Jerald Kay, MD

My selected articles this year were not limited to those appearing in psychiatric journals. One group of publications is devoted to psychotherapy topics, another to issues in genomic medicine and the impact of technology and burnout on the practice of medicine, and last, more traditional clinical articles addressing diagnosis and treatment of psychiatric disorders. This somewhat atypical selection was prompted by another writing assignment for The 

World Psychiatric Association-Lancet Psychiatry Commission on the Future of Psychiatry

 in which my colleagues and I were asked to address clinical and technological issues potentially affecting the centrality of the doctor-patient relationship and therefore ultimately clinical care.

Included on my list, therefore, are tempered articles on the unrealized promises of genomics and the shortcomings of precision or personalized medicine. It was abundantly clear as I reviewed the literature, that to speak of precision psychiatry without acknowledging the severe limitations of its scientific foundation is quite risky. In psychiatry, we have had an unfortunate legacy of promising much more than we could ever deliver to our patients and the public. No one disagrees with advancing science and improving care. However, as an emeritus professor, now looking back on the grandiosity of the claims of psychoanalysis, psychopharmacology, diagnostic classification schemes, community mental health, the electronic medical record (EMR) and its inextricable relationship to physician burnout, and the reductionistic biomedical approaches to treatment that undercut the clinician’s ability to tolerate uncertainty and ambiguity, a slow medicine approach appears to be increasingly attractive to me.

Moreover, personalized psychiatry, if and when it becomes scientifically sound, must always be delivered within the context of the doctor-patient relationship. Computer-generated genomic analyses, neuromodulation, deep brain stimulation (DBS), new drug delivery mechanisms, and perhaps someday, stem cell therapy, to name but a few, all require the participation of a physician. (With respect to DBS and FDA scrutiny over rogue stem cell therapy clinics, initial excitement has given way to mixed findings and resultant physician ambivalence and caution lest we oversell this technique as well.)

Promises of scientific advances often appear to downplay the value of the psychiatrist’s subjective understanding of patients. And, of course, there is the yearly plethora of studies each of whose findings is so obvious that I refer to them as “duh” articles. For example, an endless number of studies each year substantiate the impact of bad things happening to good little people. Does any clinician doubt that maltreatment and other adverse childhood experiences produce psychological vulnerability? Does anyone not believe that a disorganized attachment style has a profound effect on development throughout the life cycle? Have we not accepted the concept of intergenerational transmission of unresolved trauma in mothers?

A final point to be made is the enduring dismissal of psychotherapy either as a monotherapy or in conjunction with medication. When will the field embrace this proven therapeutic intervention for the treatment of our patients? Can we stop the self-defeating infighting about efficacious psychotherapy treatments?

→ Roy-Byrne P, Dubovsky S, Yager J. When genetic testing is unproven: the case of depression treatments. 

https://www.jwatch.org/na44895/2017/08/31/when-genetic-testing-unproven-case-depression-treatments

This article highlights the myth of precision psychiatry, that, in my opinion, has insufficient scientific support at present. It alerts us to be cautious and thoughtful about jumping on a bandwagon that favors adopting approaches that are not ready for prime time.

Testing positive for a genetic predisposition to depression magnifies retrospective memory for depressive symptoms

Given a strong reliance on self-report measures in assessing depression and other disorders, this creative investigation assessed the impact of feedback about genetic testing results on study participants’ memories about depressive symptoms. Retrospective falsification by patients through exaggerating symptoms as recorded by well-accepted symptom checklists, that are a component of many treatment outcomes and drug studies, is a vital finding. If future research supports the need for greater concern, clinicians must be sensitive to this effect on diagnosis and treatment.

Is cognitive behavioral therapy the gold standard for psychotherapy? The need for plurality in treatment and research

This is but the last in a long line of articles going back more than 50 years elucidating the value of psychodynamic psychotherapy and countering its alleged inferiority when compared with CBT. Those who follow the psychotherapy outcome literature know of Falk Leichsenring’s impressive meta-analyses explicating the efficacy of dynamic therapy in head to head comparison with other types of psychotherapy. Recent studies have verified that dramatically fewer psychiatrists now conduct psychotherapy with their patients. This alarming trend is irrespective of the fact that the Accreditation Council for Graduate Medical Education still mandates proficiency in dynamic therapy for our psychiatric residents because this approach provides an in-depth understanding of many psychological phenomena outside of awareness that compels patients to re-enact self-defeating and destructive behaviors. (More complete assessment of these issues can be found in my 

→ Dunlop BW, Rajendra JK, Craignead WE, et al. 

Functional connectivity of the subcallosal cingulate cortex and differential outcomes to treatment with cognitive-behavioral therapy or antidepressant medication for major depressive disorder

An article that supports the notion that imaging may someday enable the routine prediction of what type of treatment works for what kind of patient. However, this article also affirms the point that patient preferences for psychotherapy or medication are often related to treatment/study retention. Although there is some controversy surrounding this finding, nevertheless, it assists us in assessing the findings of some studies that pit medication against psychotherapy without permitting the option of patient preference.

→ Swift JK, Greenberg RP, Tompkins KA, Parkin SR. 

