Mixed Depression
Mixed depression describes a state of depression accompanied by a few symptoms typically associated with mania. At the 2015 meeting of the International Society for Bipolar Disorders, researcher Roger McIntyre shared some findings about mixed depression.
People with mixed depression have higher levels of MHPG, which is produced as the neurotransmitter norepinephrine breaks down. They also have higher levels of the stress hormone cortisol and their depressions are more difficult to treat. Those with unipolar mixed depression may respond poorly to traditional antidepressants.
There are also medical risks associated with mixed depression. People with mixed depression are more susceptible to cardiovascular disease than are people with depressive symptoms alone.
The drugs lurasidone, olanzepine, and ziprasidone have each shown efficacy in mixed depression.
Lamotrigine potentiates the antidepressant effects of quetiapine in bipolar depression
At the 2015 meeting of the International Society for Bipolar Disorders, researcher John Geddes presented an important study showing in inadequate responders to quetiapine that compared to adding placebo, adding the anticonvulsant lamotrigine to their treatment improved depression rapidly and lastingly. Some psychiatrists have been prescribing this combination to patients for some time, but this is the first formal clinical trial documenting its efficacy. The article was published online in December in the journal Lancet Psychiatry.
Researcher Guy Goodwin described details of the study, called CEQUEL, at the meeting. It included 202 patients with bipolar I or II disorder who required treatment for a depressive episode. Participants who did not respond completely to 14 days of treatment with quetiapine were prescribed either an additional dose of lamotrigine or a placebo. Lamotrigine was very slowly titrated up to maximum doses of 200mg/day. Its antidepressant effects were striking. They began early and persisted for 50 weeks. (The published article covers only the first 12 weeks.) Response rates for the combination of quetiapine and lamotrigine were 52%, compared to 22% for quetiapine alone. Remission rates were 35% for quetiapine and lamotrigine and 12% for quetiapine alone.
Folic acid interaction
Another part of the study assessed whether folic acid supplements could improve outcomes, but in fact they did the opposite, reversing the benefits of adding lamotrigine. Geddes did not have an explanation for why this might be the case. Lamotrigine can inhibit folate metabolism, and it had been thought that adding folate would be useful. Until further data are gathered on folate augmentation in patients taking the combination of lamotrigine and quetiapine, folate should be used cautiously if at all in these patients.
Possible combination with lithium
In Goodwin’s talk, he also noted lithium’s potential to lower suicide rates, premature mortality, and cognitive impairment, and to increase hippocampal and cortical volume.
Since lamotrigine was shown to potentiate the antidepressant effects of lithium in a study by Van der Loos and colleagues, and quetiapine is approved by the Food and Drug Administration for the prevention of depression as an adjunct to lithium (or valproate), there might be theoretical acute and long-term benefits to combining the three: lithium, quetiapine, and lamotrigine.
Reduced Cognitive Function and Other Abnormalities in Pediatric Bipolar Disorder
At the 2015 meeting of the International Society for Bipolar Disorders, Ben Goldstein described a study of cognitive dysfunction in pediatric bipolar disorder. Children with bipolar disorder were three years behind in executive functioning (which covers abilities such as planning and problem-solving) and verbal memory.
There were other abnormalities. Youth with bipolar disorder had smaller amygdalas, and those with larger amygdalas recovered better. Perception of facial emotion was another area of weakness for children (and adults) with bipolar disorder. Studies show increased activity of the amygdala during facial emotion recognition tasks.
Goldstein reported that nine studies show that youth with bipolar disorder have reduced white matter integrity. This has also been observed in their relatives without bipolar disorder, suggesting that it is a sign of vulnerability to bipolar illness. This could identify children who could benefit from preemptive treatment because they are at high risk for developing bipolar disorder due to a family history of the illness.
There are some indications of increased inflammation in pediatric bipolar disorder. CRP, a protein that is a marker of inflammation, is elevated to a level equivalent to those in kids with juvenile rheumatoid arthritis before treatment (about 3 mg/L). CRP levels may be able to predict onset of depression or mania in those with minor symptoms, and is also associated with depression duration and severity. Goldstein reported that TNF-alpha, another inflammatory marker, may be elevated in children with psychosis.
Goldstein noted a study by Ghanshyam Pandey that showed that improvement in pediatric bipolar disorder was related to increases in BDNF, a protein that protects neurons. Cognitive flexibility interacted with CRP and BDNF—those with low BDNF had more cognitive impairment as their CRP increased than did those with high BDNF.
