Antipsychotics That Worked for A First Episode May Not Work As Well a Second Time
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.
ECT versus Drug Therapy for Bipolar Depression
Electroconvulsive therapy is often considered a primary treatment option for patients with severe bipolar disorder that has resisted pharmacological treatment. Researcher Helle K. Schoeyen and colleagues recently published the first randomized controlled trial comparing ECT (in this case right unilateral brief pulse ECT) with algorithm-based pharmacological treatment in 76 patients with treatment-resistant bipolar depression.
The response rate was significantly higher in the ECT group than in the patients who received drug treatment (73.9% versus 35.0%). However, the two treatment groups had similarly low remission rates (34.8% for ECT and 30.0% for pharmacological treatment).
The algorithm-based pharmacological treatment used in the study was based on a sequence of treatments endorsed by researchers Frederick K. Goodwin and Kay Redfield Jamison in their 2007 book Manic-Depressive Illness. A selected treatment was chosen for each participant based on his or her medical history. If the first treatment was ineffective or intolerable, the patient would be switched to the next treatment option. Antipsychotics, antidepressants, anxiety-reducing drugs, and hypnotics were some of the other treatments included in the algorithms.
Patients in the study had previously showed a lack of response to at least two different antidepressants and/or mood stabilizers with documented efficacy in bipolar disorder (lithium, lamotrigine, quetiapine, or olanzapine) in adequate doses for a period of 6 weeks (or until they quit because of side effects).
Editor’s Note: Even when ECT is effective, there is the issue of how to maintain that good response. We previously reported that in a 2013 study by Axel Nordenskjöld et al. in the Journal of ECT, intensive followup treatment with right unilateral brief pulse ECT combined with pharmacotherapy was more effective than pharmacology alone at preventing relapses. Patients who improved after an acute series of ECT (three times/week) then received weekly ECT for six weeks and every two weeks thereafter, totaling 29 ECT treatments in one year.
Other studies of more intermittent continuation ECT have not proved more effective than medication. Thus high intensity right unilateral brief pulse ECT is one option for extending the effects of successful ECT.
HDAC Inhibitors Treat Mania-Like Symptoms in Mice
Mice with a particular genetic mutation affecting circadian rhythms exhibit symptoms that resemble those of human mania: disruption of sleep and wake cycles, hyperactivity, and reduced anxiety and depression. It has been found that these behaviors can be normalized by inhibiting a type of enzyme called histone deacetylases (HDACs). HDACs bring about epigenetic changes to gene transcription by removing acetyl groups from histones, the structures around which DNA is wrapped. Removal of the acetyl group tightens the structure of the DNA, making it more difficult to transcribe. The drug valproate (trade name Depakote) is one type of HDAC inhibitor. It prevents the removal of the acetyl groups, loosening the structure of the DNA, making it easier to transcribe.
A recent study by Ryan Logan and colleagues compared the effects of valproate and other HDAC inhibitors on mice with a mutation in the Clock delta 19 gene, which causes mania-like symptoms. Valproate and the HDAC inhibitor SAHA both normalized the mice behavior. MS275, another HDAC inhibitor that targets only class I HDACs, also normalized the behaviors. The researchers were able to determine that all of these treatments targeted a specific class I HDAC called HDAC2, which has been implicated in schizoaffective and bipolar disorders.
These data link epigenetic mechanisms (HDAC inhibition) to the antimanic effects of valproate in this animal model of mania. It appears that maintaining the presence of acetyl groups on histones has antimanic effects in mice with a mutation in the Clock delta 19 gene.
Psychotherapy of Childhood Bipolar Disorder
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, there was an excellent symposium on different psychotherapeutic approaches for children and adolescents with bipolar disorder and related illnesses.
Amy West of the university of Illinois at Chicago started off this symposium by describing the effectiveness of child-and family-focused cognitive-behavior therapy or what is sometimes called RAINBOW therapy. Rainbow stands for Routine, Affect regulation, I can do it, No negative thinking, Be a good friend and balance life stressors, Oh how can we solve problems, and Ways to find support.
West emphasized the importance of routine in sleep, diet, medications, and homework, and indicated that frequent soothing is necessary. Posted reminders are also helpful.
Affect regulation can be encouraged by promoting coping skills, particularly around identifying what triggers mood swings and rage attacks and creating plans for dealing with them.