Treatment refusal and premature termination in psychotherapy, pharmacotherapy, and their combination: a meta-analysis of head-to-head comparisons

In support of one finding in the previously cited article by Dunlop and colleagues, this meta-analysis of 186 comparative studies showed that while the average refusal for treatment was over 8% for all treatment approaches, those assigned to pharmacotherapy were 1.76 times more likely to refuse help than those participants who were assigned to psychotherapy; this was particularly true for depressive (for which there is research support) and anxiety disorders. Dropout rates were 1.2 times higher in the pharmacotherapy group.

Electronic health record logs indicate that physicians split time evenly between seeing patients and desktop medicine

Concern is expressed once again about the intrusion of the EMR and its impact on patient care and, by extension, physician well-being as the following article indicates.

→ Sinsky CA, Dyrbye LN, West CP, et al. 

Professional satisfaction and the career plans of US physicians

The findings from a large national AMA 2014 survey of more than 6600 physicians (550 or 8.3% of respondents were psychiatrists) revealed that 1 in 4 physicians is considering significant changes to his or her practice. Nearly 20% would move to part-time within the next year; more than 26% would change practices by retiring or find a new practice, move to the administrative side, or begin a new career outside of medicine.

Those aged between 50 and 59 years were more likely to leave medicine within the next 2 years. Burnout, dissatisfaction with lifestyle, and the EMR were all significant (P < .001) predictors of career change. Authors expressed concern with the potential impact on workforce through decreased continuity of care and medical accessibility for patients, as well as financial threats to health care organizations.

No shortcuts on the long road to evidence-based genomic medicine

This is a thoughtful piece from a CDC staff member in the Office of Public Health Genomics. Khoury argues for greater humility about the promises of genomic medicine, since analytic validity of genomic tests (are tests accurate?) and clinical validity (do they demonstrate an association with disease end points?) leave much to be desired in the prediction of improved health care.

Epigenetic and translational mechanisms in infection-mediated neurodevelopmental disorders

This is an in-depth review of the role of maternal inflammation in initiating prenatal immune responses that may contribute to the pathogenesis of psychiatric disorders. 

 published in 2017 showed higher levels of cytokines in mothers of offspring who developed significant childhood disorders.

 The possible role of chronic inflammation in conferring vulnerability to psychiatric disorders is receiving increasing scientific attention.

Although the tension between psychoanalytic thinkers and empiricists has lessened, the authors argue for recognition by neuroscientists and those providing CBT that much of psychopathology is better viewed in relational terms with increased sensitivity to social/cultural issues. Relational theory has supplanted insight with respect to change as in the traditional models of psychoanalytically oriented psychotherapy. Accordingly, a more socially based concept of the mind as manifested within interpersonal relationships could better accommodate both empiricism and more cognitive psychotherapies. Many clinician-educators feel the relational/interpersonal model is less theory bound with less jargon and therefore attractive to psychiatry trainees.

→ Carhart-Harris RL, Roseman L, Bolstridge M, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. 

https://www.nature.com/articles/s41598-017-13282-7

This article is among a number of publications this year that address the possible role of hallucinogens in the treatment of psychiatric disorders. This, of course, is not a new line of investigation. MDMA and, I include, ketamine studies as well are representative of this line of inquiry. At this point, greater research is required and more restraint in using these compounds off label is warranted. Many in our field appropriately are critical of the mushrooming numbers of free-standing clinics (some managed by non-psychiatrists) that offer ketamine treatment to those with treatment-resistant depression.

Unintended consequences of machine learning in medicine

Much has been made recently of the transformative powers of machine learning and its attractive potential for analyzing very large data sets that may better inform treatments. In this viewpoint article, authors detail pitfalls in wholesale adoption of machine learning with respect to promoting a less skillful clinician who may over rely on new treatment algorithms while denying the basic uncertainty in the practice of medicine. Vital research goals in the application of machine learning are presented as well.

Although neurobiological advances in our field are exciting and will one day undoubtedly be translated into marked change in the practice of psychiatry, the centrality of the doctor-patient relationship has been scientifically acknowledged and remains the cornerstone of all psychotherapeutic and somatic treatments. It behooves psychiatrists to moderate their enthusiasm for, and adoption of, novel but scientifically unsupported treatments. We owe this to our patients, their families, and the public at large.

Dr. Kay is Emeritus Professor, Deparment of Psychiatry, Boonshoft School of Medicine of Wright State University, Dayton, OH, and Clinical Professor of Psychiatry, Tulane University School of Medicine, New Orleans, LA.

The WPA-Lancet Psychiatry Commission on the Future of Psychiatry

Psychotherapy by psychiatrists: why choose a bugle when you can play the trumpet?

Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation

Articles

Here's a hit list of publications devoted to psychotherapy topics; to issues in genomic medicine; the impact of technology, and burnout on the practice of medicine; and to more traditional clinical articles addressing diagnosis and treatment of psychiatric disorders.

