At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Lakshmi Latham presented a poster on three studies of the atypical atypical antipsychotic caripazine, a treatment that has not yet been approved by the Federal Drug Administration. We call it an atypical atypical because it is a partial agonist at dopamine D2 and D3 receptors, meaning it stimulates the receptors a little, but in the presence of high levels of dopamine it blocks excess activity by sitting on the receptor and preventing the actions of the excess dopamine. Aripiprazole is also a partial agonist at dopamine and serotonin 5HT1a receptors, but caripazine differs in that it has a particular affinity for the D3 receptor.
Previous analyses had revealed that cariprazine has good acute antimanic efficacy. All three studies described by Latham were randomized, double-blind, placebo-controlled three-week studies in patients with bipolar mania. In total the studies included 1065 patients, 442 of whom received placebo and 623 of whom received cariprazine.
Cariprazine doses from three studies were pooled, and ranged from 3-12 mg/day. Additional analyses evaluated the 3-6 and 9-12 mg/day groups specifically.
Approximately 70% of patients completed the study. The most common side effects included akathisia or restless legs (placebo, 5%; cariprazine, 20%), extrapyramidal disorder characterized by abnormal motor symptoms (5%, 13%), restlessness (2%, 6%) and vomiting (4%, 9%). The incidence of serious side effects was similar across the placebo and the treatment groups. Side effects that led to discontinuation of participation in the study occurred in 7% of placebo patients and 12% of cariprazine patients. Suicidal ideation was an infrequent side effect (placebo, 4; cariprazine, 2), and there were no suicide attempts.
Mean changes in weight were small (averaging 0.17kg in patients taking placebo and 0.54kg in those taking cariprazine), and the proportion of patients with 7% or higher increase in weight were similar across the two groups (both 2%). Mean changes in blood pressure and pulse were slightly greater with cariprazine and were related to dosage. Cariprazine was not associated with mean increases in electrocardiogram (EKG) parameters except for a slight increase in ventricular heart rate versus placebo (5.0 and 0.9 bpm, respectively). Mean changes in lipids and glucose were generally small and similar between groups. Levels of the hormone prolactin decreased in both groups.
Latham concluded that cariprazine treatment for three weeks was safe and well-tolerated.
Lithium Plus An Atypical Antipsychotic Was More Effective Than Valproate Plus An Atypical Antipsychotic In One Study, But Not Another
Evaristo Nieto et al. of Spain presented a poster about the naturalistic study of the efficacy of acute treatment of manic inpatients with lithium and valproate at the 2014 meeting of the International College of Neuropsychopharmacology. In the lithium group, all patients were treated with lithium and oral antipsychotics (N=85). In the valproate group, all were treated with valproate and oral antipsychotics (N=92). Outcome was measured using scores on scales for mania and for general functioning (the YMRS and the CGI-S). The atypical antipsychotic was typically olanzepine or risperidone.
Nieto et al. found that the mean change in CGI scores from baseline to the day of discharge was significantly higher in the lithium group (-2.84 versus -2.6), and concluded that, “Although it is used in more severe cases, treatment of manic inpatients with lithium associated with antipsychotics is more effective than treatment with valproate associated with antipsychotics.”
However, W.M. Bank et al. came to the opposite conclusion in a Korean study. Bank et al. “compared the 1-year rehospitalization rates of first-episode bipolar manic patients?who were discharged while being treated with lithium or valproate in combination with an?atypical antipsychotic….The rehospitalization rate was 17.3% during the 1-year follow-up period.”
Bank et al. found significantly higher rates of rehospitalization in the lithium (23.1%) compared to the?valproate (13.3%) group using the Kaplan-Meier formula for estimations.
In a special symposium on bipolar disorder at the 2014 meeting of the American Psychiatric Association, researcher Mike Bauer reviewed a new meta-analysis that showed lithium not only has significant effects in preventing manias, but also depressions. Researcher Geddes et al. had, in a previous study called BALANCE, found that lithium was superior to valproate (Depakote). Together these findings led Bauer to the conclusion that lithium is under-used in the treatment of bipolar disorder, especially in the US, where lithium is prescribed less often than valproate.
An article by researcher Kessing in the British Journal of Psychiatry in 2012 relied on naturalistic follow up data and also showed that lithium was superior to valproate in preventing hospitalizations.
A study by researcher Willem Nolen indicated that in mono-therapy, levels of lithium in the blood needed to be 0.6 meq/L or higher in order for lithium to work better than placebo. Lithium augmentation that produced lower blood levels of 0.3 meq/L was not significant on its main outcome measure of preventing new episodes. However, compared to treatment as usual, those randomized to lithium used lower doses of atypical antipsychotics, and other data indicated that these patients had fewer suicide attempts and increased hippocampal volume.
