Oxytocin Improves Social Cognition In Schizophrenia
Researcher Josh Woolley and colleagues at the University of California, San Francisco have found that intranasal oxytocin (at doses of 40 IU) improved social cognition in patients with schizophrenia when compared with placebo. Oxytocin is a hormone that facilitates social bonding. Social cognition refers to the way we understand what emotions other people are communicating through facial expression, voice, etc.
Interestingly, less complicated aspects of social cognition like recognizing affect and distinguishing between sincerity and sarcasm were not affected by the oxytocin treatment. However, more complex types of social inference (such as decoding whether an actor intended sarcasm versus telling a white lie) were substantially improved. These tasks evaluate “theory of mind”—the ability to attribute mental states to oneself and others, and to recognize that another person’s mental state may be different from one’s own. These abilities are sometimes lacking in those with schizophrenia and other disorders, such as autism. Given that these abilities have been related to real world social functioning, Woolley and colleagues suggest that oxytocin could, for example, help these individuals to make more friends.
Adjunctive Topiramate Is Effective In Schizophrenia
Many patients with schizophrenia do not reach full remission on antipsychotic drugs alone. The anticonvulsant drug topiramate (Topamax) has shown some promise as an adjunctive treatment for schizophrenia. To clarify the results of studies of topiramate, researcher Christoph Correll and colleagues performed a meta-analysis of nine randomized, placebo-controlled clinical trials of the drug. They found that when topiramate was added to antipsychotic treatment, it improved both positive and negative symptoms of schizophrenia, and it also led to reduced weight.
Editor’s Note: Topiramate might also be useful for patients with schizophrenia who have the common comorbidities of alcohol and cocaine abuse, since in other studies of patients with these primary disorders, topiramate was helpful.
Aspirin added to Regular Treatment Reduces Symptoms of Schizophrenia
Most drugs used to treat schizophrenia target dopamine and serotonin receptors in the brain. While these are effective in many patients, relapse is common and side effects can be severe. Researchers are looking for ways to target other mechanisms that cause schizophrenia, and inflammation seems to be one of these. There is evidence that a treatment as simple as aspirin, when added to regular treatment with antipsychotics, can improve schizophrenia by targeting inflammation.
In a 2010 study by Laan et al. published in the Journal of Clinical Psychiatry, patients with moderate or severe schizophrenia were given either placebo or aspirin (acetylsalicylic acid, 1000mg) in addition to their regular treatments every day for three months. The patients who received aspirin showed a significant reduction in the positive symptoms of schizophrenia, and to a lesser extent the negative symptoms, compared to those who received placebo. Cognitive function was not improved. The effect size (Cohen d) for the total scale score was 0.5, which is considered a “medium” effect and one that is clinically relevant.
The reductions in symptoms were greater in those patients who had more altered immune function.
Family History Of Alcoholism Predicts Positive Response To Ketamine
The drug ketamine can bring about antidepressant effects rapidly when given intravenously, but these effects last only a few days. In a recent study, bipolar depressed patients with alcoholism or a family history of alcoholism in first-degree relatives had a more extended positive antidepressant response to IV ketamine than those without this history, and fewer adverse effects from the treatment. The study, published by David Luckenbaugh et al. from the National Institute of Mental Health in the journal Bipolar Disorders in December 2012, replicates similar findings in patients with unipolar depression, where positive family history of alcoholism also predicted better response and fewer adverse effects from IV ketamine.
Alcohol and ketamine have a common mechanism of action. They are both antagonists of the glutamate NMDA receptor, meaning they limit the effects of glutamate, the major excitatory neurotransmitter in the brain. This suggests a theoretical explanation for why a history of alcoholism might relate to ketamine response.
Editor’s Note: Family history appears to be linked to how patients respond to different mood stabilizers. Lithium works best in those patients with a positive family history of mood disorders (especially bipolar disorder). Carbamazepine works best in those without a family history of bipolar disorder among first-degree relatives. Lamotrigine works best in those with a positive family history of anxiety disorders or alcoholism.
Drugs that are effective in patients with a family history of alcoholism all target glutamate in the brain. Lamotrigine decreases glutamate release, while ketamine reduces glutamate’s effects at the receptor. Both decrease glutamate function or activity. Like lamotrigine, carbamazepine also decreases glutamate release and has good effects in those with a history of alcoholism.