“I can do it” reminds parents and children to focus on strengths, successes, positive feedback, and the ability to call for help.
“No negative thinking” encourages positive restructuring and reframing of negative perspectives. Part of this includes mindfulness training for children and parents, who are taught to focus on breathing and accepting thoughts and emotions.
Being a good friend focuses on listening, engaging friends, and enhancing communication.
“Oh how can we solve problems” reminds families to have an attitude of problem solving.
Remembering ways to find support reminds parents to connect with relevant resources, and also coaches parents to be advocates for their children.
In a randomized study of 12 sessions of child and family focused cognitive behavior therapy, the children did much better than those receiving treatment as usual and showed greater improvement in mania and depression as well as overall functioning.
The second presentation was given by Mary Fristad of Ohio State University. She treated children with bipolar disorder not otherwise specified (BP-NOS) with psychotherapy and omega-3 fatty acids. Some research had suggested the efficacy of omega-3 fatty acids in childhood mood disorders and a much larger literature was positive in adult mood disorders. Given the safety of the manipulation, she felt it was worth trying in young children and those with BP-NOS who are rarely studied formally. She also cited a 2010 study by Amminger et al. in children who were at ultra high risk for schizophrenia. In that study, patients were randomized to 12 weeks of omega-3 fatty acids or placebo, and omega-3 fatty acids were associated with a very low conversion rate to full-blown psychosis, 4.9%, compared to 27.5% for those receiving placebo. Fristad’s psychotherapy also emphasized education, support, and skill building in order to enhance understanding of the illness and its treatment. This would help ensure better compliance and better treatment outcome. Her formal treatment manual is available at www.moodychildtherapy.com.
Fristad randomized children with bipolar not otherwise specified, average age 10.2 +/- 0.2 years to either her psychotherapy plus omega-3 fatty acids or therapy plus placebo. Therapy plus omega-3 was much more effective on most outcome measures.
Editor’s Note: Given the safety of omega-3 fatty acids, even these limited data would appear to justify their use in children with BP-NOS in the context of psychotherapy and psychoeducation.
The third presenter was David Miklowitz of UCLA who discussed family focused therapy. This approach has proven effective in studies of both adults and adolescents with bipolar disorder, and as well for those with prodromal symptoms. Read more
More Evidence That Lithium Prevents Mania and Depressions
There is a large body of research showing that lithium is better than placebo and a variety of comparison drugs at preventing manic episodes in people with bipolar disorder. It has been less clear whether lithium is as effective in preventing depressions in bipolar patients. In a 2014 meta-analysis in the International Journal of Bipolar Disorders, Emanuel Severus and colleagues confirmed that lithium was more effective than placebo at preventing mood episodes overall and manic episodes. In a fixed effect statistical analysis, lithium was also better at preventing depressive episodes.
The portion of the meta-analysis comparing lithium to placebo included seven randomized controlled trials that included a total of 1,580 patients. Lithium was more likely than placebo to lead to patients dropping out of a study for reasons other than a mood episode, but patients who received lithium were more likely to complete their clinical trials.
Another part of the meta-analysis compared lithium to anticonvulsant drugs. Seven trials were included totaling 1,305 patients. Lithium was better than anticonvulsants at preventing manic episodes, but equally effective at preventing mood episodes overall and depressive episodes specifically. There was also no difference in patients dropping out of the trials or completing the trials.
The researchers concluded that lithium remains the most valuable treatment option for bipolar disorder, because no other drug has such consistent efficacy in preventing manias and depressions and mood episodes in general.
Depression in Children with Inflammatory Bowel Disease
The incidence of irritable bowel disease has been increasing in recent years as obesity has increased. At a symposium at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Eva Szigethy discussed depression in inflammatory bowel disease, which most often involves Crohn’s disease or ulcerative colitis. These conditions are associated with increased levels of inflammatory markers such as interleukin 1 (IL-1), interleukin 6 (IL-6), and TNF alpha, and these in turn induce the acute phase reactive protein called c-reactive protein (CRP). The interleukins peak in the first 12 hours after an inflammatory challenge and CRP peaks at 48 hours and returns to normal at 120 hours. Il-6 is most closely associated with the somatic symptoms of inflammation, including depression, fatigue, loss of appetite, and decreased sleep, while TNF alpha is associated with non-somatic symptoms, such as irritability.