The Best and Not So Great Articles of 2017

Fear extinction requires a functional ventral-medial prefrontal cortex, rostral anterior cingulate cortex, and hippocampus. Activation of these regions leads to decreased amygdala activity. Clinical studies have demonstrated that the addition of D-cycloserine, a partial N-methyl-D-aspartate (NMDA) glutamate agonist, may improve outcomes in exposure-based therapies for acrophobia and social phobias.

 Conversely, NMDA antagonists, by decreasing NMDA activity, can inhibit the formation of long-term fear extinction.

While decreasing the activity in the amygdala leads to an acute reduction in perceived fear, the long-term persistence of fear extinction requires the activity of the ventral-medial prefrontal cortex and rostral anterior cingulate cortex. These appear to be vital in connecting the cognitive and emotional experiences and solidifying the learning.

The hippocampus aids in fear extinction by placing events into a context. This context helps determine how generally the brain applies the new learning. Because the previous fear is not erased, when the individual encounters the once feared stimuli there is activation of both the fearful and fear extinguished pathways. The context, provided by interactions between the hippocampus and ventromedial prefrontal cortex, determines which set of behaviors is predominately activated. The work of the psychotherapist is to help solidify the most healthy and adaptive responses.

1. Britton JC, Gold AL, Feczko EJ, et al. D-cycloserine inhibits amygdala responses during repeated presentations of faces. 

Poll

When treating social phobias, the addition of D-cycloserine has been noted to enhance the response to behavior therapy. How does D-cycloserine promote fear extinction?

Mini Quiz: Social Phobias

 proposed a new period of the life cycle in the US-

. According to this theory, distinct features characterize young people who are roughly 18 through 25 years old. This stage differs from the developmental stages of late adolescence and young adulthood. Differences include, but are not limited to, instability from successive changes in residence and romantic partners, intense introspection about future careers and intimate relationships, significant struggles in identity consolidation, and persistent ambivalence about reliance on others.

Despite the fact that there is now a professional society and journal devoted to the study of emerging adulthood and that those in child and adolescent psychiatry/psychology and college mental health, for example, wish to demarcate an area of specialty practice, emerging adulthood as a concept remains controversial and without robust research support.

 In part, this lack of research reflects that the study of adult development takes many years, is inextricably linked with cohort effects, and is highly dependent on the era in which people live. Poverty, family constellation shifts, trends in substance use, demographic changes, ethnic and gender diversity, and economics are but a few of the factors we face during our rapidly changing lifetime.

This 2-part Special Report on Young Adult Psychiatry reflects my belief that many of the clinical challenges in the treatment of young adult patients are developmentally continuous with and heavily influenced by pre-existing vulnerabilities. The challenges in providing mental health care to the college community, for example, are significant and have been well documented given the large number of students matriculating to institutions of higher education with previous psychiatric diagnoses and treatment in conjunction with those seeking mental health services for the first time.

[[{"type":"media","view_mode":"media_crop","fid":"44412","attributes":{"alt":"Â© Sergey Nivens/shutterstock.com","class":"media-image media-image-right","id":"media_crop_414655566936","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4960","media_crop_rotate":"0","media_crop_scale_h":"124","media_crop_scale_w":"175","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Â© Sergey Nivens/shutterstock.com","typeof":"foaf:Image"}}]]Epidemiologically, many psychiatric disorders are disorders of young people and occur in precollege students. These include those related to substance abuse, mood and anxiety disorders, attention disorders, eating disorders, phobias, personality disorders, gender identity issues, maltreatment and abuse experiences, and schizophrenia. Although the prevalence of some of these disorders does increase between the ages of 18 and 25-and others decrease-I remind clinicians to examine childhood and adolescent development prior to high school graduation to appreciate gene-

Many of the clinical challenges in the treatment of young adult patients are developmentally continuous with and heavily influenced by pre-existing vulnerabilities.

 conducted by the CDC sampled more than 13,500 9th through 12th graders and demonstrated, among many findings, that before the 12 months of the survey

• 14.8% had been electronically bullied, and 19.6% had been bullied on school property

• 29.9% felt so sad or hopeless almost daily for at least 2 weeks that they discontinued some usual activities

• 17% seriously considered suicide; 13.6% made a suicide plan; and 8.0% made an attempt, of which 2.7% were treated by a health care professional for either overdose, injury, or poisoning

• 18.6% drank alcohol for the first time before the age of 13, and 20.8% had 5 or more drinks in a row on at least one occasion (the definition of binge drinking)

• 23.4% used marijuana on at least one occasion

• 47.7% tried to lose weight, and approximately 5% vomited, took laxatives, or used diet pills

• 7.3% were forced to have unwanted intercourse, and 17.8% had taken non-prescribed drugs (painkillers, stimulants, benzodiazepines) at least once in their life

It is undoubtedly true that the transition from high school to college is a critical time for many. Yet the identification of students who are emotionally unprepared for higher education is a major public health focus, since college mental health services are 

As the articles in this Special Report illustrate, access to psychiatric care is critical, but so too is the identification of young persons at risk-both those in college and their non-college peers (including active armed forces members and veterans)-because the consequences of untreated problems pose significant threat for lifelong success. Mindfulness and positive-psychology–based interventions are common and often helpful to many students who access college mental health programs. However, as the evidence cited in this article also reinforces, psychiatrists must treat complex disorders and behavioral problems that require sophisticated clinical psychotherapeutic and psychopharmacologic interventions, beyond stress reduction approaches.