Memantine is another mood-stabilizing drug that is an antagonist of the NMDA receptor, like ketamine and alcohol. It will be interesting to see whether memantine will also be successful in those with a personal or family history of alcoholism.
Psychiatric Revolution: Changes in Behavior Are Associated with Dendritic Spine Shape and Number
Neuron cell
New research shows that cocaine, defeat stress, the rapid-acting antidepressant ketamine, and learning and memory can change the size, shape, or number of spines on the dendrites of neurons. Dendrites conduct electrical impulses into the cell body from neighboring neurons.
Cocaine
Several researchers, including Peter Kalivas at the Medical University of South Carolina, have reported that cocaine increases the size of the spines on the dendrites of a certain kind of neurons (GABAergic medium spiny neurons) in the nucleus accumbens (the reward center in the brain). This occurs through a dopamine D1 selective mechanism. N-acetylcysteine, a drug that can be found in health food stores, decreases cocaine intake in animals and humans, and also normalizes the size of dendritic spines.
Depression
Depression in animals and humans is associated with decreases in Rac1, a protein in the dendritic spines on GABA neurons in the nucleus accumbens. Rac1 regulates actin and other molecules that alter the shape of the spines.
In an animal model of depression called defeat stress, rodents are stressed by repeatedly being placed in a larger animal’s territory. Their subsequent behavior mimics clinical depression. This kind of social defeat stress decreases Rac1 and causes spines to become thin and lose some function. Replacing Rac1 returns the spines to a more mature mushroom shape and reverses the depressive behavior of these socially defeated animals. Researcher Scott Russo has also found Rac1 deficits in the nucleus accumbens of depressed patients who committed suicide. Russo suggests that decreases in Rac1 are responsible for the manifestation of social avoidance and other depressive behaviors in the defeat stress animal model, and that finding ways to increase Rac1 in humans would be an important new target for antidepressant drug development.
Another animal model of depression called chronic intermittent stress (in which the animals are exposed to a series of unexpected stressors like sounds or mild shocks) also induces depression-like behavior and makes the dendritic spines thin and stubby. The drug ketamine, which can bring about antidepressant effects in humans in as short a time as 2 hours, rapidly reverses the depressive behavior in animals and converts the spines back to the larger, more mature mushroom-shape they typically have.
Learning and Extinction of Fear
Researcher Wenbiao Gan has reported that fear conditioning can change the number of dendritic spines. When animals hear a tone paired with an electrical shock, they begin to exhibit a fear response to the tone. In layer 5 of the prefrontal cortex, spines are eliminated when conditioned fear develops, and are reformed (near where the eliminated spines were) during extinction training, when animals hear the tones without receiving the shock and learn not to fear the tone. However, in the primary auditory cortex the changes are opposite: new spines are formed with learning, and spines are eliminated with extinction.
Editor’s Note: It appears that we have arrived at a new milestone in psychiatry. In the field of neurology, changes seen in the brains of patients with strokes or Alzheimer’s dementia have been considered “real” because cells were obviously lost or dead. Psychiatry, in comparison, has been considered a soft science because neuronal changes have been more difficult to see and illnesses were and still are called “mental.” Now that new technologies have made a deeper level of precision, observation, and analysis possible, we know that the brain’s 12 billion neurons and 4 times as many glial cells are exquisitely plastic–capable of biochemical and structural changes that can be reversed using appropriate therapeutic maneuvers.
The changes associated with abnormal behaviors, addictions, and even normal processes of learning and memory now have clearly been shown to correspond with the size, shape, and biochemistry of dendritic spines. These subtle, reproducible changes in the brain and body are amenable to therapeutic intervention, and are now even more demanding of sophisticated medical attention.
Intranasal Ketamine Helps Some Kids with Bipolar Disorder
The anesthetic ketamine given intranasally may help children with a certain type of bipolar disorder. In an article published in the Journal of Affective Disorders in 2013, Demetri Papolos et al. reported seeing marked improvement in a subgroup of 12 children aged 6 to 19 years of age who were nonresponsive to the usual treatment regimens of lithium, mood stabilizers, and antipsychotics. Papolos has described these children as having the “fear of harm (FOH) subtype.” In addition to having typical mood swings, these children also have a fear of aggression, separation anxiety, sleep and circadian rhythm disorders, nightmares, thermoregulatory problems, and carbohydrate craving.
