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.
At the 2014 meeting of the International Society for Bipolar Disorders, researcher B.N. Kim discussed symptoms that could distinguish between bipolar disorder and attention deficit hyperactivity disorder (ADHD) in childhood. Both disorders are characterized by decreased attention, concentration, and frustration tolerance, and increased activity, impulsiveness, and irritability.
Kim shared several differential symptoms that are more indicative of a bipolar diagnosis and that are inconsistent with a simple ADHD diagnosis (and this editor Robert Post has added several more). Signs and symptoms that suggest bipolar disorder and not ADHD include: decreased need for sleep, brief and extended periods of euphoria, hypersexuality, delusions, hallucinations, suicidal or homicidal impulses and/or actions, extreme aggression, and multiple areas of extreme behavioral dyscontrol. ADHD, on the other hand, is characterized by more difficulty focusing attention, and by less extreme symptoms in general.
Danish researcher Lars Kessing recently performed the first randomized controlled study of the efficacy of early intervention in bipolar disorder.
Patients who had been hospitalized for a first episode of mania were randomly assigned to two years of treatment in a specialized clinic versus two years with treatment as usual in the community (the control condition). The researchers predicted that then specialized clinic would decrease subsequent hospitalizations, and increase adherence to medication and patient satisfaction compared to treatment as usual over the subsequent six years.
Treatment at the special clinic began with a phase of post-hospitalization settling in, followed by psychoeducation (15 weeks of 1 session/week). Emphasis was placed on the recognition of breakthrough symptoms—early warning signals of an impending mood episode.
All three outcomes were better in the group who were treated at the specialized clinic than in control group who received treatment as usual. Hospitalizations were reduced 40%, medication compliance was enhanced, and patients were more satisfied. Patients younger than age 36 showed greater improvement and greater differences from the control group than were seen among older patients.
One striking observation was that the difference observed after patients had spent two years in the specialized clinic compared to the control group persisted and grew over the following four years, even though these patients left the specialized clinic after the first two years.
The specialized clinic was not only successful, but was also cost-effective. Clinic patient care led to a savings of €3,194 per patient. The costs for clinic patients were 11% of those for control patients.
Editor’s Note: We already know that treatment delay is related to poor outcome. (See article by this editor Robert Post et al. in the Journal of Clinical Psychiatry in 2010.) This study is groundbreaking in demonstrating that the quality of care in a specialized clinic has enormous personal, societal, and financial benefits, and can render the course of illness more benign over a sustained period of at least 6 years.
This means that a revolution in the care and treatment of patients with bipolar disorder is needed throughout the world, but especially in the US, where the typical treatment paradigm is as bad or worse than the treatment as usual condition in Kessing’s Danish study. When patients are discharged from the hospital, they are immediately at increased risk for relapses and, most alarmingly, at 200-fold increased risk of suicide. This post-hospitalization gap in treatment between episodes needs to be better managed. Transitional care is rarely handled well, psychoeducation is rarely given for a sufficient duration, therapy is often unavailable, and medication non-compliance is high. These factors lead to increased illness, re-hospitalizations, and skyrocketing personal and societal costs. Moreover, only 20% of bipolar patients identified in epidemiological studies in the US are in any kind of treatment.
Treatment guidelines must be changed to better address these issues. A first episode of mania should trigger a cascade of sequential treatments: Read more
Methylene blue is a chemical compound that has been used to treat a variety of medical conditions. This drug has some actions that resemble lithium’s: it inhibits guanylate cyclase, which generates second messenger cyclic GMP, and decreases nitric oxide. New evidence shows it may help depression and anxiety in bipolar disorder when added to lamotrigine.
In patients with bipolar disorder who were all treated with lamotrigine, an active 65mg dose of methylene blue three times per day (for a daily total of 195mg) versus 15mg/day (an inactive dose that produces the same side effect of blue urine) was more effective at treating depression and anxiety in a 12-week crossover study. Side effects, in addition to blue urine, included infrequent nausea, diarrhea, headache, and a burning sensation in the urinary tract. Of the 37 randomized study participants, 27 completed both phases of the entire six-month study. Martin Alda, a researcher who presented the double-blind randomized crossover data at the 2014 meeting of the International Society for Bipolar Disorders, indicated that he has also used this preparation clinically with success, although the pharmacy staff who prepared the capsules were not too happy, because everything the drug touches turns blue.