Dr Kay is Emeritus Professor in the department of psychiatry at the Boonshoft School of Medicine of Wright State University in Dayton, OH, and Clinical Professor of Psychiatry at Tulane University School of Medicine in New Orleans. He reports no conflicts of interest concerning the subject matter of this Special Report.

 Arnett JJ. Emerging adulthood: a theory of development from the late tweens through the twenties.

Emerging Adulthood: The Winding Road From the Late Teens Through the Twenties

. 2nd ed. New York: Oxford University Press; 2014.

 Beardslee WR, Vaillant G. Adult development. In: Tasman A, Kay J, Lieberman JA, et al, eds. 

. 4th ed. Chichester, UK: John R. Wiley and Sons, Ltd; 2015. In press.

Mental Health Care in the College Community

. London: John R. Wiley and Sons, Ltd; 2010.

 Tanner JL, Reinherz HZ, Beardslee WR, et al. Change in prevalence of psychiatric disorders from ages 21 to 30 in a community sample. 

 Kann L, Kinchen S, Shanklin SL, et al. Youth risk behavior surveillance-United States, 2013. 

 First year college experience. National survey of 1,502 first-year college students examines challenging transition from high school to college [press release]. New York: The Jed Foundation; October 8, 2015.

The challenges in providing mental health care to the college community are significant. Here's a brief look at the issues.

Introduction: A Demographic With a Challenging Set of Problems

A recent Institute of Medicine report acknowledges the efficacy of a broad range of psychosocial interventions.

 It challenges us to “identify key elements that drive an intervention’s effect.” The report describes key clinical tasks such as the therapist’s ability to engage with a patient, understand the patient’s worldview, and help the patient manage his or her emotional responses. The psychiatric community should also look into the neurobiological changes that accompany and may be responsible for an intervention’s effect. Although early psychoanalysts made little effort to connect functions of the mind to definable portions of the brain, from the beginning there was a belief that such a relationship may exist. Freud confidently predicted that one day there would be a neurological understanding of the work he initiated.

The deficiencies in our description would probably vanish if we were already in a position to replace psychological terms by physiological or chemical ones. Biology is truly a land of unlimited possibilities. We may expect it to give us the most surprising information and we cannot guess what answers it will return in a few dozen years to the questions we have put to it.

Almost 100 years have passed since Freud wrote those words, and many of his questions remain unanswered. Steady progress, however, has been made in the development of a neurobiological understanding of what happens in the brain when the mind is engaged in psychotherapy. Advances in cognitive neuroscience and neuroimaging have facilitated a greater appreciation of the neuroanatomy and neurophysiology of the CNS. The technology to study the real-time functioning of the brain through measurement of blood flow or glucose uptake, for example, has been widely used for a quarter of a century. Numerous challenges endure, such as subtle individual variations of neural circuitry, uncertainty as to the proper area to study, and the possibility that differing forms of therapy affect the brain differently. Within the boundaries created by these limitations, however, there is an emerging understanding of the neurobiological correlates of some common psychotherapy elements.

Although different approaches utilize various terms and concepts, there are some components that are found in most forms of efficacious psychotherapy. There must be some emotional engagement (

) between the patient and therapist. The therapist will struggle to understand and express the patient’s experience (

). By learning about themselves and their environment, patients will decide to make changes. As therapy continues, they will develop new abilities to regulate their emotions. Many patients will be forced to face and overcome feared relationships or situations (

). There is a neurobiological literature developing on each of these common components of psychotherapy.

Forming nurturing attachments with others remains a challenge throughout life especially for those with early trauma. The neurochemistry of attachment involves the neuropeptides oxytocin and arginine vasopressin. Both of these messengers are released from the hypothalamus by sexual stimulation and stress. In combination with estrogen, oxytocin helps induce maternal behavior, while the absence of oxytocin makes it more difficult for animals to adapt to social settings and leads to abnormal displays of aggression. Infusing or blocking oxytocin also causes dramatic changes in mating behaviors. Arginine vasopressin has myriad effects on normal mammals including altering displays of aggression and the animal’s tendency to affiliate with or protect others.

In humans, oxytocin is associated with a number of factors that affect attachment including trust, empathy, eye contact, and generosity. Oxytocin infusions in healthy individuals tend to decrease anxiety and the stress associated with social situations while shifting attention from negative to positive information. The reduction in distress appears related to a reduction in activity in the amygdala. In a study of women with borderline personality disorder, oxytocin infusion decreased their amygdala activation when exposed to angry faces.

 Although the effect is mediated by past experiences, intra-nasal infusion of oxytocin may increase an individual’s ability to infer the mental state and intention of others based on their facial expression. Oxytocin specifically aids in parent-child bonding. Administering oxytocin to parents increases the social engagement of the parent and child and leads to an increase in oxytocin in the child.