Ketamine was given as an intranasal spray using an inhaler in 10mg doses. Doses were increased until the targeted symptoms remitted. Average doses ranged from 30mg to 120mg, given every 3 to 7 days. All symptom areas including depression and mania improved markedly, usually within a few hours, and this improvement lasted 3 to 4 days. Four types of aggression (measured on the Overt Aggression Scale) decreased significantly.
There were some dissociative side effects that were usually mild to moderate, but occasionally severe. They resolved spontaneously, usually within the first hour after treatment, and there appeared to be tolerance to them following repeated administration.
The authors urged caution until findings from these cases are confirmed by more controlled studies, but they concluded that the magnitude and rapidity of effects in these children with treatment resistant bipolar disorder suggested effectiveness and safety.
New Drug Produces Rapid-Onset Antidepressant Effects
We have previously summarized studies on ketamine, which when given intravenously can bring about rapid-onset antidepressant effects. Ketamine is a full antagonist (or a blocker) of the glutamate NMDA receptors. Another drug currently in development may work in a related way.
At a recent scientific meeting, researcher Sheldon Preskorn showed that the compound GLYX-13, a partial agonist at the glycine binding site of the NMDA receptor (meaning it allows partial function of the glycine receptors that aid NMDA receptor function), exerts rapid antidepressant effects like the full antagonist ketamine when administered intravenously compared to placebo. GLYX-13 allows about 25% of the receptor activity of the full agonists glycine or D-serine, and thus might result in a 75% inhibition of NMDA receptor function.
GLYX-13 did not induce any psychotomimetic effects (like delusion or delirium), which are possible with the full NMDA antagonist ketamine. The effects of GLYX-13 appeared within 24 hours, lasted at least 6 days, but were gone by day 14.
Editor’s Note: Long-term effectiveness of ketamine for treatment of depression is unclear, but in addition to its potential psychotomimetic effects, it can also be abused. Whether GLYX-13 may be easier to use, longer-lasting, or safer for longer-term clinical effectiveness remains a key question.
Ketamine for OCD
At a recent scientific meeting, researcher Carolyn Rodriguez presented a randomized controlled crossover trial of ketamine in obsessive-compulsive disorder (OCD). In contrast to a previous negative study by Block and associates at the National Institute of Mental Health (NIMH), these investigators found that intravenous (IV) infusion of ketamine (0.5 mg/kg over 40 minutes) was associated with a larger reduction in obsessive-compulsive symptoms when compared with saline infusion. These effects were rapid in onset and persisted for approximately one week in 50% of the patients with OCD who had constant intrusive thoughts.
This dose of ketamine had previously been shown to induce rapid-onset improvement in depression and suicidal ideation in those with unipolar and bipolar depression. However, the improvement in obsessive-compulsive disorder symptoms appeared unrelated to any antidepressant effect because the individuals with OCD had minimal depressive symptoms at baseline.
The traditional pharmacological treatments for OCD are selective serotonin reuptake inhibitor (SSRI) antidepressants, which require high doses and weeks to months before the onset of full effect. In contrast, Rodriguez et al. found a 90% response rate to IV ketamine within 3 hours.
Ketamine is a blocker of the glutamate NMDA receptors, and these data suggest that targeting these receptors can induce rapid onset of positive effects in OCD. However, as is the case with the acute antidepressant response to ketamine in those with depression, the best ways to extend this therapeutic effect long-term remain to be determined.
Another blocker of NMDA receptors, the anti-Alzheimer’s drug memantine (Namenda), has been reported in open studies to show improvement in those with OCD as well. N-acetylcysteine, a substance found in health-food stores, likewise appears to re-regulate a hyper-responsive glutamatergic system in the nucleus accumbens by other mechanisms, and was also shown to have efficacy as an augmenting treatment in OCD in those who are inadequately responsive to SSRIs in a 2012 article by Afshaw et al.
