OHSU Vollum Institute research gives new insight into how antidepressants work in the brain

Vollum Institute scientist publishes two papers on neurotransmission in today’s edition of Nature Research from Oregon Health & Science University's Vollum Institute, published in the current issue of Nature, is giving scientists a never-before-seen view of how nerve cells communicate with each other. That new view can give scientists a better understanding of how antidepressants work in the human brain — and could lead to the development of better antidepressants with few or no side effects. The article in today’s edition of Nature came from the lab of Eric Gouaux, Ph.D., a senior scientist at OHSU's Vollum Institute and a Howard Hughes Medical Institute Investigator. The article describes research that gives a better view of the structural biology of a protein that controls communication between nerve cells. The view is obtained through special structural and biochemical methods Gouaux uses to investigate these neural proteins. The Nature article focuses on the structure of the dopamine transporter, which helps regulate dopamine levels in the brain. Dopamine is an essential neurotransmitter for the human body's central nervous system; abnormal levels of dopamine are present in a range of neurological disorders, including Parkinson's disease, drug addiction, depression and schizophrenia. Along with dopamine, the neurotransmitters noradrenaline and serotonin are transported by related transporters, which can be studied with greater accuracy based on the dopamine transporter structure. The Gouaux lab's more detailed view of the dopamine transporter structure better reveals how antidepressants act on the transporters and thus do their work Alcoholism and Drug Abuse Counselors Continuing Education The more detailed view could help scientists and pharmaceutical companies develop drugs that do a much better job of targeting what they're trying to target — and not create side effects caused by a broader blast at the brain proteins. "By learning as much as possible about the structure of the transporter and its complexes with antidepressants, we have laid the foundation for the design of new molecules with better therapeutic profiles and, hopefully, with fewer deleterious side effects," said Gouaux. Gouaux's latest dopamine transporter research is also important because it was done using the molecule from fruit flies, a dopamine transporter that is much more similar to those in humans than the bacteria models that previous studies had used. The dopamine transporter article was one of two articles Gouaux had published in today’s edition of Nature. The other article also dealt with a modified amino acid transporter that mimics the mammalian neurotransmitter transporter proteins targeted by antidepressants. It gives new insights into the pharmacology of four different classes of widely used antidepressants that act on certain transporter proteins, including transporters for dopamine, serotonin and noradrenaline. The second paper in part was validated by findings of the first paper — in how an antidepressant bound itself to a specific transporter. "What we ended up finding with this research was complementary and mutually reinforcing with the other work — so that was really important," Gouaux said. "And it told us a great deal about how these transporters work and how they interact with the antidepressant molecules." Gouaux's discoveries over the years in neurotransmission have established him as one of the top investigators in his field. His research has important implications for understanding the mechanisms of not just antidepressants, but also drugs used for the treatment of a wide range of psychiatric and neurological diseases. Gouaux's co-authors on the dopamine transporter paper were both members of his lab; Aravind Penmatsa, Ph.D., and Kevin Wang, Ph.D. Gouaux's co-authors on the second Nature paper were also members or former members of his lab: Hui Wang, Ph.D.; April Goehring, Ph.D.; Kevin Wang, Aravind Penmatsa and Ryan Ressler, Ph.D. Both papers were funded by the American Heart Association, the National Institute of Mental Health, (1F32MH093120 and 5R37MH070039) and the Howard Hughes Medical Institute. About the OHSU Vollum Institute The Vollum Institute is a privately endowed research institute at OHSU and is dedicated to basic research that will lead to new treatments for neurological and psychiatric diseases. Vollum scientists have transformed the field of neuroscience and, in particular, have been pioneers in the study of cellular signaling, neuronal development, gene regulation and the neurobiology of disease. About OHSU Oregon Health & Science University is a nationally prominent research university and Oregon’s only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children’s Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university’s social mission. OHSU’s Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer’s disease and new treatments for Parkinson’s disease, multiple sclerosis and stroke. OHSU’s Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.