The mu-opioid receptor also appears to be involved in attachment. Activation of the mu-opioid receptor leads to a general sense of pleasure as well as analgesia. In animal models, removing the mother from the child leads to distress that is at least partially mediated through mu-opioid activity. Animals with an increased activation of the opioid system had more attachment behaviors and louder and more prolonged protests when separated. Their separation distress could be partially reversed by non-sedating opioid agonists.

 Patients with borderline personality disorder have differences in baseline mu-opioid receptor concentrations and in the endogenous opioid system response to negative emotional challenges. These differences might be related to their difficulty with emotion regulation.

Attachment therefore correlates with neurochemical changes within the brain. This might be most evidenced in parent-child interactions but may play a significant role in psychotherapy as well. A study of mothers with postpartum depression undergoing psychodynamic psychotherapy found that daily infusions of oxytocin over 12 weeks were associated with a decrease in narcissistic traits but not in depressive personality traits or depressive symptoms.

 Depressed men who received oxytocin infusions while in psychotherapy performed better on tests of inferring the mental state of others but were more likely to experience anxiety during the session.6 These findings hint of a complex interaction between oxytocin and the therapist-patient relationship (

Empathy entails the ability to consider the world from another’s point of view and in some way to share his or her emotional experiences. Neurobiological correlates of empathy were first described in the early 1990s with the discovery of mirror neurons. Researchers who were studying the neuronal activity involved in organizing and monitoring movements noted that some of the same premotor cortex neurons were activated while observing others make corresponding movements.

 Neurons that were activated when a monkey grabbed food were activated when the researcher grabbed food but not when the researcher pushed or struck the food. These neurons were referred to as mirror neurons.

Mirror neurons in humans are not limited to simple movements. Watching dance leads to activation in the brains of other dancers. Greater activation occurs when dancers watch movements they already know. Mirror neurons activate while watching facial expressions and seem to be partially impaired in individuals with autistic disorders. Human mirroring networks also exist for pain and emotional distress. Researchers created pain by sticking subjects with a needle and monitored which areas of the brain were activated.

 Similar pathways were activated when the researchers brought the needle close to the subject but did not make contact and when subjects watched researchers pricking their own fingers. Witnessing others display disgust activates many of the same areas that are activated when one smells an unpleasant odor.

Mirroring neurons also fire when observing others being rejected or embarrassed. The areas most involved in mirroring physical pain, emotional distress, and social discomfort are the anterior cingulate cortex and insula. These areas help individuals automatically imagine themselves experiencing what they witness others experiencing. It should be noted that the studies of mirror neurons in humans are preliminary and not without controversy.

The posterior portions of the superior temporal sulcus have similar activities. This region activates when witnessing social behavior and predicting future actions. When a figure is walking toward you, activation of the superior temporal sulcus is greater when the figure is looking at you, which indicates the prospect of an upcoming interaction. Activation also increases when the other person’s behavior is different than expected.

 an actor displayed pleasure or disgust to one of two identical objects and then randomly picked up one of the objects. When there was incongruent action (picking the object after showing disgust or not picking the object after a display of pleasure), there was increased activity in the observer’s posterior superior temporal sulcus region.

 appears to require proper activation of portions of the insula and anterior cingulate cortex as we seek to understand the emotional experience of others. A properly functioning posterior superior temporal sulcus allows us to determine and predict the social actions of others, and will tend to activate when someone violates societal expectations.

Oxytocin and arginine vasopressin are also implicated in empathy. A study of polymorphisms in the genes of 367 young adults found that variations in the emotional aspect of empathy were associated with the oxytocin receptor gene, while the cognitive aspect of empathy was associated with the gene for the arginine vasopressin 1a receptor.

 A highly complex interaction of neurotransmitters and brain activation allows the therapist to understand the patient’s experience (

Early in the 20th century Cajal proposed that the brain stored information by modifying neuronal connections. Learning involved changing individual neurons and their connections with each other. In the mid-20th century Hebb proposed his rule stating that when one neuron’s repeated excitation is involved in the excitation of a neighboring neuron, the connection between the two of them grows more efficient. Put colloquially, “Neurons that fire together wire together.” This implies that synapses change over time.

The first demonstration of this in the hippocampus occurred in 1973. After exposing neurons to strong, high-frequency stimulation, their connection to other neurons in the hippocampus became stronger.

 The discovery of hippocampal neurogenesis established the process of neuronal plasticity and upended the long-held belief that CNS cells were neurophysiologically and neuroanatomically incapable of growth.

 demonstrated that habituation-a decrease in response to a stimulus-could be attained with a single training session of 10 stimulations. These effects lasted minutes to hours and appeared to be a result of changes in the amount of neurotransmitter released with the stimulation. Training sessions on 4 consecutive days resulted in an effect that lasted weeks. This long-term learning was associated with changes in interneuronal connections.

Preliminary studies in humans have found measurable changes in the brain based on learning stemming from juggling and playing video games.

