The hypoglycemic drug pioglitazone is typically used to treat diabetes, but a 2015 study by A. Zeinoddini and colleagues shows that it may improve depressive symptoms in patients with bipolar disorder who do not have type 2 diabetes or the metabolic syndrome (characterized by high weight, cholesterol, triglycerides, and blood pressure).
Forty-four patients with bipolar disorder and a major depressive episode were randomized to receive either 30 mg/day of pioglitazone or placebo as an adjunctive treatment to lithium. Depressive symptoms were lower in the pioglitazone group at weeks 2, 4, and 6 of the six-week study.
No serious side effect occurred in the study, but pioglitazone use is associated with some risks in those using it for diabetes treatment. People taking pioglitazone for longer than a year have shown increased rates of bladder cancer. There is an increased risk of fractures of the upper arms, hands, and feet in female patients. The drug lowers blood sugar, but not enough to be a problem in people not taking other drugs that lower blood sugar. Pioglitazone can also cause fluid retention, worsening congestive heart failure. It can also cause mild weight gain, anemia, and sinus problems.
Repeated transcranial magnetic stimulation is a non-invasive procedure that has been approved for the treatment of severe depression since 2008. In rTMS treatment, a figure-8–shaped electromagnetic coil is placed against the forehead and magnetic pulses that can penetrate the scalp are converted into small electrical currents that stimulate neurons in the brain up to 1.5 cm deep. More recently, in 2013, the Federal Drug Administration approved a device with an H-shaped coil that delivers deep transcranial magnetic stimulation (dTMS). It can stimulate a wider area, and up to 8 cm deep.
Y. Levkovitz and colleagues have published the first double-blind randomized controlled multicenter trial of dTMS, reporting in the journal World Psychiatry that the intervention was effective and safe in patients who had not responded to antidepressant medication.
The study included 212 patients aged 22–68 years. All participants had failed to respond to one to four antidepressants or had not been able to tolerate the side effects of at least two antidepressants during their current episode of depression. The patients were randomized to receive either a sham treatment or 18 Hz dTMS over the prefrontal cortex acutely for four weeks and biweekly for 12 weeks for a total of 20 sessions.
The patients who received dTMS showed significantly greater improvement in symptoms than those who received the sham treatment, with a moderately large effect size of 0.76. Response and remission rates were also better in those who received dTMS. Response rates were 38.4% for the dTMS group versus 21.4% in the sham group. Remission rates were 32.6% for the dTMS group and 14.6% for the sham group. These difference in response remained stable during the three months of the study.
Side effects were minor except for a seizure that occurred when the protocol for the treatment was breached.
In a new study by ESM Eurelings and colleague in the journal International Psychogeriatrics, the inflammatory marker C-reactive protein differentiated between older people with symptoms of apathy versus symptoms of depression. Higher levels of C-reactive protein were found in those with symptoms of apathy. The researchers concluded that apathy may be a manifestation of mild inflammation in elderly people.
Vortioxetine (Brintellix) is a relatively new antidepressant that has a range of effects on serotonin receptors, making it different from selective serotonin reuptake inhibitors (SSRIs), which work only on the serotonin transporter. In multiple studies, it has treated not only depression but also cognitive dysfunction. In a new study led by Atul Mahableshwarkar and published in the journal Neuropsychopharmacology, 10–20 mg/day of vortioxetine reduced symptoms of depression more than placebo and improved performance on tests of cognitive ability more than placebo and another antidepressant, duloxetine.
While depression is often accompanied by cognitive dysfunction, in this study vortioxetine seemed to directly treat the cognitive deficits rather than reducing them by alleviating the depression. The participants were aged 18–65.
Omega-3 fatty acids are found in some green vegetables, vegetable oils, and fatty fish. There is some evidence that omega-3 fatty acid supplements can reduce depression, but researchers are trying to clarify which omega-3s are most helpful, and for whom. A new study in Molecular Psychiatry suggests that depressed people with higher inflammation may respond best to EPA omega-3 fatty acids compared to DHA omega-3 fatty acids or placebo. Researchers led by M.H. Rapaport divided people with major depressive disorder into “high” and “low” inflammation groups based on their levels of the inflammatory markers IL-1ra, IL-6, high-sensitivity C-reactive protein, leptin, and adiponectin. Participants were randomized to receive eight weeks of treatment with EPA omega-3 supplements (1060mg/day), DHA omega-3 supplements (900mg/day), or placebo.
While overall treatment differences among the three groups as a whole were negligible, the high inflammation group improved more on EPA than on placebo or DHA, and more on placebo than on DHA. The authors suggest that EPA supplementation may help relieve symptoms of depression in people whose depression is associated with high inflammation levels, a link common among obese people with depression.
