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Patients experiencing cardiovascular or metabolic side effects while taking an antipsychotic medication may fare better if they switch to a different medication provided they are closely monitored, according to an NIMH-funded study. The study was published online ahead of print July 18, 2011, in the American Journal of Psychiatry.

Antipsychotic medications can effectively treat psychotic symptoms among people with schizophrenia or related disorders. However, the medications, especially some of those that are most commonly used, are associated with serious metabolic side effects that can lead to heart disease or diabetes. Even when patients do experience these side effects, doctors are often reluctant to change a patient’s medication regimen if the patient’s psychotic symptoms are controlled by the existing medication.

“Treating the symptoms of schizophrenia is a delicate balancing act between risks and benefits,” said National Institute of Mental Health Director Thomas R. Insel, M.D. “The possible benefits of switching medications to reduce metabolic risks must be carefully weighed against the potential risk of symptom relapse or medication failure.”

Scott Stroup, M.D., of Columbia University and colleagues aimed to determine if a medication switch could be made safely and without sacrificing clinical stability. For the Comparison of Antipsychotics for Metabolic Problems (CAMP) study, they enrolled 215 patients from 27 clinical sites whose psychotic symptoms were stabilized on one of three frequently used antipsychotics (olanzapine, quetiapine or risperidone) but were experiencing serious metabolic side effects such as weight gain and high cholesterol levels. Half of the patients were assigned to stay on their current medication, while the other half were switched to aripiprazole, another antipsychotic that is generally associated with fewer metabolic risks. All of the participants received a behavioral intervention that included a diet and exercise program designed to reduce the risk of cardiovascular disease.

After 24 weeks, the researchers found that those who switched to aripiprazole had improved cholesterol levels and other metabolic factors, and lost more weight (average of 8 lbs) than those who stayed on their original medication (average of 1.5 lbs). Those who switched also did not experience any more illness relapses or worsening of psychotic symptoms compared to those who stayed on their original medication. However, those who switched to aripiprazole were more likely to discontinue the new medication compared to those who stayed on their original medication. Almost 44 percent of those who switched discontinued the aripiprazole compared to 24.5 percent of those who were assigned to stay on their current medication.

The authors suggest that the high discontinuation rate for switchers may have been related to the fact that the study was open label, meaning both the patient and the clinician knew what drug the patient was taking. Some patients who were switched may have felt uncomfortable changing from a medication they knew worked for them, and therefore stopped the new medication. In addition, because clinicians were encouraged to closely monitor and intervene before a patient experienced severe problems, many may have discontinued aripiprazole when the clinician first determined that the patient was having difficulties, but before full-blown treatment failure occurred.

“For patients whose symptoms are stabilized but who are overweight or experiencing other metabolic problems, clinicians may want to consider switching to a medication that is less likely to cause metabolic problems. However, because switching is not always successful, clinicians must monitor patients carefully to avoid illness exacerbation,” said Dr. Stroup. “If switching medications is not an option, then adding a medication like metformin or a statin could help reduce cardiovascular risks while maintaining symptom stability,” he concluded. He also noted that the study’s behavioral intervention that focused on improved diet and exercise habits benefited even those who did not switch medications.

Reference

Stroup TS, McEvoy JP, Ring KD, Hamer RH, LaVange LM, Swartz MS, Rosenheck RA, Perkins DO, Nussbaum AM, Lieberman JA. Comparison of antipsychotics for metabolic problems (CAMP):a randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk. American Journal of Psychiatry. Online ahead of print July 18, 2011.

A widely used suicide screening tool can help determine who is most at risk for suicide by pinpointing the threshold at which a person’s suicidal thinking is severe enough to warrant professional intervention, according to a recent study published online ahead of print November 8, 2011, in the American Journal of Psychiatry.

Background

Developing effective suicide prevention strategies is a priority of theAction Alliance for Suicide Prevention , a public-private partnership developed to advance the national strategy for suicide prevention. One of its main goals is to more efficiently identify those at risk so as to better target intervention. Standardized, reliable screening tools are needed to achieve that.

The Columbia-Suicide Severity Rating Scale (C-SSRS) was developed by a team of researchers from Columbia University, the University of Pennsylvania and the University of Pittsburgh to be used as part of the NIMH-funded Treatment of Adolescent Suicide Attempters (TASA) study. It was developed to meet the need for tracking changes in a person’s suicidal thinking and behavior over time, and to determine who is most at risk. The scale addresses the full range of suicidal behavior and thinking, but includes only the most essential, evidence-based items required for thorough assessment. The scale is now widely used for assessing suicidal thinking and behavior across research and practice in both psychiatric and non-psychiatric settings. It is used domestically and internationally by numerous stakeholders such as first responders (e.g., police, EMTs, fire departments), the U.S. Army, National Guards, prisons, hospitals, schools, and judicial systems to better identify those in need and to direct limited resources.

In this current analysis, Kelly Posner Ph.D., of Columbia University, and colleagues compared the C-SSRS to other similar measures, all of which were administered in three separate studies that featured teens who had attempted suicide or adults presenting to emergency rooms with psychiatric problems. They aimed to determine the scale’s validity, reliability and internal consistency, compared to the other measures.