 Experimental data demonstrate that the neurons in the brain are capable of learning-induced change. Psychotherapy includes components of experiential and didactic learning that is expected to create change in the patient’s brain. Many psychotherapies focus on thoughts or patterns that are initially outside the awareness of the patient. Therapy creates new memories to modify older, dysfunctional ones and in some cases creates new psychic structures. This learning must involve changes in interneuronal connections (

Patients in psychotherapy are taught to understand, accept, or manage their emotional responses in new ways. Researchers are looking into how emotion regulation modifies brain activity. One common strategy for altering emotions is reappraisal, when the individual deliberately tries to alter the meaning or relevance of an event. Reappraisal strategies link cognitive control with emotional experience. Attempts to deliberately decrease aversive emotions, sadness, and sexual arousal through cognitive reappraisal have found that reappraisal strategies most commonly activate multiple areas within the prefrontal cortex and posterior parietal cortex. Activation of these areas during reappraisal leads to decreased activity in portions of the amygdala. These studies have demonstrated specific neuronal circuitry, for example, between the hippocampus, prefrontal cortex, and amygdala, which are strengthened by psychotherapeutic treatment.

Suppression, an intentional attempt to minimize the display of emotions, may also decrease the intensity of emotions. Subjects were asked to suppress their emotions while observing sad pictures. When suppressing their emotions, there was an increase in activity in the right orbitofrontal and dorsolateral prefrontal cortices.

 Other studies have found activation of the dorsal anterior cingulate cortex, dorsomedial prefrontal cortex, and lateral prefrontal cortex with suppression.

Cognitive reappraisal and suppression seem to have distinctly different neurophysiological mechanisms. In a head-to-head study both strategies were successful at decreasing subjective emotional experience, but there were differences in brain activation.

 Reappraisal led to increased activity in the prefrontal cortex and decreased activity in the right amygdala and left insula. Suppression increased activity in the right ventral-lateral prefrontal cortex but did not decrease activity in the amygdala or insula (

Learning to be afraid, or fear conditioning, involves pairing a previously innocuous stimulus (conditioned stimulus) with an aversive stimulus (unconditioned stimulus). The mind begins to associate the previously benign stimulus with the unpleasant one, and the individual experiences heightened anxiety whenever presented with the new conditioned stimulus. The process of fear conditioning involves interactions of the amygdala, insula, anterior cingulate cortex, and medial prefrontal cortex.

The process of unlearning fear is known as fear extinction. Fear extinction does not consist of erasing old memories; rather it is the creation of new, benign associations. The underlying fear is still present, but successful fear extinction leads to a reduction in the amplitude and likelihood of a fearful response. This occurs when the once feared stimulus or situation no longer brings about any adverse consequences. Fear extinction is a principal therapeutic component of exposure therapies for specific phobias and for PTSD, but learning to confront feared memories, situations, and people can be found in a broad range of psychotherapies.

Fear extinction requires a functional ventral-medial prefrontal cortex, rostral anterior cingulate cortex, and hippocampus. Activation of these regions leads to decreased amygdala activity. Clinical studies have demonstrated that the addition of D-cycloserine, a partial 

-methyl-D-aspartate (NMDA) glutamate agonist, may improve outcomes in exposure-based therapies for acrophobia and social phobias.

The hippocampus aids in fear extinction by placing events into a context. This context helps determine how generally the brain applies the new learning. Because the previous fear is not erased, when the individual encounters the once feared stimuli there is activation of both the fearful and fear extinguished pathways. The context, provided by interactions between the hippocampus and ventromedial prefrontal cortex, determines which set of behaviors is predominately activated (

). The work of the psychotherapist is to help solidify the most healthy and adaptive responses.

Studies have begun to examine the ability to predict a patient’s response to psychotherapy based on neurobiological factors. One of the many changes that occur with depression is the elevation of metabolism in the posterior insula. Studies have found that changes in connectivity and activation of the insula predicted a positive response to psychotherapy in patients with depression.

 Another study found that increased metabolism in the subcollasal cingulate cortex and superior temporal sulcus was associated with no response to escitalopram or cognitive-behavior therapy treatment for depression.

Although a precise description of the neurophysiological changes that occur during psychotherapy is currently impossible, it is likely that future imaging and neurobiological investigation will elucidate this process. The neurobiological correlates to many of the common elements of psychotherapy such as attachment, empathy, memory, learning, emotional regulation, and fear extinction are emerging. While we still cannot answer all of Freud’s questions, or our own questions, the artificial dichotomy between the functioning of the mind and brain during psychotherapy seems less imposing.

Dr Welton is Associate Professor of Psychiatry and Director of Residency Training and Dr Kay is Emeritus Professor of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH. The authors report no conflicts of interest concerning the subject matter of this article.

Psychosocial Interventions for Mental and Substance Use Disorders: A Framework for Establishing Evidence-Based Standards

. Washington, DC: The National Academies Press; 2015:S1-S16.

 Freud S. Beyond the pleasure principle. In: Strachey J, ed. 

The Standard Edition of the Complete Psychological Works of Sigmund Freud

. Vol 18. London: Hogarth Press; 1955:1-64.

 Bertsch K, Gamer M, Schmidt B, et al. Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. 

 Barr CS, Schwandt ML, Lindell SG, et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. 

 Clarici A, Pellizzoni S, Guaschino S, et al. Intranasal administration of oxytocin in postnatal depression: implications for psychodynamic psychotherapy from a randomized double-blind pilot study. 