Editor’s Note: These data add to a study by Rudolph Uher et al. in which people with high levels of C-reactive protein responded better to the tricyclic antidepressant nortriptylene, while those with low levels of the inflammatory marker responded better to the selective serotonin reuptake inhibitor antidepressant escitalopram.
Studies have found that when a depressed mother’s symptoms remit, her children are less likely to show psychiatric symptoms. A new study by Myrna M. Weissman and colleagues in the American Journal of Psychiatry randomized 76 mothers to treatment with escitalopram, bupropion, or a combination of the two, and assessed the impact of the mothers’ treatment on their 135 children (aged 7–17).
There were no significant differences in the mothers’ symptoms or remission, but children’s depressive symptoms and functioning improved more if their mothers received (only) escitalopram. Only in that group was a mother’s improvement associated with her children’s improvement.
Mothers in the escitalopram group reported greater improvement in their ability to listen and talk to their children compared to the mothers in other groups, and the children of the mothers in the escitalopram group reported that their mothers were more caring.
Children of mothers with low negative affect improved significantly, while children of mothers with high negative affect only improved if their mothers were in the escitalopram group.
The authors suggest that for a mother’s improvement to help her children’s symptoms, her anxious distress and irritability must be reduced, and these may be better targeted with escitalopram than bupropion.
Adolescence may be a period of particular vulnerability to the effects of stress. New research by Shannon Gourley indicates a possible mechanism for this vulnerability. When Gourley exposed adolescent mice to low levels of the stress hormone corticosterone (the equivalent to human cortisol), they developed habit-based rather than goal-oriented decision-making, leading to behaviors that resembled human depression, which lasted into adulthood. Adult mice that were exposed to the low levels of corticosterone were not affected by it.
Gourley also used an alternative method of producing these stress responses a second time by silencing the trkB receptor for brain-derived neurotrophic factor (BDNF) in the amygdala and hippocampus of the mice. The depression-like behaviors that resulted, such as lack of motivation, were able to be reversed by treating the mice with 7,8-dihydroxyflavone, a drug that activated the trkB receptor. In the adolescent mice, this treatment had antidepressant effects that lasted into adulthood, even though the treatment stopped earlier.
Telomeres are repeated DNA sequences that sit at the end of chromosomes and protect them during cell replication. Telomeres get shorter with aging and with stressors or psychiatric illnesses. Researcher Alexandre Mathe and colleagues recently found that in a line of rats bred to be more susceptible to stress and depression-like behavior, hippocampal telomeres were shorter than in normal rats or rats bred to be less susceptible. The susceptible rats also had lower levels of enzymes that maintain telomere length. Both telomerase activity and Tert (telomerase reverse transcriptase) expression were reduced in the susceptible rat compared to the other rats. However, lithium reversed the low levels of telomerase activity and Tert expression.
Editor’s Note: Lithium increases hippocampal volume in people, and also increases human telomerase. Researcher Lina Martinsson reported in 2013 that lithium increases telomere length in white cells. Now lithium has increased hippocampal telomerase in a rat model of depression. Short telomeres are associated with aging and increased vulnerability to a wide range of medical and psychiatric disorders. Since people with bipolar disorder are prone to memory problems, medical problems, and short telomeres, they might want to talk to their physician about including lithium in their treatment regimen, if they are not already taking it.
Both bipolar disorder and unipolar depression often begin in childhood or adolescence, but it can be difficult to distinguish the two using symptoms only. People with bipolar illness may go a decade without receiving a correct diagnosis. Researcher Jorge Almeida and colleagues recently performed a meta-analysis of previous studies to determine what neural activity is typical of children with bipolar disorder versus children with unipolar depression while processing images of facial emotion. They found that youth with bipolar disorder were more likely to show limbic hyperactivity and cortical hypoactivity during emotional face processing than youth with unipolar depression. Almeida and colleagues hope that this type of data may eventually be used to diagnose these disorders or to measure whether treatment has been successful.
Life experiences such as adversity in childhood have been linked to epigenetic changes to DNA. These changes do not affect the sequence of DNA, but can change how tightly DNA is wound, and thus how easily it is transcribed. One epigenetic change that can occur following adversity in childhood is methylation of the gene for the glucocorticoid receptor (NR3C1). A recent study by Kathryn Ridout and colleagues examined links between early adversity, methylation of this gene, and behavioral problems in childhood. Adversity was linked to methylation of the gene at exons 1D and 1F in the promoter of NR3C1. Methylation of the gene was associated with internalizing behaviors (e.g. depression, anxiety) but not externalizing behaviors (e.g. attention deficit hyperactivity disorder (ADHD) or oppositional defiant disorder) in children of preschool age. The NR3C1 methylation was a significant mediator of the internalizing behaviors in children who had experienced adversity.
Editor’s Note: Similar associations of methylation of the glucocorticoid receptor with childhood adversity have been reported in other clinical and animal studies and provide a mechanism for the long-lasting adverse effects of stressors in childhood.