Cariprazine is a new atypical antipsychotic that has positive results in the treatment of schizophrenia, bipolar mania and depression, and as an add-on treatment to antidepressants in unipolar depression. In a recent study by Frank Tarazi and colleagues, cariprazine shared some actions with aripiprazole (trade name Abilify), which is approved by the Federal Drug Administration as an adjunctive treatment for unipolar depression in addition to treating mania in bipolar disorder and schizophrenia.
Both cariprazine and aripiprazole partially block dopamine receptors. They allow a little stimulation of the receptors (activating or agonist effects) while preventing dopamine from binding there. With ongoing treatment, this blocking action prompts an increase in the number of dopamine receptors to compensate for the blocking.
In rats, both drugs led to increases in several types of dopamine receptors, but cariprazine did so at lower doses. Following 28 days of treatment with aripiprazole at doses of 5–15 mg/kg, rats had higher levels of D2 and D4 receptors in several brain regions than other rats that received no drug. Higher doses of aripiprazole also increased D3 receptors in some regions, indicating that the drug works less well at those receptors. Lower doses of cariprazine (0.06–0.6 mg/kg) increased D2 and D4 receptors significantly, and increased D3 receptors more than aripiprazole did, and in a greater number of forebrain regions.
Among antipsychotic drugs, both aripiprazole and cariprazine are unique in providing a little stimulation (partial agonist effects) at dopamine receptors, while all others drugs in the class are pure blockers (antagonists) of dopamine receptors.
The researchers concluded that cariprazine was more potent than aripiprazole at dopamine receptors, especially D3 receptors.
In new research by Ofer Agid and colleagues, patients in their first schizophrenic episode who reached remission in response to one of two antipsychotic medications (risperidone or olanzapine) and relapsed due to medication non-adherence were re-treated with the same medication regimen that had brought about remission. Reinitiating the same treatment was not as successful in bringing about remission of the patients’ second psychotic episodes.
Patients showed different types of trajectories in their first remission, from immediate to gradual improvement, and these predicted parallel trajectories of their treatment response during the second episode, though the muted response to antipsychotics existed across the board. Dopamine is the main target of antipsychotic treatments, but its role in schizophrenia is not straightforward, and Agid and colleagues stress that response and relapse are multidimensional processes.
Editor’s Note: These data are consistent with the research of J.A. Lieberman and colleagues fifteen years ago, which showed that response to antipsychotic treatment is poorer in successive episodes of psychosis. The findings are also consistent with the idea of episode sensitization in mood disorders, developed by this author (Robert Post). Episode sensitization refers to the case in which greater numbers of prior depressions or manias are associated with faster relapse and a greater degree of treatment resistance.
The data raise major doubts about the common practice of quitting medications to see if remission can be maintained without them. There are dozens of studies in patients with schizophrenia showing that continuous treatment is more effective than intermittent treatment.
Nicotine addiction is highly cue-dependent, meaning that certain situations or places will make smokers crave a cigarette even if they’re trying to quit. Researchers working with rodents are exploring a combination of treatments that address different behavioral and neurobiological mechanisms to reduce nicotine addiction. In a recent study by Cassandra Gipson-Reichardt and colleagues, N-acetylcysteine reduced cue-induced nicotine seeking, while varenicline reduced nicotine self-administration. Together the drugs worked better to reduce nicotine relapse than either drug on its own.
In the study, rats were trained to self-administer nicotine (with 0.02mg/kg infusions), and cues were used to reinstate nicotine seeking. The rats were treated with 10 and 30 mg/kg injections of NAC and 1 and 3 mg/kg injections of varenicline.
Relapse is associated with rapid synaptic potentiation in the reward area of the brain, the nucleus accumbens. In addition to the positive behavioral changes noted, NAC also inhibited this synaptic potentiation, limiting rapid changes in the size of spines on dendrites and reducing the ratio of AMPA to NMDA (two different compounds that mimic glutamate) in the core of the nucleus accumbens.