 MacDonald K, MacDonald TM, Brune M, et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. 

 Rizzolatti G, Fadiga L, Gallese V, Fogassi L. Premotor cortex and the recognition of motor actions. 

 Iacoboni M. Face to face: the neural basis of social mirroring and empathy. 

 Hutchison WD, Davis KD, Lozano AM, et al. Pain-related neurons in the human cingulate cortex. 

 Wyk BC, Hudac CM, Carter EJ, et al. Action understanding in the superior temporal sulcus region. 

 Uzefovsky F, Shalev I, Israel S, et al. Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with the emotional and cognitive empathy. 

 Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. 

 Kandel ER. Psychotherapy and the single synapse: the impact of psychiatric thought on neurobiological research. 

 Draganski B, Gaser C, Busch V, et al. Neuroplasticity: changes in grey matter induced by training. 

 Kuhn S, Gleich T, Lorenz RC, et al. Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game. 

 Ochsner KN, Ray RD, Cooper JC, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. 

 Buhle JT, Silvers JA, Wager TD, et al. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. 

 Levesque J, Eugene F, Joanette Y, et al. Neural circuitry underlying voluntary suppression of sadness. 

 Phan KL, Fitzgerald DA, Nathan PJ, et al. Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. 

 Goldin PR, McRae K, Ramel W, Gross JJ. The neural bases of emotion regulation: reappraisal and suppression of negative emotion. 

 Britton JC, Gold AL, Feczko EJ, et al. D-cycloserine inhibits amygdala responses during repeated presentations of faces. 

 Roffman JL, Witte JM, Tanner AS, et al. Neural predictors of successful brief psychodynamic psychotherapy for persistent depression. 

 Crowther A, Smoski MJ, Minkel J, et al. Resting-state connectivity predictors of response to psychotherapy in major depressive disorder. 

 McGrath CL, Kelley ME, Holtzheimer PE 3rd, et al. Toward a neuroimaging treatment selection biomarker for major depressive disorder. 

 McGrath CL, Kelley ME, Dunlop BW, et al. Pretreatment brain states identify likely nonresponse to standard treatments for depression. 

An update on what happens in the brain when the mind is engaged in psychotherapy. 

The Neurobiology of Psychotherapy

In the past few years, college mental health issues have received increasing attention by the mental health community, the public, administrators, and legislators. Events such as the death of MIT student Elizabeth Shin and the subsequent legal battle, and the series of suicides at NYU a few years ago received prominent media coverage.

 In the aftermath of the tragic murders/suicides at Virginia Tech and Northern Illinois University, college student mental health issues and campus safety have become pressing public health and policy concerns.

Psychiatrists have historically played a peripheral role in most college mental health services and, thus, have not been well informed about the mental health challenges encountered on campus.

While the tragedies at Virginia Tech and Northern Illinois University riveted the nation’s attention, professionals within the college mental health world had been discussing the mental health crisis for years before these horrific events. Research in college mental health issues has not been well funded, and epidemiological information is scarce. The American College Health Association undertakes a yearly self-report survey of college students (nearly 95,000 respondents last year), which gathers general information about students’ health and mental health.

 Dr Robert Gallagher of the University of Pittsburgh surveys college counseling center directors yearly.

 The University of Michigan is al-so in the early stages of a multiyear study of the mental health of university students.7

What have these reports shown? There are currently approximately 17.5 million university students in the United States.

 Gallagher reported that in 2006, 8.5% of students sought counseling through their school service; another 29% were seen by college-based counselors in other settings. Voelker

 noted that visits to university counseling centers rose 42% between 1992 and 2002 at 11 large Midwestern universities.

For the past 10 years, Gallagher has consistently reported that about 90% of counseling center directors believe they are treating increasing numbers of students with severe pathology. In 1994, 9% of students seen at counseling centers were taking psychiatric medications. By 2006, this number had risen to 23.3%, and 7.5% of students had such serious impairments that they could not function in college settings or without extensive psychiatric/psychological support.

Students’ self-reports seem no more reassuring. According to the most recent American College Health Association survey, about 13% of students reported having symptoms of anxiety, and more than 18% reported depression symptoms.

 Almost 15% had received a diagnosis of depression sometime in their lives; 25% reported problems with their studies as a result of sleep problems; 33% acknowledged stress-related problems; 43% said they felt so depressed at some point in the academic year that it was difficult to function; 10% had seriously considered suicide; and 1.9% had attempted suicide.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

 has gathered data on alcohol use in colleges. The news is dire on this front as well: 31% of the surveyed students met criteria for alcohol abuse.

 Moreover, there were 1.3 million yearly alcohol-related injuries or assaults among college students. While there are estimated to be about 1100 suicides each year on college campuses, 1700 deaths are attributed to alcohol-related accidents and unintentional injuries.

Large numbers of students acknowledged that they had unsafe sex while intoxicated or did something they later regretted. Rates of assault and sexual assault related to alcohol and drug use are also alarmingly high. In 2005, 83% of campus arrests were alcohol-related.

Students who abused painkillers during the previous month increased from under 1% in 1993 to 3.1% in 2005.

