Lithium inhibits the enzyme glycogen synthase kinase 3, which has been implicated in dementia. To study whether lithium may prevent cognitive decline, researchers led by Tobias Gerhard looked at the medication histories of patients with bipolar disorder who were 50 years of age or older. In their article published in the British Journal of Psychiatry, those patients who had taken lithium 301–365 days out of the previous year had substantially lower risk of dementia than those who had not taken lithium during that time. Patients who had 300 or fewer days of lithium use did not have a significant reduction in dementia risk, nor did patients who were prescribed anticonvulsant drugs.
Editor’s Note: These data are consistent with those of Lars Kessing and colleagues, which suggest that patients in Denmark who renewed their lithium prescriptions were less likely to receive a diagnosis of dementia in old age.
Relatively little attention has been paid to the children of a parent with bipolar disorder, who are at risk not only for the onset of bipolar disorder, but also anxiety, depression, and multiple other disorders. These children deserve a special focus, as on average 74.2% will receive a major (Axis 1) psychiatric diagnosis within seven years.
New research published by David Axelson and colleagues in the American Journal of Psychiatry describes a longitudinal study comparing children who have a parent with bipolar disorder to demographically matched children in the general public. Offspring at high risk for bipolar disorder because they have a parent with the disorder had significantly higher rates of subthreshold mania or hypomania (13.3% versus 1.2%) or what is known as bipolar disorder not otherwise specified (BP-NOS); manic, mixed, or hypomanic episodes (9.2% versus 0.8%); major depressive episodes (32.0% versus 14.9%); and anxiety disorders (39.9% versus 21.8%) than offspring of parents without bipolar disorder. Subthreshold episodes of mania or hypomania (those that resemble but do not meet the full requirements for bipolar disorder in terms of duration) were the best predictor of later manic episodes. This finding was observed prospectively, meaning that patients who were diagnosed with manic episodes during a follow-up assessment were likely to have been diagnosed with a subthreshold manic or hypomanic episode during a previous assessment.
The study included 391 children (aged 6–18) of at least one bipolar parent, and compared these to 248 children of parents without bipolar disorder in the community. The participants took part in follow-up assessments every 2.5 years on average, for a total of about 6.8 years. Each follow-up assessment included retrospective analysis of symptoms that had occurred since the previous assessment.
In addition to having more subthreshold manic or hypomanic episodes; manic, mixed, or hypomanic episodes; and major depressive episodes, the high-risk children also showed more non-mood-related axis 1 disorders, including attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders, and anxiety disorders than the children of parents without bipolar disorder. Axelson suggested that monitoring for these symptoms may help with early identification and treatment.
Children with a bipolar parent were diagnosed with bipolar spectrum disorders at rates of 23% compared to 3.2% in the comparison offspring. Mean age of onset of mania or hypomania in the high-risk offspring was 13.4 years. Of those offspring who had a manic episode, more than half had the episode before age 12, with the earliest occurring at age 8.1.
Compared to previous studies of children of parents with bipolar disorder, this study found that the mean age of onset of manic or hypomanic episodes was younger, possibly because other studies did not include young children. Another new finding was that major depressive episodes were risk factors for mania and hypomania but did not always precede the onset of mania or hypomania in the high-risk offspring.
Parents of children who are at high risk for developing bipolar spectrum disorders should be aware of the common precursors to mania—subthreshold manic or hypomanic symptoms and non-mood disorders—and make sure that clinicians assess for these symptoms and differentiate them from the symptoms of depression or other disorders.
Editor’s Note: In Axelson’s study, 74.2% of the offspring of a bipolar parent suffered a major (Axis I) psychiatric disorder. However, 48.4% of the offspring from the comparison group of community controls also had an Axis 1 psychiatric disorder. These high rates of illness and dysfunction indicate the importance of monitoring a variety of symptom areas and getting appropriate evaluation and treatment in the face of symptoms that are associated with impairment in both high risk children and in the general population.
One way of doing this is for parents to join our new Child Network, a study collecting information about how children at risk for bipolar disorder or with symptoms of bipolar disorder are being treated in the community and how well they are doing. Parents rate their children on a weekly basis for depression, anxiety, ADHD, oppositionality, and mania-like symptoms. Parents will be able to produce a longitudinal chart of their children’s symptoms and response to treatment, which may assist their child’s physician with early detection of illness and with treatment. See here for more information and to access informed consent documents.