Editor’s Note: The combination of NAC and varenicline has not yet been studied in humans, but because both compounds are effective in reducing smoking, it is likely that this animal research on nicotine will be replicated in humans who are addicted to the nicotine in cigarettes.
Cutting, or non-suicidal self injury, is a serious problem among adolescents, and few treatments are available. Researcher Kathryn Cullen and colleagues have found that N-acetylcysteine (NAC), an antioxidant nutritional supplement that has been effective in the treatment of depression and many addictions and habit-related behaviors, can reduce cutting.
The study included 25 participants with a history of non-suicidal self injury, aged 13–21, and 12 controls. They participated in brain scans before and after treatment. Compared to the controls, the self-injurers showed greater overall psychopathology, greater activation in a few brain regions (precuneus, posterior cingulate, insula, and temporal lobes), and reduced lower left frontal activation. Patients who received NAC up to 900mg twice daily in weeks 5–8 of the study reduced their cutting and also showed reduced psychopathology. An increase in frontal activation in response to negative emotion was linked to the reduction in cutting.
Editor’s Note: NAC improves mood in depression, many addictions, and many habits including trichotillomania (excessive hair-pulling), nail biting, and cutting. It may do this by increasing glial glutamate transporters in the nucleus accumbens, the brain’s reward center, which lessens the magnitude of the glutamate signal, mediating the compulsion to engage in the habitual behavior.
Regulation of the amygdala (the brain’s emotional center), particularly through its interaction with the ventral anterior cingulate cortex, has been implicated in the experience of fear in animals, and anxiety and depression in humans. Connectivity between the two structures is critical for emotion modulation. Repeated transcranial magnetic stimulation (rTMS) is a method of stimulating outer regions of the brain with magnets. Researchers Desmond Oathes and Amit Etkin are investigating whether rTMS can also be used to influence these deeper brain areas, or their interaction with each other.
The researchers’ study used single-pulse probe TMS delivered at a rate of 0.4 Hz at 120% of each participant’s motor threshold, targeted at the anterior or posterior medial frontal gyrus on either side of the brain. The researchers also used functional magnetic resonance imaging (fMRI) of the whole brain to observe connectivity between different sections.
RTMS to the right side of the medial frontal gyrus increased connectivity between the amygdala and the ventral anterior cingulate cortex more than stimulation to the left side. Stimulation of the posterior portion of the medial frontal gyrus increased connectivity more than stimulation of the anterior portion.
Editor’s Note: These data indicate that rTMS can alter brain activity in these deeper regions and can influence inter-regional connectivity. This is important because abnormalities in the connectivity of brain regions have increasingly been found in patients with mood disorders. Oathes and Etkin hope that these findings can be applied to others and that rTMS can be used to correct patterns of regional connectivity in the brain in order to improve emotion regulation.
An oral preparation of lavender oil called Silexan was previously found to reduce anxiety in people with generalized anxiety disorders or subthreshold anxiety symptoms without causing sedation. It seems to work by inhibiting voltage dependent calcium channels in a manner similar to the anti-anxiety drug pregabalin. Unlike pregabalin, the lavender oil treatment also reduced depression in the people with subthreshold anxiety. Researchers are now exploring lavender oil’s effects on rats who exhibit behaviors that resemble human depression, and on rat and human cells in vitro.
Silexan had positive effects on rats with depression-like behaviors, increasing the time they would swim before giving up in a forced swim test. It also increased the growth of rat and human neurons in a lab setting. These effects are usually connected with activation of a protein called CREB that turns on some genes that affect mood. The researchers, led by Walter Mueller, were able to clarify the pathway for this activation by inhibiting specific kinases, enzymes responsible for transferring phosphates across different molecules. The kinases involved included PKA, PI3K, MAPK and CaMK IV.
Editor’s Note: Oral lavender supplements may help improve anxiety and depression without sedation.
Disruptions to circadian rhythms are common in mood disorders, leading some researchers to believe that normalizing these daily rhythms may improve the illnesses. Several genes, called CLOCK genes, are implicated in circadian rhythms. In animal studies, researcher Marco Riva and colleagues are examining the expression of CLOCK genes in different brain regions as a result of chronic stress that is meant to produce behaviors resembling human depression.
