Entries in psychiatry (4)


Not so fun facts about psychiatry...

Out of all the medical disciplines psychiatry may arguably have the worst reputation. Unfortunately, this view is not entirely undeserved; the first two Nobel Prizes awarded to psychiatrists were for the discovery that infecting patients with malaria - a form of pyrotherapy - could cure certain psychotic disorders (a consequence of syphilis, and the induced fevers either killed the pathogen - or the patient) and the invention of lobotomy, in which lesioning neural connections, or basically, scraping out pieces of the frontal lobes, made aggressive patients complacent. While much easier to manage afterwards, these patients also lacked any recognizable personality. In all fairness, while these approaches were both literal and metaphorical stabs into the dark, unknown realm of mental illness, terrible treatments such as pyrotherapy and lobotomy were the only alternatives to a lifetime shuttered away in an asylum.  Unfortunately, these institutions were often overcrowded, typically poorly maintained psychiatric hospitals with the main purpose of preventing patients from doing damage to themselves or society because no cures were available.

It is until the middle of the last century that Freud’s legacy firmly controlled the discipline of psychiatry in the United States. It was a widely held belief that all psychiatric illness stemmed from unresolved conflicts of the subconscious that simply needed to be uncovered and discussed to resolve the condition.  Though a neurologist by training, Freud’s approach was not based on biological data but rather on the interpretation of patient case studies fueled by theoretical considerations, many of which when judged by today’s standards appear to be based upon idiosyncratic convictions. For example, today we know that autism is not caused by “frigid mothers” and schizophrenia is not a consequence of obscure inner conflicts.

Initial attempts to classify neuropsychiatric illness in the United States grew out of the 1840 census.  The first Diagnostic and Statistical Manual (DSM) was a medical document which emerged from the assessment of soldiers during World War II. While some biological aspects of mental illness had been considered by this time, a major step forward was the development of the DSM-III, the first guidebook to facilitate the diagnosis of psychiatric illness in a systematic way, based on data rather than on purely Kraepelinian views or Freudian anecdotes. DSM-III was published in 1980(!) as a response to public frustration over inconsistent diagnoses and treatments in psychiatry. The practitioners realized that in order to maintain public trust in psychiatry, insurance coverage for psychiatric procedures, and to find actual cures for devastating illnesses such as depression, bipolar disorder and schizophrenia, a data-based approach was indispensable.

Now, almost 40 years and two DSM versions later, we have a variety of psychopharmacological treatment options. We have also realized that neither pharmacological treatment nor psychotherapy alone can solve the big problems in neuropsychiatric illness, and that combined, these approaches are only a small step towards actually understanding and curing the most devastating disorders. Even with our most advanced neuroimaging technology it is still painstakingly difficult to advance our knowledge. But, taking the history of treatment into perspective along with our evolving  understanding of mental illness, at least we no longer infect patients with malaria or blindly poke around in the frontal lobes of patients suffering from psychoses. We are still a long way from general, reliable solutions but psychiatric illness is no longer a life sentence to an asylum.



Sources/Further Reading:

Lieberman, J., Ogas, O., (2015). Shrinks: the Untold Story of Psychiatry. London: Weidenfeld and Nicolson.

Jamison, Kay Redfield, (1995). An Unquiet Mind. New York: Knopf.

Decker, Hannah, (2013). The making of DSM-III. Oxford: Oxford University Press.


Schematic of a transorbital lobotomy:

Source: https://www.theparisreview.org/blog/2017/04/18/the-art-of-the-lobotomy-and-other-news/


New dopamine D3 receptor agonist shows promise for negative and cognitive symptom relief in schizophrenia