Bauer noted that lithium-related goiter and low thyroid are easily treated, and that kidney damage while taking lithium can be prevented by avoiding episodes of lithium intoxication. It is easy to conclude that lithium should be used more often, especially given its positive effects against suicide and brain gray matter and hippocampal volume loss.
Cariprazine is a new antipsychotic drug from Hungarian company Gedeon Richter. It functions as a dopamine D3 and D2 partial agonist. The drug has shown significant antimanic effects in three placebo-controlled studies. At the 2014 meeting of the American Psychiatric Association, researcher Robert E. Litman presented findings that 32% of patients with moderate to severe mania improved to a point of minimal or no illness while taking cariprazine, versus 22% who improved similarly while taking placebo. Doses in the studies Litman presented ranged from 3mg/day to 12mg/day.
At the same meeting, researcher Lakshmi N. Yatham discussed cariprazine tolerability. At a mean dose of 7.44mg/day, side effects of cariprazine compared to placebo included akathisia (restless legs) in 20% of patients compared to 5%, extrapyramidal side effects (irregularities in movement) in 13% of patients compared to 5%, vomiting in 9% of patients compared to 4%, and restlessness in 6% of patients compared to 2%. Twelve percent of patients discontinued treatment due to side effects while taking cariprazine, compared to 7% taking placebo. Weight increased by an average of 0.54kg among patients taking cariprazine compared to an average of 0.17kg among those taking placebo. Yatham and colleagues concluded that cariprazine treatment is generally safe and well-tolerated.
It is expected that data on the positive effects of cariprazine in bipolar depression in two placebo-controlled studies will soon be published.
Also at the meeting, researcher Nika Adham et al. reported that in animal studies, cariprazine had greater affinity for the dopamine D3 receptor than aripiprazole (Abilify), another partial agonist at D2 and D3 receptors. D3 receptors are important for the regulation of cognition and mood. It is expected that cariprazine might eventually be useful in the treatment of schizophrenia.
Psychotherapy can play an important role in treating mental illness. At the 2014 meeting of the International Society for Bipolar Disorders, researcher F. Colom gave a plenary talk indicating that just like pharmacotherapy, psychotherapy should differ depending on characteristics of the illness—both its severity and whether the patient has more manic or more depressive symptoms.
For less severe illness with more depression, Colom explained that cognitive behavioral therapy (CBT) is ideal.
Psychoeducation and family focused therapy (FFT) is recommended for intermediate severity, with a focus on maintaining remission. Family focused therapy also works for early (prodromal) symptoms, as reported by researcher David Miklowitz et al. in 2013.
Lars Kessing et al. recently reported that specialty treatment in a clinic (including psychoeducation and vigilance to breakthrough symptoms that may suggest a new episode is imminent) is highly effective following a first episode of mania.
For more severe illness, Colom recommends cognitive remediation and rehabilitation to decrease illness burden and increase functioning. Functional remediation focuses on communication, includes homework, and teaches skills such as how to deal with money, time, and organization. It also helps improve social cognition.
For the most severe illness, palliative care to relieve symptoms and decrease illness impact is recommended. Colom noted that cognitive behavioral therapy is less effective with patients who have experienced more than 12 episodes (reported by Jan Scott et al. in the British Journal of Psychiatry in 2006), as is psychoeducation (Renares et al. 2010, Colom et al. 2014). These data re-emphasize the importance of early intervention, when these psychotherapeutic approaches are more helpful. Colom stresses the importance of behavioral cognitive therapy (BCT) rather than cognitive behavioral therapy (CBT) for those late in the illness whose episodes often arrive spontaneously, unprecipitated by psychosocial stress, and one needs more behavioral approaches to the brain’s habit memory system located in the striatum, which may drive highly recurrent illness.
According to researcher David J. Bond at the 2014 meeting of the International Society for Bipolar Disorders, “Up to 75% of people with bipolar disorder (BD) are overweight or obese, and these patients suffer more severe psychiatric symptoms than normal-weight patients, including more frequent depressions, more suicide attempts, lower response rates to pharmacotherapy, and greater inter-episode cognitive impairment.” Obesity is a chronic inflammatory condition that damages body organs, and it appears as though the brain may be one of these. Adipose (fatty) tissue is an endocrine organ that produces substances that cause inflammation in blood vessels and that damage the heart.
Obesity is associated with decreased total brain volume, and in children, decreased gray matter volume. Obesity increases the risk of cognitive impairment, and decreases memory, attention, and executive functioning. Obesity increases the risk of Alzheimer’s disease, as well as multiple sclerosis, Parkinson’s, and depression.