Szigethy found that in a randomized trial of cognitive behavior therapy versus supportive therapy in children with inflammatory bowel disease, inflammatory activity decreased significantly with cognitive behavioral therapy, and the therapy particularly helped the somatic symptoms of fatigue, sleep disorder, anhedonia (loss of interest in activities once enjoyed), appetite suppression, and mood dysregulation. In contrast, when antidepressants are given to those with inflammatory bowel disease, the drugs are not particularly helpful for these somatic symptoms. Inflammatory bowel diseases are treated with steroids in 21% of patients and with a genetically engineered drug called infliximab in 30%. Adding cognitive behavioral therapy to the regimen decreases CRP and red cell sedimentation rate, an associated measure of inflammation.
The discussant of the symposium on inflammation, Frank Lotrich, described how inflammation alters sleep, and this appeared to interact with genetic risk of illness. For example, those with certain genetic variations (the short SS allele of the serotonin transporter and the val-66-met allele of proBDNF) were most likely to experience sleep disturbance following treatment with interferon gamma, a treatment that fights the virus that causes Hepatitis C, creating inflammation in the process. Interferon gamma causes depression in about one-third of the patients who take it.
Lotrich pointed out that low levels of omega-3 fatty acids are associated with increased irritability and anger, and this is related to the presence of the A allele of TNF alpha. TNF alpha is also closely linked with irritability and anger, suggesting the possible benefits of omega-3 fatty acid supplementation to target irritability and anger more selectively. This would be consistent with the data of researcher Mary A. Fristad.
Il-6 is closely associated with the somatic symptoms of depression, particularly poor sleep, which is itself associated with increases in depression. This is consistent with inflammation being a marker of poor response to antidepressants; Lotrich noted that the selective serotonin reuptake inhibitors (SSRIs), which help depression, are far more effective against the non-somatic aspects of depression and less effective against low energy, decreased interest, and fatigue. However, extrapolating from the data on inflammatory bowel disease, cognitive behavioral therapy may be most helpful on these somatic symptoms.
Statins Can Prevent Cardiovascular Risk in Patients with Mental Disorders
People with major mental disorders such as schizophrenia and bipolar disorder are at increased risk for medical symptoms including overweight, obesity, high cholesterol or triglycerides, diabetes, and the metabolic syndrome, all of which increase risk of cardiovascular disease (heart attack), cerebrovascular disease (or strokes), and other medical difficulties. In a 2013 review article in the journal Bipolar Disorders, researcher Chittaranjan Andrade discussed the use of statins to prevent cardiovascular events in people with major mental disorders.
Statins decrease lipids, and have significant benefits in decreasing cardiac events, but their use is low among psychiatric populations. Psychiatric patients often receive less cardiac care. It may be up to their psychiatrists to push for aggressive prevention of cardiac illnesses.
The most significant side effect of statins is the possibility that they can increase risk of diabetes. In a meta-analysis by Preiss et al., intensive dosing with statins increased the risk of diabetes but also lowered the risk of cardiovascular events. In a year, 1,000 patients would get two extra cases of diabetes but 6.5 fewer cases of cardiovascular events. For patients at high risk for heart attack or stroke, a cardiovascular event is more dangerous than diabetes, so it makes sense to treat these patients with statins. In patients at lower risk, there is some evidence that diabetes risk was a problem mostly in patients with other risk factors for diabetes, including metabolic syndrome, impaired fasting glucose levels, a body mass index of 30 kg/m2 or higher, or glycated haemoglobin A (1c) above 6%.
Most studies of statins are conducted on patients in middle age, but there is a rationale for treating even younger patients with statins. Patients with bipolar disorder develop cardiovascular disease more than a decade earlier than controls. There is some evidence that cholesterol deposits in arteries begin even before age 20, and are cumulative. The risk-benefit ratio for statin use improves with years of use, so starting it earlier may lead to better prevention. Long-term use may reduce the risk of Alzheimer’s disease and Parkinson’s disease and some cancers in addition to reducing heart attacks and strokes.
Despite the risk of diabetes, it is important to consider statin use in psychiatric patients, especially those who receive antipsychotic medications. Read more
Effect Size of Autism Treatments
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, Fung et al. presented a meta-analysis of treatments for autism that ranked them in terms of statistical effect size, ranging from 0.9 (large), to 0.5 to 0.8 (medium), to <0.4 (small). The only drug with a large effect size was risperidone, at 0.9. Most effect sizes were medium, including aripiprazole at 0.8 and N-acetylcysteine (NAC) at 0.7. Both clonidine and methylphenidate had effect sizes of 0.6, and tianeptine’s was 0.5.