The Pittsburgh Bipolar Offspring study, led by Boris Birmaher of the University of Pittsburgh, investigated risk of illness in the offspring of parents with bipolar disorder. The study included 233 parents with bipolar disorder and 143 controls. In addition to bipolar disorder, parents in the study had many other disorders, including anxiety (70%), panic (40%), a disruptive behavior disorder (35%), attention-deficit hyperactivity disorder or ADHD (25%), and substance use disorder (35%).
The offspring averaged age 12 at entry in the study. Offspring of parents with bipolar disorder had more illness than those of control parents, including bipolar spectrum disorders (10.6% versus 0.8%), depression (10.6% versus 3.6%), anxiety disorder (25.8% versus 10.8%), oppositional defiant disorder or conduct disorder (19.1% versus 8.0%), and ADHD (24.5% versus 6.7%). Of these differences, only bipolar spectrum disorders and anxiety were statistically significant after correcting for differences in the parents’ other diagnoses.
Two factors predicted bipolar spectrum disorders in the offspring: younger age of a parent at birth of child and bipolar disorder in both parents. Older children and those with diagnoses of anxiety or oppositional defiant disorder were more likely to be diagnosed with bipolar disorder.
On long-term follow-up that continued on average until the offspring reached age 20, 23% of those participants who had a parent with bipolar disorder developed any type of bipolar disorder, versus only 1.2% of the children of controls. Of these 23%, about two-thirds had a depressive episode prior to the onset of their bipolar disorder.
Of the offspring of parents with bipolar disorder who developed a bipolar spectrum illness, 12.3% developed bipolar I or II disorders, while 10.7% were diagnosed with bipolar not otherwise specified (NOS). Of those with bipolar NOS, which some consider to be sub-threshold bipolar disorder, about 45% converted to a bipolar I or II diagnosis after several years of prospective follow-up. These data, along with the finding that children with bipolar NOS are highly impaired and take more than a year on average to remit, stress the importance of vigorously treating this subtype, even if it does not meet the full threshold for bipolar I or bipolar II.
Birmaher indicated that although about 50% of the offspring of a bipolar patient had no diagnosis, the high incidence of multiple psychiatric difficulties developing over childhood and adolescence spoke to the importance of attempts at early intervention and prevention. Studies of effective treatment and prevention strategies are desperately needed. So far only family focused therapy (FFT), an intervention developed by researcher David Miklowitz, has shown significant benefits over standard treatment in children with a positive family history of bipolar disorder who already have a diagnosis of anxiety, depression, or bipolar not otherwise specified.
In 2013 we described a speech given by Congressman Patrick J. Kennedy about the need for parity in care for people with mental illnesses. In late 2013, Health and Human Services Secretary Kathleen Sebelius issued a final rule on the Mental Health Parity and Addiction Equity Act of 2008, effectively requiring that health insurance coverage for mental health and substance abuse treatment be comparable to coverage of physical ailments.
The rule was prompted in part by mass shootings that were linked to mental health patients. Sebelius announced the new rule at a press conference with former first lady Rosalynn Carter, who has been a supporter of mental health research for decades.
According to the New York Times, state insurance commissioners will need to enforce the new rule, and more money may be required to fund behavioral health clinics.
This historic milestone may allow patients to get medical care they had previously been unable to afford.
Suicide is a serious risk for people with mood disorders. We have noted before that various studies of lithium show that the drug lowers suicide risk in people with mood disorders. A 2013 meta-analysis by Andrea Cipriani et al. in the journal BMJ confirms this finding. The review of 48 randomized controlled trials comparing lithium with placebo or other active drugs in the long-term treatment of mood disorders showed that lithium reduces the risk of suicide and death from any cause.
Lithium was more effective than placebo at reducing number of suicides and deaths from any cause, and more effective than carbamazepine and anticonvulsants in general at reducing deliberate self-harm. The authors wrote that lithium seems to reduce risk of suicide and death by more than 60% compared to placebo.
Lithium may reduce suicide risk by preventing relapse of mood disorders, but it may also have other mechanisms of action, such as decreasing aggression or impulsivity.