Schizophrenia is a highly heterogeneous psychiatric illness that affects approximately 1% of the 
population. Three major classes of symptoms (positive, negative, and cognitive) define this 
illness. Positive symptoms refer to “above normal” and include two main features, delusions and 
hallucinations. Negative symptoms refer to “below normal” and include many behaviors 
associated with depression. Cognitive symptoms refer to a fundamentally disorganized thought 
process. Currently, there is no molecular or imaging biomarker for schizophrenia. Diagnoses are 
made on the basis of symptoms through direct clinical interview. Notably, symptoms will 
be different for each patient and may change over time.
The cause of schizophrenia is not well understood and there is no cure. Two types of 
medications (typical and atypical antipsychotics) are currently used for symptom management. 
Typical anti-psychotics, such as chlorprozamine and haloperidol, are strong dopamine D2 
receptor antagonists. Typical antipsychotics are not the preferred method of treatment because 
they often cause strong movement-related side effects reminiscent of Parkinson's disease. 
Atypical antipsychotics, such as aripiprazole and clozapine, are weak dopamine D2 antagonists. 
Atypical antipsychotics often result in metabolic-related side effects including sedation, 
hypotension, and weight gain. Overall, current antipsychotic medications are intolerable and 
largely ineffective for negative and cognitive symptoms. These untreated symptoms can be 
devastating. Patients often suffer unemployment, homelessness, and drug addiction; 
approximately 10% of patients commit suicide1.
Undoubtedly, new medications are desperately needed to better manage schizophrenia. 
However, novel treatment mechanisms have not been discovered in over sixty years! 
Cariprazine may be a step in the right direction. Cariprazine, developed by Gedeon 
Richter, preferentially acts as a dopamine D3/D2 receptor partial agonist2. The dopamine D3 
receptor is implicated in mood regulation and cognition3. A recent phase III clinical trial showed 
that cariprazine significantly reduces positive, negative, and cognitive symptoms in patients 
suffering severe acute psychosis2. In this multinational double-blind study, patients were 
randomized (1:1:1:1) to receive placebo (n=153), cariprazine 3 mg/d (n=155), cariprazine 6 
mg/d (n=157), or aripiprazole 10 mg/d (n=152) for six weeks2. The primary outcome 
measurement was the mean change from baseline to week 6 in the Positive and Negative 
Syndrome Scale (PANSS) total score, which measures overall symptom severity4. Both doses 
of cariprazine significantly improved all PANSS subscales, including the depression cluster, 
within 3 weeks2. Further, the 6mg/d cariprazine dose showed a 50% PANSS response 
improvement from baseline, as compared to placebo2. Akathisia (an inability to sit) was the most 
frequent treatment-related side effect and encouragingly, cariprazine was not associated with 
metabolic-related side effects2. Based on this study and many others, cariprazine (VRAYLAR) is 
now FDA-approved for schizophrenia and bipolar disorder I-related mania2.
Clinicians suggest however, that cariprazine is not yet a “home-run”2. Future studies are 
required to test cariprazine head-to-head with commonly prescribed antipsychotics in stabilized 
schizophrenic patients2. This is particularly important, as negative and cognitive symptoms 
commonly decrease with antipsychotic treatment in patients suffering acute psychosis5. A true 
cariprazine victory would arise from strong negative and cognitive symptom reduction in the 
stabilized schizophrenic population.


Figure taken from: Durgam S. et al., Cariprazine in Acute Exacerbation of Schizophrenia: A Fixed-Dose, Phase 3, Randomized, Double-Blind, Placebo- and Active-Controlled Trial. J Clin Psychiatry 76(12):e1574–e1582 (2015).


1) Saha S. et al., A systematic review of mortality in schizophrenia. Is the differential mortality gap 
worsening over time? Arch Gen Psychiatry 64, 1123-1131 (2007).
2) Durgam S. et al., Cariprazine in Acute Exacerbation of Schizophrenia: A Fixed-Dose, Phase 3, 
Randomized, Double-Blind, Placebo- and Active-Controlled Trial. J Clin Psychiatry 76(12):e1574–e1582 
3) Sokoloff P. et al., The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric 
disorders. CNS Neurol Disord Drug Targets 5(1):25–43 (2005).
4) Kay S.R., Fiszbein A., and Opler L.A. The Positive and Negative Syndrome Scale (PANSS) for 
Schizophrenia. Scizophrenia Bulletin 13(2) (1987).
5) Kirkpatrick B. et al., The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 
32(2):214–219 (2006).



An open mind for improving human health

‘Astounding’ is how I would describe the results presented by Dr. Roland Griffiths (a 40+ year veteran researcher at Johns Hopkins University School of Medicine) at the closing sessions of the 54th annual meeting of the American College of Neuropsycho-pharmacology.  Dr. Griffith and his colleagues shared study results that after a single treatment with the study drug, the severely depressed mood of terminally-ill cancer patients had been dramatically improved (and I would wager this as an understatement). Their perspective on life had been powerfully changed for the better and was evidenced not only on the way the patients felt about themselves but also from the feedback of members of the patients’ individual communities – the patients seemed much happier and more at peace to family, loved-ones, co-workers and community.  Even more incredible was that these positive changes were not only profound in magnitude, but remained very strong, even 6 MONTHS after treatment.  The effects seemed a bit like magic; the test drug was psilocybin – ‘magic mushrooms’.

Dr. Griffiths' landmark paper in 2006 remains a watershed in modern psilocybin research (http://www.ncbi.nlm.nih.gov/pubmed/16826400) and caused a resurgence of interest in the compound as a pharmacological tool that could be safely investigated in humans after a decades-long lag in research. The 2006 report, through a careful scientific approach, provided some of the best-controlled evidence for the positive and lasting effects of psilocybin in healthy volunteers. Highlights can be seen in his 2009 TEDxMidAtlantic talk, currently posted on YouTube.

Where had psilocybin gone? After widespread, and arguably fallible research (poor study design) in the 1950s and 1960s on then-legal psilocybin, concern of substance abuse as a street drug led to classification as a Schedule I drug in the US (high abuse potential with no accepted medical use). Psilocybin is a naturally occurring psychoactive compound produced by more than 200 types of mushrooms. Considered an ‘entheogen,’ it has been used for centuries in religious ceremonies to “generate the divine within” however its illegal status relegated it as an underground psychoactive drug, known also as ‘mushrooms’ or ‘shrooms’. 