 During the same period, daily marijuana use more than doubled from 1.9% to 4%; the use of illegal drugs other than marijuana, such as heroin and cocaine, increased from 5.4% to 8.2%.

When most college clinicians discuss the crisis in college mental health, they emphasize that the demands on ser-vices have dramatically outpaced the capacity and rate of growth of available mental health care systems. Most college counseling services provide free, short-term care for students and are usually funded by student services fees. Historically, the counseling centers were conceptualized as settings where students could be helped through a specific developmental challenge or adjustment problem (eg, homesickness, failure to establish a social network). The centers are frequently staffed by psychologists (more often counseling psychologists rather than clinical psychologists) and, until recently, often had little if any psychiatric staff.

Because many students have limited or no insurance coverage and many communities have limited options for low-fee care, colleges find themselves providing services for larger numbers of seriously ill students for longer periods. With the availability of effective treatment options, students with serious mental illness are now able to attend college. The need for clinicians equipped to care for these students has grown simultaneously. Colleges must decide whether to spend money hiring lower-salaried therapists (social workers and nurse practitioners) or psychiatrists.

Colleges are not in the business of providing health and mental health care. While the schools recognize the need to provide ample services, this is often done somewhat grudgingly and often after a crisis (such as a campus suicide).

Colleges have a complicated relationship with their students. Most students are legal adults and entitled to privacy and autonomy. However, colleges have some responsibility to oversee their students’ conduct and to provide in some general way for their safety and well-being.

 Parents expect to be part of the discussion if their child is having difficulties. College administrators, policy makers, legislators, and judges have all struggled to strike a balance between these values of privacy/autonomy and oversight/safety/ parental involvement.

The concerns around this conflict of values have been acutely heightened by the tragedies at Virginia Tech and Northern Illinois University. There have been calls from many corners to increase oversight of students, curtail their privacy and autonomy, and lower current legal thresholds for parental contact and mandatory leaves of absence.

These concerns have placed new pressures on college mental health services to keep campuses safe but sometimes without appropriate strategic planning. While there may be circumstances in which sharing clinical information or mandated medical leaves might be appropriate, these pressures have increased the challenge and conflict experienced by campus clinicians to keep patient care the primary goal of the clinical interaction. Lowering the threshold for communication is likely to erode the often fragile trust between a troubled student and the campus mental health systems and/or university administrators.

Currently, fewer than 1% of college counseling centers are directed by psychiatrists, and only 63% of schools provide psychiatric services on campus. The average weekly number of consultation hours is 17 per 100,000 students.

 [APA] president) convened a Presidential Task Force on College Mental Health to increase awareness and promote advocacy for college mental health in the psychiatric community. This group, now an APA committee, has become a “meeting place” (both real and virtual) for psychiatrists who work in college mental health settings. Many of these psychiatrists experience professional isolation.

College mental health services play an important role in promoting healthy and safe college communities and campuses. Having robust services available improves student retention and, thus, good services make good economic sense. With increasingly severe psychopathology of students, psychiatric services must be enhanced. Clinicians who support and treat the most troubled students and who can assess and manage psychiatric emergencies are needed. If an on-site psychiatrist is not economically feasible, referrals to accessible and affordable psychiatric services off-campus need to be provided.

Residency training and fellowship electives at college mental health ser-vices provide wonderful opportunities for residents to learn about college mental health issues (and to learn about short-term therapies and combined and split treatment). Experts in college mental health have begun to be invited to address grand rounds and professional meetings. The APA has established a college mental health area on its Web site (Healthy Minds. Healthy Lives

]) and there are a growing number of other Web sites devoted to college mental health and substance abuse.

While there are some efforts at careful epidemiological work, much more needs to be done to continue to understand and explain the growing number of increasingly troubled students presenting to college services and the best approaches for their care.

 The stigma associated with mental health problems on campus needs to be addressed, and integrated models of mental health care need to be put into practice.

The best college mental health services, while scrupulously maintaining the privacy of their patients, also find ways to educate their college communities about mental health issues. Tragedies on college campuses are more likely to be prevented by establishing open lines of communication and a strong collaboration among students, faculty, and administrators.

College mental health clinicians and administrators need to be well versed in the laws pertaining to college students but primarily should act in the “best interest of the student.” Relevant laws such as the Family Educational Rights and Privacy Act and the Americans with Disabilities Act provide a framework for decision making in complex cases. However, these laws do not, and should not, dictate case management in crisis situations; ultimately, clinicians should follow sound clinical judgment and appropriate consultation with colleagues in the decision-making process.

Despite all the problems and challenges that face college mental health services, work in this setting is generally quite rewarding. University students are usually intelligent, hard working, and resilient; and they often make substantial strides in treatment, however brief. Helping a student to remain in school, complete an education, and actualize his or her potential is a deeply gratifying professional experience.

 Sontag D. Who was responsible for Elizabeth Shin? 

 Hegranes C. Walking the edge: NYU confronts its suicide problem. 

 American College Health Association–National College Health Assessment; 2008. 

 International Association of Counseling Services: the Accreditation Association for University and College Counseling Services; 2008. 

 IES National Center for Education Statistics; 2008. 

Author | Jerald Kay, MD

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