tension, depression, anger, confusion, and fatigue, as determined from their mental health component scores. Furthermore, they had significantly higher mental health composite summary scores on the 12-Item Short Form Health Survey and fewer sleep problems than did those in the aerobic exercise group.

Despite gains in the treatment of major depression in recent decades, Lavretsky said that “only about 30% of older depressed patients achieve remission with the first-line antidepressant pharmacotherapy.”

“Therefore, nonpharmacological interventions-such as mind-body interventions-can improve a partial response to antidepressants via stress reduction, improved physical functioning, increased socialization, and reduced risks of polypharmacy.” She noted that her average depressed older patient takes between 10 and 15 drugs.

Lavretsky described one of the first randomized controlled trials to test the efficacy of complementary use of Tai Chi Chih (TCC), an abbreviated form of Tai Chi that involves 20 movements, versus health education (HE), an active control intervention, as an adjunct to standard antidepressant treatment of geriatric depression.

In depressed older adults, the prevalence of apathy and anxiety is higher than in younger adults, Lavret­sky said. “Symptoms of depression contain some pain and somatic symptoms that may overlap with under­lying medical conditions, comorbid diseases, and the effects of multiple medications. Cognitive impairment is also more common in older adults.”

For the study, Lavretsky and her team recruited 112 adults with major depression who were 60 years and older. They were treated with standard doses of escitalopram (Lexapro; 10 mg/d) for the first 4 weeks. Dosage adjustments up to 20 mg/d were made in the following 2 weeks. Thirty-nine participants dropped out in the dosage-adjustment phase.

Then 73 partial responders to escitalopram were randomized to receive 10 weeks of adjunctive TCC or HE for 2 hours per week.

All participants were evaluated for depression, anxiety, resilience, health-related quality of life, cognition, and inflammation at baseline and during 14-week follow-up.

“Both TCC and HE participants demonstrated decreases in severity of depression, but the improvement was significantly greater in the TCC participants,” Lavretsky said.

According the published study, 94% of the participants in the escitalopram/TCC group achieved Hamilton Depression Rating Scale (HDRS) scores of 10 or less, and 65% achieved remission (HDRS score of 6 or less). Their scores were better than those of the escitalo-pram/HE group, in which 77% achieved HDRS scores of 10 or less and 51% achieved remission. Those in the escitalopram/TCC group also showed significantly greater improvements in 36-Item Short Form Health Survey physical functioning and cognitive tests and a decline in C-reactive protein levels.

While adherence and satisfaction did not differ between the two groups, Lavretsky said, there was 1 dropout from the escitalopram/HE group and 4 from the escitalopram/TCC group.

The “bad news” from the study for her as a researcher, Lavretsky noted, was that participants in the escitalopram/HE group actually enjoyed their group.

“These were socially isolated older adults with medical problems who didn’t go anywhere, so coming to the study was a big intervention for them. They liked the teacher of the HE class, it was easy to follow, and they really enjoyed it,” she said.

A few participants in the escitalopram/TCC found the TCC practice relatively difficult, although those “who got it were able to improve and continue the practice after the end of the study,” said Lavretsky, who is Professor of Psychiatry and Behavioral Sciences at UCLA and Director of the Late-Life Depression, Stress, and Wellness Research Program at the Semel Institute for Neuroscience and Human Behavior at UCLA. She is also board-certified in holistic and integrative medicine.

She observed that a personalized approach to mind-body medicine might improve treatment response in those who understand the approach and who are willing to continue to practice it.

The study findings, she said, also provide “an opening for the complementary use of mind-body exercise combined with standard antidepressants. The mechanisms would be stress reduction, decreased inflammation, and improved social support.”

A more comprehensive investigation of mechanisms was conducted by Lavretsky and colleagues,

 who examined the effects of daily brief yogic meditation on distress and coping in caregivers of family members with dementia.

“Currently there are more than 5 million people with dementia and as many caregivers-so it is almost a 1 to 1 ratio,” Lavretsky said. “Most caregivers are elderly women, and about 40% provide care for 5 years or longer, so it is a chronic stress exposure model.” On average, the incidence and prevalence of clinical depression among family dementia caregivers approaches 50%, and caregivers are twice as likely as noncaregivers to report high levels of emotional distress.

Even though they are mildly depressed, many caregivers decline to use antidepressants because of the associated cost and adverse drug effects, according to Lavretsky. Instead, they prefer to use complementary and alternative medicine approaches for stress reduction.

For their study, Lavrestsky and her team recruited stressed and mildly depressed adult children and spouses who were taking care of family members with dementia. The 39 caregivers (mean age, 60.3 years; SD = 10.2) were randomized to learn and practice Kirtan Kriya or to listen to instrumental music on a relaxation CD for 12 minutes per day for 8 weeks.

