Longer Periods of Untreated Depression Linked to More Brain Inflammation
A 2018 study by researchers Elaine Setiawan, Sophia Attwells and colleagues reports that inflammation seems to increase with duration of untreated unipolar depression. This implies that depression may be a progressive illness, and later stage depression may require different treatments than early stage depression, such as those that directly target inflammation.
The study published in the journal The Lancet Psychiatry used positron emission tomography (PET scan) to examines levels of translocator protein in the brain. Higher levels of translocator protein indicate activation of microglia, the brain’s immune cells, which can respond to trauma or injury.
The study included 80 participants between the ages of 18 and 75. Ten had a history of more than 10 years of depression, ten had experienced fewer than 10 years of depression, and 30 comprised a healthy comparison group.
The best predictors of high levels of translocator protein were duration of untreated major depressive disorder, total illness duration, and duration of antidepressant exposure. These three factors explained about half of the variation in translocator protein levels. Those participants whose depression went untreated for 10 years or longer had inflammation levels 29–33% higher than those whose depression was untreated for 9 years or less.
Participants who had received antidepressant treatment appeared to avoid an average yearly increase in the extent of their microglial activation.
The study took place at Canada’s Centre for Addiction and Mental Health.
Editor’s Note: Since inflammation is a predictor of poorer response to antidepressants, these data add a further neurochemical rationale to the already strong clinical rationale for earlier and more sustained antidepressant treatment and prevention. Virtually all treatment guidelines suggest that after two or three prior unipolar depressions, patients should receive long-term (lifelong) antidepressant treatment.
There is now a large body of data, including a 2012 article by this editor Robert M. Post and colleagues in the Journal of Psychiatric Research that too many episodes can hurt the brain, and the current study adds to this perspective. Avoiding preventive treatment for too long may actually foster the development of more episodes and more treatment resistance. A good mantra is “prevent episodes, protect the brain.”
Consensus is now also building that comprehensive long-term treatment is indicated after a first manic episode. A 2013 article by Lars Kessing and colleagues in the British Journal of Psychiatry suggested that high quality initial treatment can improve the long-term course of illness. Moreover, a 2016 article by Jan-Marie Kozicky and colleagues and a 2017 article by Christine Demmo and colleagues, both in the journal Bipolar Disorders, suggest that after a first mania, cognition recovers over the next year only if no further episodes occur in that time.
Antioxidant N-Acetylcysteine Improves Working Memory in Patients with Psychosis
In a 2017 article in the journal Psychological Medicine, researcher Marta Rapado-Castro and colleagues reported that among 58 patients with bipolar disorder or schizophrenia and symptoms of psychosis, those who took two grams per day of the antioxidant n-acetylcysteine (NAC) showed improvements in working memory after six months compared to those who took placebo over the same study period.
Antipsychotic medications can typically reduce psychotic symptoms such as delusions or hallucinations, but cognitive symptoms such as problems with learning, memory, or information processing may remain. NAC, which is sold over-the-counter as a nutritional supplement, seemed to improve these symptoms.
The researchers suggest that larger studies of NAC are needed, particularly to determine whether giving NAC to patients during their first episode of psychosis could prevent cognitive decline from occurring at all during the course of their illness.
NAC has been found to have a range of benefits, including reducing substance abuse and interfering with habit-based behaviors such as compulsive hair-pulling, obsessive-compulsive disorder, and gambling.
Researcher Michael Berk, a co-author of the study, reported in the journal Biological Psychiatry in 2008 that NAC could also improve depressive symptoms in bipolar disorder and negative symptoms in schizophrenia.
Editor’s Note: Since cognitive deficits are common in both schizophrenia and bipolar disorder, using NAC in addition to antipsychotic medications could be a useful tool to address these types of symptoms.
Large Finnish Study Finds Lithium is Best at Preventing Re-Hospitalizations in Bipolar Disorder
A 2018 article in the journal JAMA Psychiatry reports that lithium and long-acting antipsychotic injections were most effective at preventing re-hospitalizations among people with bipolar disorder.
The study by Markku Lähteenvuo and colleagues included 18,018 Finnish patients with bipolar disorder. A national database contained information on any hospitalizations that occurred among the patients and what medications were dispersed to patients.
Among the participants, 54% (9,721 patients) were re-hospitalized at least once over a study period of 16 years. Medications associated with the smallest risk of re-hospitalization for psychiatric reasons were long-acting injections of risperidone, gabapentin, long-acting injections of perphenazine, and lithium carbonate.
When the researchers looked at hospitalizations for any cause (not just psychiatric illness), lithium was associated with the least risk of re-hospitalization, while benzodiazepines had the greatest risk, both for psychiatric re-hospitalization and re-hospitalization for any cause.
Long-acting injectable medications were associated with less risk of re-hospitalization compared to the identical medications delivered orally.