Where has the anxiety gone? Whereas subjects in Dr. Griffiths studies emerged from treatment with a deeply positive recalibration of life’s meaning, a lead question during last week’s ACNP session was in the apparent absence of experiences occasioned by the lay user which are highly variable and dominated by feelings of intense panic and fear.  Here a key feature of Dr. Griffiths’ studies - ‘supportive conditions’  - are highly important and being with several visits between test subjects and study staff prior to psilocybin administration to develop trust and rapport. During the 8-hour psilocybin treatment session, study staff were present as ‘guides’ to reassure subjects and navigate darker experiences with greater confidence and a philosophy of discovery. 

Modern neuroscience has a close eye on this ancient drug, and beyond subjective mood testing, research led by Dr. Robin Carhart-Harris (Imperial College London) is using functional magnetic resonance imaging to better understand how brain activation patterns are modulated by psilocybin (http://www.ncbi.nlm.nih.gov/pubmed/22308440). In addition to the growing evidence from studies by Dr. Griffiths and similar trials at New York University (see a great article in the New Yorker from Feb. 2015; http://www.newyorker.com/magazine/2015/02/09/trip-treatment), the in vivo imaging results provide compelling evidence that under controlled conditions, psilocybin is safe and highly effective in improving the well-being patients in need. This is a fascinating example of science to me and I am excited to see how psilocybin’s status as an illegal drug with ‘no accepted medical use’ will change when the benefit to patients seems so clear.



Photo credit: RollingStone.com

Media links:

1.  Griffiths, et al, 2006 Psychopharmacology (Berlin) http://www.ncbi.nlm.nih.gov/pubmed/16826400.

2.  Griffiths, 2009 TED talk: https://www.youtube.com/watch?v=LKm_mnbN9JY.

3.  Carhart-Harris, et al, 2012 PNAS (http://www.ncbi.nlm.nih.gov/pubmed/22308440)

4. Feb. 2015 New Yorker article: (http://www.newyorker.com/magazine/2015/02/09/trip-treatment



The disciplines I am most interested in are neuroscience and psychiatry, which are still distinct, though scientists hope to bridge the gap between these two fields. There are a number of neuroscience-based investigations conducted on psychiatric disease, but as Dr. Paulus mentions in a recent JAMA Psychiatry opinion piece, there is yet to exist a definitive biological explanation for any particular psychiatric illness. Yes, it is true that psychiatry deals with complex conditions, which are influenced by genetic and environmental factors exerting effects at the neuronal to systems levels.  Understandably, this makes it difficult to determine exactly what happens in different psychiatric illnesses. For medical conditions pertaining to other body systems (e.g., cardiovascular and infectious diseases), the biological determinants for disease manifestation and treatment efficacy are better understood. It would be great if psychiatric status could be examined in ways similar to monitoring for abnormal blood test results (e.g., CRP, HDL and LDL cholesterol, triglycerides, etc.) to minimize the chances of developing heart disease or MRI imaging to view a brightly-enhanced area likely to represent a tumor), but this approach to psychiatric diagnosis is too simplistic. Dr. Paulus believes that many scientific investigations focus on “mechanisms” and “mechanistic explanations” (admittedly vague expressions wildly thrown around in scientific publications) to study disease and that this way of conducting research is contributing to the rarity of biological breakthroughs in psychiatry.


In her opinion piece, Dr. Paulus also brings up the problem of reverse inference in neuroscience research. Yes, when discussing brain structure and function, you will frequently hear of a certain brain area being implicated in a particular behavior, emotion, affect, etc. Unfortunately, almost always secondary is the elaboration on the conditions in which the association was found. For example, if during resting state patients with a disease show increased activity in a brain region previously found to be active during tasks aimed at assessing reward-related behaviors, would you say there is heightened reward-associated activity in a disease? No, this is not necessarily true since brain areas are involved in multiple processes.


Dr. Paulus advocates for a prediction-based approach to solve clinical problems. However, is there sufficient information available on predictors to make estimates of diagnoses and prognoses for psychiatric illnesses, as she proposes to the neuropsychiatric research community?  I believe that there is need for computational predictive models to help determine the likelihood of developing a particular condition based on different factors, but we must also remain cautionary of an absolute utility of such models. How can a computational predictive model explain why a patient develops a disease despite expressing a neurobiological or genetic propensity for that disease?  What reasoning do you provide to the patient? Another vital piece of this puzzle is appropriate avenues for effective patient treatment.  How do you address the question of why something like CBT works for one patient but not another? What are the processes taking place in the brain leading to these outcomes? “Best practice” models for effective treatment are still subject to each patient’s unique biological makeup and environmental circumstances.

Furthermore, psychiatry is a field in which prescribed medications often have a variety of side effects, which can vary from person to person. Reliance on prediction models is unlikely to bring about novel understanding of disease or major improvements in therapeutic treatments. Neuroscience investigations should continue studying what exactly is altered in the brain of patients with a particular disease, and to what extent these changes are present. Research on!




Paulus, M.P. Pragmatism Instead of Mechanism: A Call for Impactful Biological Psychiatry. JAMA Psychiatry.2015; 72(7): 631-632.