“Many of the caregivers had not had 12 minutes to themselves in years,” Lavretsky added.

Kirtan Kriya (pronounced KEER-tun KREE-a) is a meditation from the Kundalini yoga tradition, and it has multiple components. Practitioners are asked to close their eyes and imagine the sound flowing in through the top of their heads and out the middle of their foreheads (the third-eye point). They are asked to repeat mudras, pressing the fingers one after another, and to simultaneously chant the mantra “Sa, Ta, Na, Ma,” which means birth, life, death, and rebirth in Sanskrit. The mantra is sung in a normal voice for 2 minutes, then a whisper for 2 minutes, then silently for 4 minutes, then a whisper for 2 minutes, and then out loud for 2 minutes.

“There are several action sequences they have to alternate that give rise to brain metabolic changes as those seen on the PET scan as a result of this practice,” Lavretsky said (

For the caregiver study, the researchers assessed the severity of depressive symptoms, mental and physical functioning, and cognition at baseline and at the end of the 8-week study or on early termination. They analyzed changes in telomerase levels. They looked at neural activation as measured in functional MRI (fMRI) and fludeoxyglucose (18F)-PET. Genome-wide transcriptional profiles were collected from peripheral blood leukocytes sampled at baseline and 8-week follow-up.

Lavretsky said they found an improvement across measures of mental health and cognitive functioning, psychological distress, and telomerase activity in caregivers who performed daily Kirtan Kriya as compared with the relaxation group.

Of those in the meditation group, 65.2% showed 50% improvement on the HDRS and 52% showed 50% improvement on the Mental Health Composite Summary (MCS) score of the Short Form-36 scale. In contrast, 31.2% of the relaxation group showed improvement on the HDRS and 19% showed improvement on the MCS.

Shortened telomere length and reduced telomerase (the cellular enzyme primarily responsible for telomere length and maintenance) have been proposed as biomarkers of cellular aging. In the study, the meditation group showed a 43.3% improvement in telomerase activity, compared with a 3.7% improvement in the relaxation group.

The study also sought to determine whether meditation might alter the activity of inflammatory and antiviral proteins that shape immune cell gene expression. “Our analysis showed a reduced activity of those proteins linked directly to increased inflammation,” Lavretsky said.

In a separate journal article, Lavretsky and her team reported that the Kirtan Kriya intervention suppressed nuclear factor-ÎºB–related transcription of proinflammatory cytokines and up-regulated interferon regulatory factor 1–related transcription of innate antiviral response genes.

Lavretsky said the research team also arranged for caregivers to receive PET scans and fMRI scans. They were able to compare each component of the meditation (eg, chanting, visualization, mudras, and resting) and its effects on different brain regions. In addition, they demonstrated that meditation is not the same as relaxation.

Patient interest in these techniques is spreading rapidly, Lavretsky said, adding that the baby boomers, in particular, are “very keen on alternative and complementary approaches.”

 Siddarth D, Siddarth P, Lavretsky H. An observational study of the health benefits of yoga or Tai Chi compared with aerobic exercise in community-dwelling middle-aged and older adults. 

 Lavretsky H, Alstein LL, Olmstead RE, et al. Complementary use of tai chi chih augments escitalopram treatment of geriatric depression: a randomized controlled trial. 

 Lavretsky H, Epel ES, Siddarth P, et al. A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity. 

 Alzheimer’s Research and Prevention Foundation. Practice the 12-minute yoga medication exercise. 

https://www.alzheimersprevention.org/research/12-minute-memory-exercise

 Pomykala KL, Silverman DH, Geist GL, et al. A pilot study of the effects of meditation on regional brain metabolism in distressed dementia caregivers. 

Black DS, Cole SW, Irwin MR, et al. Yogic meditation reverses NF-ÎºB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. 

Nonpharmacological interventions-such as mind-body interventions-can improve a partial response to antidepressants via stress reduction, improved physical functioning, increased socialization, and reduced risks of polypharmacy.

Mind-Body Interventions for Mood Disorders in Older Adults

[[{"type":"media","view_mode":"media_crop","fid":"17337","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_5612963676768","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"917","media_crop_rotate":"0","media_crop_scale_h":"294","media_crop_scale_w":"160","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Not only is obstructive sleep apnea (OSA) linked with coronary artery disease, heart failure, systemic hypertension, stroke, and diabetes, but it is also a significant risk factor for depression, said sleep expert Karl Doghramji, MD, Medical Director of the Jefferson Sleep Disorders Center, Thomas Jefferson University, Philadelphia.

Speaking at the recent American Psychiatric Association’s annual meeting in San Francisco, Doghramji described the bidirectional and interactive relationship between sleep-wake disorders and coexisting medical and psychiatric disorders.