In bipolar disorder, obesity decreases response to mood stabilizers and atypical antipsychotics. Bond found that in patients with a first episode of mania, body mass index (BMI) was inversely related to white matter volume and temporal lobe gray matter volume. Higher BMIs also led to neurochemical changes including increased hippocampal glutamate and reduced N-acetylaspartate. Bond also noted findings by Roger S. McIntyre that weight loss surgery in patients with bipolar disorder led to more positive treatment outcomes.
Editor’s Note: These findings speak to the importance of exercise and good diet, using medications with the least likelihood of weight gain, and treating obesity once it has developed. We have previously noted the weight loss effects of topiramate and zonisamide, and new data support the substantial weight loss with the combination of bupropion (150-300mg) and naltrexone (50mg).
The lateral hypothalamus is responsible for certain physiological functions (the sleep-wake cycle, appetite, energy expenditure, and sexual functions) that are disrupted during mania. At the 2014 meeting of the International Society for Bipolar Disorders, researcher O. Abulseoud et al. presented evidence that a mania-like state could be produced in rats by “kindling” the lateral hypothalamus with an electrode.
The kindled rats engaged in more motor activity; less rest; more sexual self-stimulation; excessive rearing, feeding, and grooming; and more ethanol consumption. Non-kindled rats (and those kindled in other areas such as the nucleus accumbens shell and the infralimbic cortex) did not engage in this combination of behaviors.
To test the similarity between the mania-like behaviors and human mania, the researchers treated the kindled rats with saline solution, lithium, or valproic acid. Lithium and valproic acid reduced these behaviors significantly compared to the saline solution. These treatments also produced long-term increases in mRNA for certain genes (Per1 and CLOCK) that are dysregulated in people with mania.
This animal model may become useful in future research on manic psychopathology in humans.
A 2004 meta-analysis of previous research showed that lithium was better than placebo at preventing affective episodes and preventing manic episodes. The evidence for the drug’s efficacy in preventing depression was less clear. A new meta-analysis by E. Severus et al. (not yet published) confirms the previous findings and provides new evidence that lithium is also better than placebo at preventing depressions.
The study also suggested that lithium is better than anticonvulsant mood stabilizers at preventing relapse and recurrence, but this finding only reached statistical significance in the prevention of new manic and hypomanic episodes.
Editor’s Note: These findings highlight the desirability of greater lithium use. The drug is currently prescribed less often in the US than it is in Europe. In addition to lithium’s efficacy in the long-term preventative treatment of bipolar disorder, there is evidence that lithium is also the best agent for suicide prevention and for neuroprotective effects.
There is increasing evidence of a link between mood disorders and inflammation in the body.
At the 2014 meeting of the International Society for Bipolar Disorders, Shang-Ying Tsai discussed increases in measures of inflammation that occur in bipolar disorder as a function of the clinical state of depression, mania, or euthymia (remission). He found that in both mania and depression, there were elevations in various markers of inflammation: STNF-R1, CRP, IL-Ira and SLR-2r. However, SLR-2r showed some particularly interesting results. In mania, elevation of SLR-2r, a marker of cell-mediated inflammation, was state-related, meaning it increased during an episode of mania and remained normal during euthymia. In depression, SLR-2r elevation was trait-related, or persistently elevated (even in remission).
Editor’s Note: This study adds to a growing list of studies that confirm the presence of inflammation in patients with bipolar disorder compared to normal controls, including a 2012 article by Tsai in the Journal of Affective Disorders. How elevations in inflammatory markers in a given individual should direct specific types of treatment intervention remains to be further clarified.
While the reasons why one person develops bipolar disorder and another does not remain mysterious, the current thinking is that genes contribute some risk while immunological abnormalities contribute other risks. Researchers have identified certain antibodies whose levels spike during an episode of mania, as if the patient is having an immune reaction. These are referred to as biomarkers or inflammatory markers.
While various biomarkers for mania have been identified, until recently their effects had only been examined independently. A 2013 article by Dickerson et al. published in the journal PLOS ONE examined four biomarkers in combination. Each was a type of antibody: to the NR peptide of the NMDA receptor, to gliadin (a protein derived from gluten), to Toxoplasma gondii (a parasitic protozoan), and to Mason-Pfizer Monkey Virus. Measures of these four types of antibodies made up a combined inflammation score for participants in the study.
The study compared 57 patients presenting with a manic episode with 207 non-psychiatric controls and 330 patients who had had recent onset of psychosis, schizophrenia, or bipolar depression. The combined inflammation score of the mania group was significantly higher than the other groups at the time of hospital admission and at the time of evaluation several days later. It had returned to normal (i.e. not different from the other groups) at followup six months later, although those with the highest combined inflammation scores were at risk for re-hospitalization during that period.
The findings of this study suggest that hospitalization for mania is associated with immune activation, and the level of this activation predicts subsequent re-hospitalization. Treatments for mania that target this inflammatory response should be investigated.