Fung and colleagues noted that the first two on the list, the atypical antipsychotics risperidone and aripiprazole, often have problematic side effects (such as sedation, weight gain, and motor symptoms) that must be balanced against their effectiveness. In contrast, NAC is well tolerated with few side effects, and two placebo controlled studies showed that it was effective both alone and as an adjunctive treatment to the antipsychotic risperidone.
Lithium Effective In Adolescent Mania And Increases White Matter Volume
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Adelaine Robb reported that in 81 children with mania (aged 7-17), lithium was superior to placebo in reducing the severity of mania measured on the Young Mania Rating Scale. There had been some debate about the efficacy of lithium in young children with mania, but this study clearly indicates lithium’s effectiveness. The drug is approved by the Federal Drug Administration (FDA) for use in patients with bipolar disorder aged 12 and up.
Another researcher, Vivian Kafrantaris, found that in children who averaged 14.5 years of age, lithium increased the volume of the corpus callosum, a bundle of neural fibers that connects the brain’s right and left hemispheres. Lithium also normalized white matter integrity in other neural fiber tracts—the cingulum bundle and the superior longitudinal fasciculus. The authors concluded that lithium may “facilitate microstructural remodeling of white matter tracts involved in emotional regulation.”
Editor’s Note: There is much research showing that in adults, lithium has positive effects on the brain, including increases in hippocampal and cortical grey matter volume. Now it appears that lithium can improve white matter integrity in the developing brain as well.
Differentiating ADHD and Bipolar Disorder
Three articles in the September 2014 issue of the journal Psychiatric Annals (Volume 44 Issue 9) discussed differentiating pediatric bipolar disorder from attention deficit hyperactivity disorder (ADHD). The first article, by Regina Sala et al., said that reasons to suspect bipolar disorder in a child with ADHD include:
- The ADHD symptoms appear for the first time after age 12.
- The ADHD symptoms appear abruptly in an otherwise healthy child.
- The ADHD symptoms initially responded to stimulnts and then did not.
- The ADHD symptoms come and go and occur with mood changes.
- A child with ADHD begins to have periods of exaggerated elation, grandiosity, depression, decreased need for sleep, or inappropriate sexual behaviors.
- A child with ADHD has recurring severe mood swings, temper outbursts, or rages.
- A child with ADHD has hallucinations or delusions.
- A child with ADHD has a strong family history of bipolar disorder in his or her family, particularly if the child does not respond to appropriate ADHD treatments.
The second article, by this editor Robert Post, Robert Findling, and David Luckenbaugh, emphasized the greater severity and number of symptoms in childhood onset bipolar disorder versus ADHD. Children who would later develop bipolar disorder had brief and extended periods of mood elevation and decreased sleep in the early years of their lives. These, along with pressured speech, racing thoughts, bizarre behavior, and grandiose or delusional symptoms emerged differentially from age three onward. In contrast, the typical symptoms of ADHD such as hyperactivity, impulsivity, and decreased attention were equal in both diagnoses.
In the third article, Mai Uchida et al. emphasized the utility of a family history of bipolar disorder as a risk factor. Moreover, a child with depression plus ADHD is at increased risk for a switch into mania on antidepressants if there is a family history of mood disorders, emotional and behavioral dysregulation, subthreshold mania symptoms, or psychosis.
The differential diagnosis of ADHD versus bipolar disorder (with or without comorbid ADHD) is critical, as drug treatment of these disorders is completely different.
Bipolar disorder is treated with atypical antipyschotics; anticonvulsant mood stabilizers, such as valproate, carbamazepine, or lamotrigine; and lithium. Only once mood is stabilized should small doses of stimulants be added to treat residual ADHD symptoms.
ADHD, conversely, is treated with short- or long-acting stimulants such as amphetamine or methylphenidate from the onset, and these may be augmented by the noradrenergic alpha-2 agonists guanfacine or clonidine. The selective noradrenergic re-uptake inhibitor atomoxetine is also approved by the Federal Drug Administration (FDA) for the treatment of ADHD. The dopamine-active drug bupropion and the anti-narcolepsy drugs modafinil and armodafinil have mild anti-ADHD effects but have not been FDA-approved for that purpose.