Ketamine Cousin Rapidly Lifts Depression Without Side Effects

Neurons in a subsection of the adult rat hippocampus are stained with a monoclonal antibody (yellow) that enhances learning and memory. A portion of this antibody is where GLYX-13 came from. Source: Dr. Joseph Moskal, Ph.D., Northwestern University GLYX-13, a molecular cousin to ketamine, induces similar antidepressant results without the street drug side effects, reported a study funded by the National Institute of Mental Health (NIMH) that was published last month in Neuropsychopharmacology. Background Major depression affects about 10 percent of the adult population and is the second leading cause of disability in U.S. adults, according to the World Health Organization. Despite the availability of several different classes of antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), 30 to 40 percent of adults are unresponsive to these medications. Moreover, SSRIs typically take weeks to work, which increases the risk for suicide. Enter NMDA (N-methyl-D-aspartate) receptor modulators. In the 1970s, researchers linked the receptors to learning and memory. Biotech and pharmaceutical companies in the 1980s attempted to apply chemical blockers to these receptors as a means to prevent stroke. But blocking these receptors led to the opposite effect—--the rise of cardiovascular disease. Research in the field dampened until a glutamate receptor antagonist already approved for anesthesia, and known on the streets as “Special K”, ketamine, made headlines in the early 2000s. Human clinical studies demonstrated that ketamine can ward off major and bipolar depressive symptoms within 2 hours of administration and last for several days. Ketamine is fraught with serious side effects including excessive sleepiness, hallucinations, and substance abuse behavior. “Ketamine lit the field back up,“ said Joseph Moskal, Ph.D., a molecular neurobiologist at Northwestern University and senior study author. “Our drug, GLYX-13, is very different. It does not block the receptor ion channel, which may account for why it doesn’t have the same side effects.” Moskal’s journey with GLYX-13 came about from his earlier days as a Senior Staff Fellow in NIMH’s Intramural Research Program. While at NIMH, he created specific molecules, monoclonal antibodies, to use as new probes to understand pathways of learning and memory. Some of the antibodies he created were for NMDA receptors. When he moved to Northwestern University, Moskal converted the antibodies to small protein molecules. Comprised of only four amino acids, GLYX-13 is one of these molecules. Previous electrophysiological and conditioning studies had suggested that GLYX-13, unlike ketamine, enhanced memory and learning in rats, particularly in the brain’s memory hub or hippocampus. GLYX-13 also produced analgesic effects. Using several rat behavioral and molecular experiments, Moskal’s research team tested four compounds: GLYX-13, an inactive, “scrambled” version of GLYX-13 that had its amino acids rearranged, ketamine, and the SSRI fluoxetine. Results of the Study GLYX-13 and ketamine produced rapid acting (1 hour) and long-lasting (24 hour) antidepressant-like effects in the rats. Fluoxetine, an SSRI that typically takes from 2–4 weeks to show efficacy in humans, did not produce a rapid antidepressant effect in this study. As expected, the scrambled GLYX-13 showed no antidepressant-like effects at all. The researchers observed none of the aforementioned side effects of ketamine in the GLYX-13–treated rats. Protein studies indicated an increase in the hippocampus of the NMDA receptor NR2B and a receptor for the chemical messenger glutamate called AMPA. Electrophysiology studies in this brain region showed that GLYX-13 and ketamine promoted long-lasting signal transmission in neurons, known as long-term potentiation/synaptic plasticity. This phenomenon is essential in learning and memory. The researchers propose how GLYX-13 works: GLYX-13 triggers NR2B receptor activation that leads to intracellular calcium influx and the expression of AMPA, which then is responsible for increased communication between neurons. These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug’s antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4–6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents. Significance NMDA receptors need a molecule each of the amino acid chemical messengers glutamate and glycine to become activated. Moskal speculates that GLYX-13 either directly binds to the glycine site on the NMDA receptor or indirectly modulates how glycine works with the receptor. Resulting activation of more NMDA and AMPA receptors leads to an increase in memory, learning—and antidepressant effects. By contrast, ketamine only blocks the NMDA receptor, but also increases the activity of the AMPA receptor. Knowledge of these mechanisms could lead to the development of more effective antidepressants. What’s Next GLYX-13 is now being tested in a Phase 2 repeated dose antidepressant trial, where Moskal and his colleagues at Naurex, Inc., a biotechnology company he founded, hope to find in humans the optimal dosing for the drug. They also want to see if this molecule, and others like it, regulate other NMDA receptor subtypes—there are over 20 of them—and whether it will work on other disorders, such as schizophrenia, attention-deficit hyperactivity disorder, and autism. “One could call NMDA modulators such as GLYX-13 ‘comeback kids,’” said Moskal. “A toolkit that I developed in 1983 is now setting the stage in 2013 for the development of possible new therapeutics that may provide individuals suffering from depression with a valuable new treatment option.” Alcoholism and Drug Abuse Counselors Continuing Education Reference Burgdorf J, Zhang X-l, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskal JR. GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects. Neuropsychopharmacology, April 2013. 38:729–742.