Male rats were exposed to chronic mild stress for two weeks, and divided into those that were susceptible to stress (identified by their loss of interest in sucrose) and those who were not. Then the rats were randomized to receive either a placebo treatment or 3 mg/kg/day of the atypical antipsychotic lurasidone (trade name Latuda), which has been effective in bipolar depression, during five more weeks of the stress procedure.
The researchers observed the expression of clock genes Clock/Bmal1, Per1, Per2, Cry1, and Cry2. In susceptible rats, the chronic mild stress decreased the clock genes Per1, Per2, and Cry2 in the prefrontal cortex. Lurasidone reversed these CLOCK gene abnormalities and the rats’ depression-like behaviors, which may explain some of the drug’s efficacy in bipolar depression.
Editor’s Note: Lurasidone is also a potent inhibitor of 5HT7 serotonin receptors, an effect that has been linked to antidepressant efficacy. Lurasidone also increases brain-derived neurotrophic factor (BDNF), which is important for learning and memory, and prevents stress from decreasing BDNF. Now it seems that lurasidone’s normalization of CLOCK genes may be another mechanism that explains the drug’s antidepressant effects.
In a recent randomized, controlled clinical study comparing two types of omega-3 fatty acid supplements (one with EPA and one with DHA) with placebo in 196 adults with major depression, there were no statistically significant differences in outcomes across the three groups. The participants received the treatments for eight weeks, and response and remission rates were 40-50% in those receiving either omega-3 preparation (at doses of 1000mg/day) and 30% for placebo. The research was published by David Mischoulon and colleagues in the Journal of Clinical Psychiatry.
In 2012 we reported on an open study by Athanasios Koukopoulos and colleagues that explored whether the NMDA glutamate receptor antagonist memantine (Namenda), which is used to treat dementia, could be helpful to people with treatment-resistant bipolar disorder. In an update of that study, the researchers, led by Giulia Serra, compared patients’ symptoms during three years of treatment as usual, followed by three years with memantine added to their stable medication regime (at doses of 20–30 mg/day). Patients improved progressively over the three years of taking memantine.
Improvements in symptoms included decreased time ill, decreased severity of symptoms, decreased duration of new episodes, and fewer episodes per year. Memantine was particularly helpful for those patients who had had rapid or continuous cycling. Side effects were minimal.
Given the success of this open study, randomized controlled trials are needed to explore this much-needed option for people with treatment-resistant bipolar disorder.
Women are more likely than men to experience depression, and this difference begins in adolescence, when girls show more sensitivity to stress. Researchers are studying how animals react to stress in the hopes of learning what mediates these gender differences in mental illness.
At a recent scientific meeting, researcher Jodi Lukkes and colleagues presented a recent study of stress and inflammation in female rats. The rats were exposed to different types of stressors. Some were separated from their mothers for four hours a day during the first 20 days of their lives. Later, some rats were exposed to an acute stressor, witnessing another rat receiving shocks. All the rats were placed in a box in which they could escape a shock by jumping to the other end of the box, in order to measure their motivation. Because drugs that inhibit the inflammatory enzyme COX-2 had reversed the effects of maternal separation in earlier studies, the researchers also treated some rats with these anti-inflammatories.
The researchers found that anti-inflammatory treatment could prevent behavioral consequences of stress in adolescent female rats. Witnessing another rat being shocked brought about deficits in motivation (a depression-like behavior), but in rats that had received treatment with a COX-2 inhibitor, these deficits were reduced. The COX-2 treatment was only helpful to rats that had experienced an acute stressor in their lifetime, either maternal separation in infancy, or witnessing another rat receive the shocks. A history of stress was required for the anti-inflammatories to improve motivation.
Lukkes and colleagues hope that this research begins to clarify the relationship between stress, inflammation, and gender. This may eventually lead to new targets in the treatment of depression.