Lähteenvuo and colleagues concluded, “Lithium…should remain as the first line of treatment for bipolar disorder, after decades of underprescription.” They suggest that long-acting injectable medications may be a good alternative to prevent relapse in patients for whom lithium is unsuitable.
Editor’s Note: In addition to lithium’s ability to prevent depressions and manias, it also increases the volume of the hippocampus and protects against a diagnosis of dementia in old age. Lithium decreases the risk for suicide and also increases the length of telomeres, bits on the ends of DNA strands that protect them as they replicate, which are important to the maintenance of both physical and psychiatric health. When lithium is used cautiously to maintain doses below a given patient’s side effects threshold, it is very well tolerated by most individuals.
Specific Probiotics Reduce Re-Hospitalizations for Bipolar Disorder
In a 2018 article published in the journal Bipolar Disorders, researcher Faith Dickerson and colleagues reported that in a small study of 66 people who had been hospitalized for mania, taking specific probiotic supplements upon their release reduced re-hospitalizations compared to taking placebo.
The study followed patients for 24 weeks after their hospitalization. They were randomized to receive either the combination of Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12 or placebo in addition to their regular medications. While 17 of the 33 participants in the placebo group (51.5%) had at least one re-hospitalization during the study period, only eight (24.2%) of the participants taking probiotics had a re-hospitalization. The duration of the re-hospitalizations was also shorter for those taking probiotics (2.8 days on average versus 8.3 days for those taking placebo).
In a personal communication to this editor (Robert M. Post), Chris Aiken, Instructor in Clinical Psychiatry at Wake Forest University School of Medicine, who was not involved in the study, provided some clarifying details to this editor about the use of probiotics to reduce manic relapse. Aiken explained, “Apparently, it’s important to get both the right species (e.g. Bifidobacterium lactis) and the right strain (e.g. Bb-12) in choosing a probiotic. The study mentions that one of the strains (Bb-12) is patented and only available in Europe, but it has been licensed to a few U.S. companies.
“I found two products that contain the exact strains in the study and wrote this up for patients: In [the] study [noted above], a probiotic capsule containing Bifidobacterium lactis Bb-12 and Lactobacillus rhamnosus GG lowered the risk of psychiatric hospitalization threefold. [Both] strains are available in the supplement Emergen-C and in a liquid probiotic designed for infants, Culturelle Baby Grow and Thrive. The infant serving would suffice for adults as well. You could also get the two strains by combining two separate probiotic capsules: Align Daily Immune Support and Culturelle Digestive Health Daily Priobiotic.”
Editor’s Note: We are grateful to Dr. Aiken for this added information. We also found that USANA probiotic also contains both strains used in the study. Recent research has found more and more connections between inflammatory processes and mental health. This study contributes to our understanding of the connection between gut health and the brain.
NAD Precursor May Improve Cardiovascular Health
NAD, or nicotinamide adenine dinucleotide, is found in all living cells. Its oxidized form, NAD+, rose in popularity as a nutritional supplement following a 2013 Harvard study that suggested it might slow aging in mice. A 2018 article by researcher Christopher R. Martens and colleagues in the journal Nature Communications reports that a precursor vitamin to NAD+ called nicotinamide riboside (NR) can stimulate NAD+ metabolism in healthy middle-aged and older adults compared to placebo, which might improve cardiovascular health. In the crossover study, participants received NR or placebo for six weeks, and then received the other option for a second six-week period. NR was associated with increased NAD+ metabolism.
The researchers suggest that more research is needed to investigate whether chronic NR supplementation might be able to reduce blood pressure and arterial stiffness.
Third Study Suggests Cariprazine Is Effective in Bipolar Depression
The atypical antipsychotic drug cariprazine (sold under the name Vraylar in the US) is currently approved by the US Food and Drug Administration for the treatment of schizophrenia and manic or mixed episodes of bipolar disorder. Based on recent successful phase 3 trials in bipolar depression, the pharmaceutical companies that produce cariprazine, Allergan and Gedeon Richter, plan to apply for a change in FDA labeling later this year to reflect the drug’s apparent ability to treat bipolar depression as well.
While many drugs can prevent or treat mania, treating bipolar depression has typically been more of a challenge. The most recent 6-week trial of cariprazine in 493 patients showed that a dose 1.5mg/day was significantly more effective than placebo at reducing depression ratings. (A dose of 3mg/day did not show superiority over placebo as it had in previous trials of cariprazine.)
Side effects reported in the trial were mild and included restless legs, nausea, and fatigue. Five percent of those who received cariprazine discontinued the drug due to side effects, compared to three percent of those who received placebo.