One thing to note about these findings is that the reduction in suicide risk also applies to those with unipolar depression, not just those with bipolar disorder. There is a case to be made that lithium treatment could be targeted specifically to reduce suicide risk.
Many patients with bipolar disorder experience cognitive deficits that impede their recovery and that persist during times of wellness. In a double-blind placebo-controlled study by K. N. Roy Chengappa et al. published in the Journal of Clinical Psychiatry in 2013, the herb Withania somnifera (WSE, commonly called ashwagandha and sold under the name Sensoril) was significantly better than placebo at improving patients’ performance on three different cognitive tasks.
In the eight-week study, 53 patients took either 500 mg of WSE or placebo in addition to their regular medications.
The herb, which has traditionally been used in Ayurvedic medicine in India as an aid to resisting stress and disease, improved performance on digit span backwards (a test of short-term memory in which the subject must repeat a sequence of numbers backwards), Flanker neutral (a test of response time in which a subject must repress their instinct to give an incorrect response), and the Penn Emotional Acuity Test (which requires subjects to correctly identify facial emotions depicted in photographs).
Mood and anxiety levels were not different for the group taking WSE and the group taking placebo.
The researchers hope to continue their investigation of WSE with larger and longer-term studies that will explore the effects of different doses of WSE.
The combination of antidepressant bupropion (Wellbutrin) and naltrexone (Revia), a drug that helps alcoholics resist the craving for alcohol, can help patients keep their weight down. Last year we summarized an article by Smith et al. in the journal Diabetes, Obesity, and Metabolism that showed that obese patients with diabetes treated with the combination of bupropion and naltrexone had excellent weight loss and reduction in body fat compared to those treated with either drug alone or with placebo.
A more recent study by G. J. Wang et al. published in the International Journal of Obesity in 2013 shows that the combination of 360mg of bupropion sustained release and 32mg of naltrexone sustained release works by reducing patients’ response to food cues. Forty women were shown a video of their favorite food being prepared, which stimulated parts of the brain associated with visual stimuli and other functions. Those who received the combination of naltrexone and bupropion had lessened hypothalamic response to the videos compared to those who received placebo, and also showed activity in parts of the brain associated with inhibitory control (the anterior cingulate), internal awareness (the superior frontal cortex, the insula, and the superior parietal cortex), and memory (the hippocampus).
Editor’s Note: It looks like the drug combination prompts the brain to say, “Wow, that looks good, but maybe I shouldn’t take in any more calories today.”
Marijuana Addiction Associated with White Matter Loss and Brain Changes in Healthy People and Those with Schizophrenia
It has been established that cannabis use is associated with impairments in working memory, but researchers are still investigating how these impairments come about. A 2013 study by Matthew J. Smith et al. in the journal Schizophrenia Bulletin compared regular marijuana users both with and without schizophrenia with demographically similar people who did not use marijuana.
Using magnetic resonance imaging (MRI), the researchers were able to map each participant’s brain structures. Healthy people who were marijuana users showed deficits in white matter (axons of neurons that are wrapped in myelin) compared to healthy people who did not use the drug. Similarly, patients with schizophrenia who used marijuana regularly had less white matter than those patients with schizophrenia who did not use the drug. There were also differences in the shapes of brain structures, including the striatum, the globus pallidus, and the thalamus, between cannabis users and non-users.
Differences in the thalamus and striatum were linked to white matter deficits and to younger age of cannabis use disorder onset.
Differences between cannabis users and non-users were more dramatic across the populations with schizophrenia than across the healthy populations.
Editors note: Future research is needed to determine whether marijuana causes these brain changes, or whether the brain changes are a biomarker that shows a vulnerability to marijuana addiction (although the latter is less likely than the former).
Other data show that marijuana is associated with an increase in psychosis (with heavy use), cognitive deficits, and an earlier onset of both bipolar disorder and schizophrenia in users compared to non-users. These findings make pot begin to look like a real health hazard. With legalization of marijuana occurring in many states, ease of access will increase, possibly accompanied by more heavy use. The most consistent pharmacological effect of marijuana is to produce an amotivational syndrome, characterized by apathy or lack of interest in social activities. Particularly for those already struggling with depression, pot is not as benign a substance as it is often thought to be.