Offspring of Parents with Psychiatric Disorders At Increased Risk for Disorders of Their Own
At a symposium at the 2015 meeting of the International Society for Bipolar Disorder, researcher Rudolph Uher discussed FORBOW, his study of families at high risk for mood disorders. Offspring of parents with bipolar disorder and severe depression are at higher risk for a variety of illnesses than offspring of healthy parents.
Uher’s data came from a 2014 meta-analysis by Daniel Rasic and colleagues (including Uher) that was published in the journal Schizophrenia Bulletin. The article described the risks of developing mental illnesses for 3,863 offspring of parents with schizophrenia, bipolar disorder, or major depression compared to offspring of parents without such disorders.
Previous literature had indicated that offspring of parents with severe mental illness had a 1-in-10 likelihood of developing a severe mental illness of their own by adulthood. Rasic and colleagues suggested that the risk may actually be higher—1-in-3 for the risk of developing a psychotic or major mood disorder, and 1-in-2 for the risk of developing any mental disorder. An adult child may end up being diagnosed with a different illness than his or her parents.
At the symposium, Uher focused on families in which a parent had bipolar disorder. These families made up 1,492 of the offspring in the Rasic study. The table at right shows the risk of an illness among the offspring of bipolar parents compared to that risk among offspring of healthy parents, otherwise known as relative risk. (For example, offspring of parents with bipolar disorder are 4.24 times more likely to be diagnosed with bipolar disorder themselves than are offspring of non-bipolar parents.) The table also shows the percentage of offspring of parents with bipolar disorder who have each type of disorder.
Editor’s Note: These data emphasize the importance of vigilance for problems in children who are at increased risk for mental disorders because they have a family history of mental disorders. One way for parents to better track mood and behavioral symptoms is to join our Child Network.
Psychiatric Symptoms in Childhood Linked to Struggles in Adulthood
Psychiatric illness is one of the most common health problems among children. A study by William E. Copeland and colleagues in the journal JAMA Psychiatry indicates that psychiatric symptoms and diagnoses in childhood can lead to struggles with health, the legal system, personal finances, and social functioning in early adulthood, even if the psychiatric symptoms themselves do not last.
The study included 1420 participants from 11 mostly rural counties in North Carolina, who participated in structured interviews up to six times between the ages of 9 and 16 to determine the existence of psychiatric symptoms and diagnoses. Of these, 1273 were assessed three times during young adulthood, at the ages of 19, 21, and 24–26, for any evidence of social, legal, financial, or health problems.
Participants who had had a childhood psychiatric disorder were six times more likely to have at least one adverse outcome in adulthood compared to participants with no history of psychiatric problems, and nine times more likely to have two or more adverse outcomes in adulthood. Those participants who had psychiatric symptoms that were not sufficient for a particular diagnosis were still three times more likely to have at least one adverse outcome in adulthood, and five times more likely to have at least 2 adverse outcomes. The cumulative number of psychiatric disorders to which a participant was exposed was the best predictor of adverse outcomes in adulthood.
Even moderate psychiatric problems in childhood can disrupt a person’s transition to adulthood. However, early treatment and prevention can help reduce the long-term impact of psychiatric illness. Parents of children (aged 2–12) with mood and behavioral symptoms are welcome to join the Child Network, a system for collecting weekly ratings of their children’s symptoms and displaying them longitudinally for the child’s doctor.
Childhood Maltreatment Associated with Suicide Attempts
A history of childhood maltreatment increases the risk that a person will attempt suicide. Different types of maltreatment, such as physical abuse, emotional abuse, sexual abuse, and neglect, often overlap. In a 2015 study in the Journal of Clinical Psychiatry, researcher Nicolas Hoertel and colleagues used data from an epidemiological survey of 34,653 Americans to clarify the mechanism by which maltreatment is linked to suicide risk.
Hoertel and colleagues found that childhood maltreatment in general was associated with an increased risk of attempting suicide and an earlier age at first suicide attempt. The analysis controlled for demographic characteristics and psychiatric diagnoses. Most of the risk came from effects that were shared across all the types of maltreatment. However, sexual abuse directly conferred an additional risk of suicide attempt.
In an earlier study of 648 outpatients with bipolar disorder by this editor Robert Post and colleagues (led by Gabriele Leverich), 34% had a history of suicide attempts, and these participants had a higher incidence of traumatic stressors in childhood and more stresses at illness onset than those without a history of suicide attempts. A history of sexual abuse in childhood was also linked to an increased risk of a serious suicide attempt in the earlier study, which appeared in the Journal of Clinical Psychiatry in 2003.