Results of the Study

The researchers found that compared to other measures, the C-SSRS could reliably predict a potential suicide attempt in those who had previously attempted suicide. It also was able to determine clinically meaningful points at which a person may be at risk for an impending suicide attempt, something that other scales have been unable to consistently determine. According to the researchers, this type of predictive information can more precisely identify who needs the most help and when, while saving time and money by not having to refer people for treatment who are not at imminent risk.

Significance

This was the first major study showing how well the C-SSRS works with regard to identifying those most at risk for suicidal behavior. It was able to show, for the first time, that behaviors beyond previous suicide attempts—such as self-injury or making preparations for an attempt—may be used as predictors of subsequent suicide attempts.

What’s Next

Because the studies used in this analysis were not widely representative, additional research is needed to replicate the findings among diverse community samples.

Reference

Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings from Three Multisite Studies with Adolescents and Adults. American Journal of Psychiatry. Online ahead of print Nov 8,2011.

People with treatment-resistant bipolar disorder experienced relief from symptoms of depression in as little as 40 minutes after an intravenous dose of the anesthetic medication ketamine in a preliminary study; while the patient group was small, this work adds to evidence that compounds in the class to which ketamine belongs have potential as rapid and effective medications for depression, including bipolar depression. The potential for side-effects makes ketamine an impractical drug for standard use, but it provides a way to test this approach for developing novel treatments that act more rapidly than existing ones.

Background

Bipolar disorder (BD) is a potentially debilitating illness marked by severe swings in mood, energy, and behavior. Episodes of depression alternate with spells of mania but depressive episodes tend to be more frequent and longer-lasting and the depression is difficult to treat. BD is usually treated with mood stabilizing medications such as lithium, valproate, carbamazepine or other medications with the goal of preventing mood episode relapse. Antidepressant medications are often used in addition to a mood stabilizer for depressive episodes, but antidepressants typically take weeks to have an effect and many patients do not respond adequately to existing medications.

Previous research has suggested that a disruption of signaling between neurons involving the neurotransmitter glutamate is likely to play a role in depression. The anesthetic medication ketamine shuts down one class of receptor for glutamate (NMDA receptors).

This Study

Eighteen people with BD participated in this study of ketamine. All received maintenance treatment with a mood stabilizer medication during the study. All had previously been unsuccessfully treated with at least one antidepressant medication and a mood stabilizer; the average number of medications they had tried unsuccessfully was seven.

In the first phase of the study, each person was randomly assigned to receive a single dose of either intravenous ketamine or placebo (saline). After two weeks, treatment was switched, so those initially receiving ketamine received placebo, and vice versa. Neither patients nor those treating them were told whether they were receiving ketamine or placebo. Investigators used standard surveys of depression symptoms to assess the effect of medication.

Within 40 minutes, 9 of 16 (56 percent) patients receiving ketamine had at least a 50 percent reduction in symptoms, and 2 of 16 (13 percent) became nearly symptom-free. The response to ketamine lasted an average of about a week. By contrast, no patients receiving placebo had declines in symptoms close to the magnitude seen with ketamine within the first 3 days.

Significance

In this study, carried out by scientists Nancy Diazgranados, Carlos Zarate, Jr., and colleagues at the Experimental Therapeutics & Pathophysiology Branch of NIMH’s intramural research program, a single intravenous dose of ketamine brought relief from depression in severely treatment resistant patients with BD, in over half of them within 40 minutes. This study supports a previous one by the same group in which they also found a rapid antidepressant effect in patients with treatment-resistant major depression (unipolar). (NIMH press release, August 7, 2006). The authors note that the rapid antidepressant response observed in these two different disorders (major depressive disorder and bipolar disorder) highlights the importance of the NMDA receptor in developing treatments with a rapid onset of action.

The work adds to the evidence of the potential of medications targeting the glutamate system for rapid relief from depression, even in cases of people who have failed to respond to other existing therapies. Rapid and effective treatment of depression is an urgent public health need. BD can be disabling—nearly all the patients in this study were unemployed as a result of the severity of their illness. BD is among the psychiatric disorders with the highest risk of suicide.

Continuing research is focusing on developing NMDA-targeting medications that are suitable for clinical use; and investigating the use of this class of drugs for long-term maintenance of the rapid antidepressant effect seen in this study.

Reference

Diazgranados, N., Ibrahim, L., Brutsche, N.E., Newberg, A., Kronstein, P., Khalife, S., Kammerer, W. A., Quezado, Z., Luckenbaugh, D.A., Salvadore, G., Machado-Vieira, R., Manji, H.K., and Zarate, C. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry2010;67(8):793-802.

GLYX-13, a molecular cousin to ketamine, induces similar antidepressant results without the street drug side effects, reported a preclinical study funded by the National Institute of Mental Health (NIMH) that was published last month inNeuropsychopharmacology.

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.”

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.

Note: This is an updated version of the science update that first appeared on May 23, 2013.