Atypical antipsychotic more effective than older drugs in treating childhood mania, but side effects can be serious

The antipsychotic medication risperidone is more effective for initial treatment of mania in children diagnosed with bipolar disorder compared to other mood stabilizing medications, but it carries the potential for serious metabolic side effects, according to an NIMH-funded study published online ahead of print January 2, 2012, in the Archives of General Psychiatry social worker continuing education

Background

Childhood bipolar disorder is a relatively rare but seriously impairing condition. It is also associated with an increased risk of substance use disorders and suicide. To treat symptoms of mania, a key symptom of the disorder, medications such as mood stabilizers or antipsychotics are often prescribed. However, no prior study has addressed the question of which medication to try first.

In the Treatment of Early Age Mania (TEAM) study, Barbara Geller, M.D., of Washington University in St. Louis, and colleagues randomized 290 children ages 6-15 years diagnosed with bipolar I disorder (having mixed or manic symptoms) to treatment with lithium, divalproex sodium or risperidone for an 8-week trial. None of the children had taken an anti-manic medication before. Lithium has been used to treat bipolar disorder for many years. Divalproex sodium is an anticonvulsant mood stabilizer commonly prescribed to treat bipolar disorder as well. Risperidone is an atypical antipsychotic that has been approved by the U.S. Food and Drug Administration for the treatment of mania in youth age 10 and older.

Results of the Study

After eight weeks, 68.5 percent of the children taking risperidone showed improvement in manic symptoms, compared to 35.6 percent of those taking lithium and 24 percent of those taking divalproex sodium. Overall, 24.7 percent discontinued the trial, but more children taking lithium—32.2 percent—discontinued the trial compared to those taking risperidone (15.7 percent discontinued) or divalproex sodium (26 percent discontinued.)

However, those taking risperidone also gained more weight than those on the other medications—an average of more than 7 lbs compared to around 3 lbs for those taking lithium and 3.7 lbs for those taking divalproex sodium. Those taking risperidone were also more likely to experience other metabolic side effects, such as an increase in cholesterol levels, compared to those on the other medications.

Significance

The researchers concluded that risperidone was significantly more effective than lithium or divalproex sodium for initial treatment of childhood mania. In addition, the children were less likely to discontinue the drug compared to those taking lithium or divalproex sodium, indicating a higher tolerance for it. This finding is consistent with other studies that have compared second-generation antipsychotics like risperidone to placebo in treating childhood mania.

However, the researchers caution that risperidone is associated with adverse metabolic effects that can increase the risk for diabetes and cardiovascular problems. They note that many children responded to low doses of the medication, suggesting that clinicians should be conservative when determining how to dose the medication. A lower dose may minimize the potential for serious side effects. The researchers also caution that because diagnostic measures for childhood bipolar disorder are not always consistent across studies, and because the validity of such a diagnosis in younger children is under debate, TEAM findings may not generalize to patients diagnosed using other measures.

What’s Next

More research is needed to develop safer, more effective interventions for children with early onset bipolar disorder for both initial and longer term treatment.

Reference

Geller B, Luby J, Josh P, Wagner KD, Emslie G, Walkup JT, Axelson DA, Bolhofner K, Robb A, Wolf DV, Riddle MA, Birmaher B, Ryan ND, Severe J, Vitiello B, Tillman R, Lavori P. A randomized controlled trial of risperidone, lithium and divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Archives of General Psychiatry. Online ahead of print January 2, 2012.