Treating Women During Pregnancy and Breastfeeding
A Danish working group has released guidelines for prescribing psychotropic drugs to women who are pregnant or breastfeeding. After a comprehensive review of the literature, researchers from several different Danish medical societies reported that sertraline and citalopram are the first choice among selective serotonin reuptake inhibitors (SSRIs) for depression in women who are pregnant or breastfeeding. The working group suggested that women with bipolar disorder who need a mood stabilizer because of frequent relapses could be prescribed lithium, though lithium use is associated with a small risk of cardiac abnormalities in the child. Lamotrigine may also be used, and has not been associated with any congenital abnormalities.
Valproate and carbamazepine are not recommended for use during pregnancy and breastfeeding. Use of valproate among women of child-bearing age should particularly be avoided due to several risks for the potential child. These include spina bifida and other serious congenital problems, but also severe developmental delay and loss of about 9 IQ points. Other possible treatments for bipolar disorder and schizophrenia in pregnant and breastfeeding women include olanzapine, risperidone, quetiapine, and clozapine. The data about the safety of these medications are not extensive.
The working group included members of the Danish Psychiatric Society, the Danish Society of Obstetrics and Gynecology, the Danish Paediatric Society, and the Danish Society of Clinical Pharmacology. The recommendations may be found in an article by E.R. Larsen and colleagues in a 2015 supplement to the journal Acta Psychiatrica Scandinavica.
Obesity Linked to Illness Severity
In a talk at the 2015 meeting of the International Society for Bipolar Disorder, researcher David Bond reported that 75% of patients in a study of first episode mania had unhealthy body mass indices (BMIs). Forty percent were overweight while thirty-five percent were obese. Higher weight was associated with greater illness severity. Bond said that in other studies obesity has been associated with less time well and a greater risk of relapse into depression.
Obese patients also had lower brain volume, worse memory, and a greater risk of developing early onset dementia compared to other patients. Those who were overweight or obese had a 35% higher risk of developing Alzheimer’s disease.
In a different talk at the same meeting, researcher Roger McIntyre reported that among patients with bipolar disorder, those who were obese have greater cognitive problems and more evidence of inflammation than those who were not obese. He has seen indirect antidepressant effects and other health benefits following weight loss from bariatric surgery.
Lori Altshuler, Leading Figure in American Psychiatry, 1957–2015
We are sad to report the death of Dr. Lori Altshuler, one of the leading figures in American psychiatry. She passed away last month after a 10-year battle with cancer. She was the director of the Mood Disorders Research Program at UCLA and a founding member of the Bipolar Collaborative Network, which included US sites in Los Angeles, Dallas, Cinncinatti, and Bethesda and European sites in Utrecht, Freiberg, and Munich, and spawned the BNN newsletter.
Dr. Altshuler made important contributions to the understanding of bipolar disorder, particularly with her work on brain imaging. She also conducted countless treatment studies so that patients could be treated based on the best available evidence.
After funding for the Bipolar Collaborative Network ended in 2002, she organized all of the researchers to continue working together, and this resulted in more than 90 publications from the group. Her tireless and heroic efforts to improve the lives of people with bipolar disorder will be sorely missed.
Low Vitamin D Linked to Cognitive Decline
Low levels of vitamin D levels are common, particularly in older adults and in African Americans and Hispanics. Unfortunately, low vitamin D is associated with decline in two types of cognitive functioning: episodic memory (memories of autobiographical events) and executive function (reasoning, problem-solving, planning, etc.).
A recent study with a particularly diverse group of participants, over half of whom were African American or Hispanic, found that over a period of about 5 years, episodic memory and executive function declined faster in older adults with low levels of vitamin D.
Average vitamin D levels for the entire group of 382 adults were below national standards. Levels of 25-hydroxy vitamin D should be between 20 and 50 nanograms per milliliter of blood. The average fell just below this, at 19.2 ng/mL. Over a quarter of participants had vitamin D deficiency, with levels below 12 ng/mL, and another 35.1% had vitamin D insufficiency, with levels between 12 and 20 ng/mL.
African Americans and Hispanics had lower levels of vitamin D (17.9 ng/mL and 17.2 ng/mL, respectively) than whites (21.7 ng/mL). Average vitamin D levels were lower in participants with dementia compared with those who had mild cognitive impairment or normal cognitive function.
Vitamin D levels can depend on factors such as dairy intake, sun exposure, and exercise. It has not been determined whether taking vitamin D supplements could slow down cognitive decline, but vitamin D supplementation has several benefits. Compared to placebo, supplementation with vitamin D increases response to antidepressants. A high percentage of children with major psychiatric disorders are vitamin D deficient, and it is also estimated that about 40% of adults in the US have a vitamin D deficiency.
The study by researcher Joshua W. Miller and colleagues was published in the journal JAMA Neurology in September.