Editor’s Note: Taken together, the data with ketamine, memantine, and N-acetylcysteine suggest that glutamate-based mechanisms are involved in OCD and may provide an alternative target for therapeutics in addition to serotonin.
New Findings On IV Ketamine For Treatment-Resistant Depression
We’ve written before about the rapid-onset antidepressant effects of ketamine, an anesthetic that is used in human and veterinary medicine. At lower doses, intravenous (IV) ketamine can induce antidepressant effects in both unipolar and bipolar depressed patients. When doses of 0.5mg/kg are infused over a period of 40 minutes, antidepressant effects appear within two hours but are short-lived, typically lasting only three to five days. Results have been consistent across studies at Yale University, the Icahn School of Medicine at Mount Sinai, and the National Institute of Mental Health. So far, clinical use has been limited by the short duration of the effects and the required presence of an anesthesiologist, which can be prohibitively expensive for many patients.
In a cover story in the January 2013 issue of Psychiatric Times, Arline Kaplan reviewed new findings about ketamine. The drug is a high-affinity, noncompetitive NMDA-glutamate receptor antagonist. It is not yet FDA-approved for use in depression.
According to a recent article by Murrough and Charney, response rates to ketamine are around 54% and the drug “appears to be effective at reducing the range of depressive symptoms, including sadness, anhedonia [the loss of ability to experience pleasure], low energy, impaired concentration, negative cognitions, and suicidal ideation.”
David Feifel, Director of the Neuropsychiatry and Behavioral Medicine Program at the University of California at San Diego (UCSD), instituted a program there in which patients can receive treatment with ketamine for clinical purposes (rather than for research) after signing detailed informed consent forms and being warned that the treatment is not yet approved for depression and that its effects may be temporary. The UCSD Medical Center’s Pharmacy and Therapeutics Committee, with the support of the anesthesiology department, agreed that nurses may administer the ketamine in an outpatient setting, making the procedure more affordable.
There is still the question of how to make ketamine’s effects last. Read more
Lifetime Heart Disease Risk Increases Dramatically When One or More Risk Factors Are Present in Middle Age
A meta-analysis of 18 studies that was published by Donald Lloyd-Jones in the New England Journal of Medicine in 2012 shows that increasing cardiovascular risk factors during middle age can dramatically increase a person’s risk of experiencing fatal cardiovascular disease, fatal coronary heart disease, nonfatal heart attack, or stroke later in life.
Data were analyzed from 257,384 patients, who included black and white men and women spanning a 50-year range of birth cohorts. The studies examined cardiovascular risk factors such as smoking, cholesterol levels, diabetes, and blood pressure at ages 45, 55, 65, and 75.
Having even one risk factor at age 55 dramatically increased the lifetime risk of cardiovascular disease compared to having no risk factors, and having more risk factors during middle age increased risk even further. Among people with no risk factors at age 55 (meaning cholesterol under 180mg/dL, blood pressure under 120 mm Hg systolic and 80 mm HG diastolic, nonsmoking and nondiabetic), men had 4.7% risk of death from cardiovascular disease by age 80 (compared to 29.6% for those with 2 or more risk factors). Women had a 6.4% risk of death from cardiovascular disease by age 80 (compared to 20.5% among those with 2 or more risk factors).
Lifetime risk of death from cardiovascular disease and coronary heart disease and risk of nonfatal heart attack were about twice as high in men, while risk of stroke was similar for men and women.
Across race, trends were similar, but this finding can be misleading. While African-Americans have more cardiovascular risk factors than whites, they are also more likely to die at younger ages from other causes before developing serious cardiovascular illnesses. Large studies with Latino and Asian American participants were begun too recently to provide robust data about long-term risk, but this research is expected to become available soon.
Editor’s Note: Watch your risk factors for heart disease, including high blood pressure, cholesterol, weight, and blood sugar. The more risk factors one has, the greater the increased risk of fatal cardiovascular illness.
Depression is also a risk factor for coronary artery disease, and should be treated just as aggressively and persistently as the other risk factors. Exercise is one element of a healthy lifestyle that can positively affect all of these risk factors. Implementing a healthy diet and exercise regimen by middle age will have long-term positive effects in reducing risks in older ages.
