Monday
Jan252016

GABA mediated vulnerable developmental periods: a potential target for diseases such as epilepsy and autism

Proper excitation-inhibition balance is crucial for normal brain function and particularly during critical periods of development, when neurons are still immature and brain circuits not yet fully formed. 

For example increases in neuronal excitability through inactivation of Kv7 voltage gated K+ channel current results in epilepsy in mice. A recent study by Marguet et al. showed that restoring excitation-inhibition balance in these mice during a critical window (first two weeks of life) prevents later development of epilepsy. The authors used Bumetanide, an FDA approved NKCC1 antagonist (cation-chloride cotransporter) to reduce intracellular chloride concentration and thereby reduce excitatory action of GABA in immature neurons. Notably, treatment during the critical window with Bumetanide was able to normalize network activity and prevent later epileptogenesis before the onset of symptoms in these mice. 

GABA mediated hyper-excitability in immature brain circuits has also been identified in autism models. In 2014, Tyzio and colleagues showed that maternal treatment with the same drug, Bumetanide, restored electrophysiological and behavioral phenotypes in rodent models of autism (Valproate and Fragile X). 

Translation of these findings to humans is undoubtedly very difficult. A first step are ongoing studies investigating the effect of Bumetanide treatment in individuals with autism and manifest epilepsy. However, preclinical studies investigating the basic underlying mechanisms may help understand the importance of excitation and inhibition of normal network activity and suggest future research avenues to go as far as investigating the potential for disease prevention in some cases. 

References:

Marguet et al. Nature Medicine 2015

Tyzio et al. Science 2014

Tuesday
Jan192016

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.
-TMG

 

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 
(2015).
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).

 

Tuesday
Jan122016

Epigenetics rules the ant kingdom

Typically in an ant colony, roles are split among workers based on their physical characteristics.  There are two major paths for workers of a colony.  One type, which consists of about one-third of the workers, are called majors.  The other workers are smaller and are called minors.  Minors typically forage for food much more often compared to the majors, who are much larger in comparison to their counterpart. 

What researchers have discovered about the caste system in a colony of carpenter ants is that both the size and the occupation that the worker ants acquire are based on epigenetic characteristics in their DNA.  Researchers at University of Pennsylvania conducted a study in which they administered two mood-stabilizing drugs to specific subjects within the colony through brain injection. After, they observed their overall foraging and scouting behavior.  Overall, they found that after an increase in histone acetylation (through the use of the bipolar drug) in the ants, minors foraged more aggressively and starting scouting for new food.  Majors began to exhibit foraging behavior, which is a characteristic usually only seen in minors. The effects of the drug treatment lasted for up to 50 days. They also found that the overall ability to change the behavior was greater in younger workers, suggesting a timeframe in which ants are more susceptible to being influenced by drug treatment at a younger age. 

More importantly, this research suggests a possible mechanism to the nurture component in the nature versus nurture dispute.  It also highlights the importance of epigenetic markers and the need for more research in epigenetics. In addition, researchers think that certain social situations could influence epigenetic changes in vertebrate species, giving clues to biologic mechanisms involved in social interactions and behaviors.

"Epigenetic (re)programming of Caste-specific Behavior in the Ant Camponotus Floridanus." Science 351.6268. 2015.

Tuesday
Dec152015

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.

 

-FAS

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

Wednesday
Dec092015

Manipulating Memory: From Inception to Neuroscience 

In Christopher Nolan's 2010 movie, Inception, Leonardo DiCaprio plants an idea or a specific memory in another person’s subconscious through a dream. Is this possible? Might be. MIT neuroscientists Liu and Ramire et al. have shown that they were able to create false memories in mice via optogenetics. Optogenetics is a technique that utilizes light stimuli to control specific genetically modified cells in living tissue via light-gated ion channel.

In their study, the mice were firstly subjected to a safe environment, Box A. Memories of this new environment were recorded in certain cells, which were programmed to respond to pulses of light. By applying light pulses, the mice will recall the memory of Box A. Then the mice were placed in a completely different environment, Box B, where the mice were subjected to foot shocks, with simultaneous delivery of light pulses into their brains to reactivate the memory of Box A. This resulted in a negative association between the light-reactivated memory of Box A and the foot shocks that the mice obtained in Box B. When the researchers put the mice back into Box A, it was observed that the mice displayed heightened fear responses. A false fear memory was implanted into the mice brain via artificial means.

This work has shown that memories can be altered during the recall process. The researchers pointed out that recall could make memories more labile and external information might be incorporated into existing memories occasionally over time. As Ramirez explained in their TEDx Boston talk, “The mind, with its seemingly mysterious properties, is actually made of physical stuff that we can tinker with.” Their work illustrates the increasing ability of neuroscientists to control, manipulate, and engineer memory in the brain.

 

Ref:

(1) Liu, X., Ramirez, S., Pang, P. T., Puryear, C. B., Govindarajan, A., Deisseroth, K., Tonegawa, S. Nature, 2012, 484 (7394), 381-385.

(2) Ramirez, S., Liu, X., Lin, P. A., Suh, J., Pignatelli, M., Redondo, R. L., Tonegawa, S. Science, 2013, 341(6144), 387-391.

(3) https://www.youtube.com/watch?v=kDXJhxLzmBQ