The mechanism by which cariprazine improves depression is not yet clear. The drug is a dopamine partial agonist, but unlike aripiprazole (Abilify) and brexpiprazole (Rexulti), which have more potent effects on D2 receptors than on D3 receptors, cariprazine is more potent at dopamine D3 receptors. Whether this difference accounts for the positive effects in bipolar depression that aripiprazole and brexpiprazole do not have remains to be seen.
Three-Minute ‘Theta Burst’ Treatment as Effective as 37-Minute RTMS
A variation on repeated transcranial magnetic stimulation (rTMS) called intermittent theta burst stimulation (iTBS) may be able to deliver the same benefits in a tenth of the time. RTMS is a non-invasive treatment in which a magnetic coil placed near the skull transmits electrical signals to the brain. It is effective in depression and has been shown to improve aspects of schizophrenia, autism, and addictions as well.
A typical rTMS session lasts for 37.5 minutes and consists of high frequency (10 Hz) stimulation. Access to the treatment remains somewhat limited, so the newer form of iTBS treatment may help more people access treatment by allowing clinicians to treat more patients in a day.
The 2018 study, published by Daniel Blumberger and colleagues in the journal The Lancet, compared iTBS to standard rTMS and evaluated the effectiveness, safety, and tolerability of the new treatment compared to the old. 414 patients aged 18–65 with major depression that had persisted despite treatment with several antidepressant options were randomized to receive either iTBS or rTMS delivered to their left dorsolateral prefrontal cortex. They received the given treatment five days/week for four to six weeks.
Patients who received iTBS showed a nearly identical level of improvement in depression to those who received rTMS. Self-reports of pain intensity were worse among those who received iTBS, but the dropout rate was not higher for that group. Headaches were the most common side effect reported, and rates were similar across both groups. The authors judged iTBS to be a comparable, non-inferior alternative to rTMS for people with major depression.
Among participants who received iTBS, depression improved significantly, with 32 percent reporting a remission of depression symptoms. Those who received standard rTMS had a remission rate of 27 percent.
Psychoeducation Is a Must for Bipolar Disorder
In 2018, researcher S.A. Soo and colleagues published a systematic review in the Journal of Clinical Psychiatry that analyzed findings from 40 randomized studies of psychoeducation for the management of bipolar disorder and compared the results for different types of psychoeducation: group, family, individual, and internet-based. Most of the randomized controlled trials (28 of 40 studies, 70.0%) assessed group or family psychoeducation, which had many benefits, while studies of individual or internet-based psychoeducation tended to be inconsistent.
The findings: “Group psychoeducation was associated with reduced illness recurrences, decreased number and duration of hospitalizations, increased time to illness relapse, better treatment adherence, higher therapeutic lithium levels, and reduced stigma. Family psychoeducation was associated with reductions in illness recurrence, hospitalization rates, and better illness trajectory as well as increased caregiver knowledge, skills, support, and sense of well-being and reduced caregiver burden.”
Editor’s Note: Given these results, it appears that group or family psychoeducation is a critical component to good care. Soo and colleagues suggest that future studies should directly compare different types of psychoeducation to each other to evaluate whether specific benefits are useful at various stages of illness.
Poll Finds 87% of US Adults Think Children Need More Mental Health Support
In a poll of 2,014 adults in the US, 87% believed that children need more mental health support. For over a decade, the editors of the BNN have been emphasizing the great need for earlier recognition and treatment of children with bipolar and related mood and behavioral disorders. With so many Americans in agreement, now could be the time to direct public health and research funds to the better support of children’s mental health. Sadly this does not yet seem to be the case, but this is an election year. We need stand-up leaders in Congress to marshal the resources to increase the well-being of current and future generations.
Vortioxetine Improves Processing Speed in Depression
In May 2018, the US Food and Drug Administration (FDA) approved a label change for the antidepressant vortioxetine (Trintellix), reflecting new data that show the drug can improve processing speed, an aspect of cognitive function that is often impaired in people with depression. Vortioxetine was first approved by the FDA for the treatment of depression in 2013.
The approval followed eight-week double-blind placebo-controlled studies of vortioxetine’s effects on cognitive function in adults aged 18–65 who have depression. The studies were known as FOCUS and CONNECT. Patients received either 10mg/day, 20mg/day, or placebo. Those who took vortioxetine showed improvement on the Digit Symbol Substitution Test, a measure of processing speed, in addition to improvement in their depression.
Editor’s Note: This is the first time the FDA has approved labeling that describes an antidepressant as improving aspects of cognition in depression. Cognition is impaired in many patients with depression, such that this component of the drug’s effects could be of clinical importance. Among the 5 serotonin (5HT) receptor effects of the drug (in addition to the traditional blockade of serotonin reuptake shared by all selective serotonin reuptake inhibitor antidepressants (SSRIs)), it is likely that vortioxetine’s effects in blocking 5HT-3 and 5HT-7 receptors are important to the drug’s effects on processing speed.