“More than half of all psychiatric patients complain of disturbances of sleep and wakefulness,” he wrote in his summary. “Sleep disorders are associated with impaired daytime function and predict a heightened future vulnerability to psychiatric disease. They also diminish life span.”

As an example, Doghramji, Professor of Psychiatry and Human Behavior at Thomas Jefferson University, described a recent study by Chen and colleagues

 that examined the risk of depressive disorder within the first year following an OSA diagnosis. The nationwide, population-based study found that patients with sleep apnea had a 2.18 times increased risk of subsequent depressive disorder, compared with those without OSA.

Doghramji also described research by Schwartz and Karatinos

 that assessed the effects of continuous positive airway pressure (CPAP) therapy in patients who had both OSA and symptoms of depression. Patients who continued CPAP therapy had a statistically significant improvement in depressive symptoms as measured by the Beck Depression Inventory-Fast Screen for Medical Patients.

The odds ratio for having anxiety and mood disorders is much higher in patients with narcolepsy than in control subjects.

 Most narcolepsy cases with cataplexy are thought to be caused by a deficiency of orexins (neuropeptides that are also known as hypocretins). In addition, growing evidence from preclinical and clinical studies suggests that orexins and their receptors may be involved in the physiopathology of depression.

Rapid eye movement (REM) sleep behavior disorder (RBD; part of the parasomnias grouping) is present concurrently in some 30% of patients with narcolepsy and can be a prodrome of neurodegenerative disease, according to Doghramji. Such diseases include Parkinson disease, multiple system atrophy, and major or mild neurocognitive disorder with Lewy bodies.

RBD, Doghramji warned, can be triggered by alcohol and the use of various antidepressants, notably TCAs and MAOIs. “If you have a patient with RBD, search for antidepressants in the list of medications,” he said.

Much of Doghramji’s presentation updated attendees on nosological changes for sleep-wake disorders and some new developments in the management of these disorders.

In DSM-5, the classification sleep-wake disorders encompasses 10 disorders or disorder groups: insomnia disorder; hypersomnolence disorder; narcolepsy; breathing-related sleep disorders (obstructive sleep apnea hypopnea, central sleep apnea, and sleep-related hypoventilation); circadian rhythm sleep-wake disorders (delayed sleep phase type, advanced sleep phase type, irregular sleep-wake type, non–24-hour sleep-wake type, and shift work type); non-REM sleep arousal disorders; nightmare disorder; RBD; restless legs syndrome; and substance/medication-induced sleep disorders.

Doghramji pointed out changes from DSM-IV-TR to DSM-5, some of which are the following:

• Removal of sleep disorders related to another mental disorder, and sleep disorders related to a general medical condition

• Use of the terminology “coexisting with” or “comorbidity” instead of “related to” or “due to”

• Greater specification of coexisting conditions for each sleep disorder

• Discussion of the bidirectional and interactive relationship between sleep disorders and coexisting medical and mental disorders

• “Primary insomnia” is referred to as “insomnia disorder”

• Specifier “jet lag type” was removed from the category of circadian rhythm sleep-wake disorders

• DSM-5 text emphasizes the use of biological validators for such sleep-wake disorders as breathing-related disorders

To facilitate diagnosis of sleep-wake disorders, Doghramji singled out some procedures and resources he recommends.

“Polysomnography is the diagnostic sine qua non for sleep apnea,” he said. “You can’t make the diagnosis without a sleep study.”

Exploring how a clinician might detect patients who are at high risk for OSA, Doghramji noted that there are no inventories validated in a psychiatric population. Yet he mentioned the STOP-BANG Questionnaire validated in the perioperative setting.

. The STOP questions relate to snoring, tiredness during daytime, observed apnea, and high blood pressure, while the BANG questions relate to body mass index, age, neck circumference, and gender.

“If a patient has a STOP-BANG score of 3 out of 8 or more, then OSA should be suspected and he or she should be referred for a sleep study,” Doghramji said.

Another method is to have the patient open his mouth and stick out his tongue, so the clinician can see the back of the throat and uvula.

 Applying the Mallampati scoring of the oropharynx, Doghramji said, is a simple, noninvasive method that can be used to evaluate patients for possible OSA. On average, the odds of having OSA increase more than 2-fold for every 1-point increase in the Mallampati score.

For some patients with sleep-wake disorders, safety is particularly important. For example, patients with RBD, Doghramji warned, often exhibit disturbing behaviors during sleep.

“Patients behaviorally act out their dreams,” he said. “One of my patients was dreaming that he was fighting with his brother, but he hit his wife so hard he fractured her jaw. There are reports of patients walking out of bed and into streets and getting hit by trucks.”

More than half of all patients with psychiatric disorders report disturbances of sleep and wakefulness. "Sleep disorders are associated with impaired daytime function and predict a heightened future vulnerability to psychiatric disease. They also diminish life span.” Details from an expert here. 

Arline Kaplan

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