Studies in Japan, Austria, and Texas have reported that trace amounts of lithium in drinking water are associated with lower suicide rates. A new study seeks to clarify these findings by removing any statistical factors other than lithium levels that could produce these results.
The study, published in the Journal of Clinical Psychiatry, collected 434 lithium samples in drinking water over three years, and compared these with suicide rates in the population of 274 municipalities of Kyushi Island in Japan.
The researchers, led by Nobuyoshi Ishii, then controlled for size of population, proportion of elderly people, proportion of one-person households, proportion of people with a college education or more, proportion of people engaging in primary industry, overall unemployment rates, annual marriage rates, annual mean temperature, and annual savings in per person in Japan’s popular postal bank. In places with slightly higher trace levels of lithium in drinking water, there was a lower rate of suicides in men. Suicide rates for women and overall were not significantly associated with lithium levels.
A new study from Finland suggests that low vitamin D levels in childhood and adolescence can predict atherosclerosis, or hardening of the arteries, in adulthood. The study, by Markus Juonala and colleagues in the Journal of Clinical Endocrinology & Metabolism, included 2,148 people whose vitamin D levels were measured at ages 3–18. They were checked for atherosclerosis at ages 30–45. Those participants with the lowest levels of vitamin D in their youth were at much higher risk for thickened arteries as adults. The finding was independent of other cardiovascular risk factors such as smoking, high blood pressure, poor eating, lack of exercise, and obesity.
Editor’s Note: While it is not yet clear if low vitamin D levels directly cause the development of atherosclerosis, it is important to maintain sufficient vitamin D in childhood for a host of reasons, including strong bones. Children with sufficient vitamin D levels are more likely to have normal moods and behavior than those deficient in vitamin D.
New research shows that expressions of maternal warmth following corporal punishment do not reduce children’s anxiety, and may even increase it.
The study by Jennifer E. Lansford and colleagues was published in the Journal of Clinical Child & Adolescent Psychiatry. The researchers interviewed over a thousand children aged 7–10 and their mothers about what type of physical punishment occurs in their family, and about anxiety and aggression in the children. They followed up again after one and two years. The study took place in eight countries: China, Colombia, Italy, Jordan, Kenya, the Philippines, Thailand, and the United States.
In general, corporal punishment increased anxiety in the children, while maternal warmth decreased it. How warmth and physical punishment interacted depended on the country. Anxiety increased over time in families where the mothers were high on both corporal punishment and warmth. Lansford and colleagues wrote that it might be “simply too confusing and unnerving for a child to be hit hard and loved warmly all in the same home.”
The researchers suggest that parents use nonphysical ways to promote desirable behavior in their children, including putting younger children in time-out and requiring teenagers to participate in activities that help others.
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.
Prazosin, an alpha-1 adrenoreceptor antagonist, has been found to be effective at reducing symptoms of post-traumatic stress disorder (PTSD), including nightmares. Researchers led by Murray Raskind hypothesized that there may be a link between blood pressure and response to prazosin, since resting blood pressure can be used to measure alpha-1 adrenoreceptor responsiveness. In a study of active duty combat soldiers with PTSD, higher resting blood pressure and smaller drop in blood pressure when going from lying down to standing up predicted a better response to prazosin.
The researchers believe that blood pressure can be used to estimate the central nervous systems’s responsiveness to norepinephrine, which prazosin blocks. In patients with PTSD who received placebo instead of prazosin, blood pressure did not predict improvement. Raskind and colleagues hope to be better able to predict response to prazosin in PTSD by measuring patients’ baseline blood pressure.
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.
Several genes have previously been implicated in bipolar illness. In a recent study, researchers at the Mayo Clinic, led by Paul Croarkin, compared variations in three genes (CACNA1C, ANK3, and ODZN) across 69 children aged 6–15 with mania, a 776-person control group from the Mayo Biobank database, and 732 adults with bipolar disorder (some with onset in childhood and adolescence and some with onset in adulthood, also from the Biobank). All participants were Caucasian, to minimize confounding by population stratification. The researchers found that the minor allele of rs10848632 in CACNA1C was associated with childhood onset of bipolar disorder. The haplotype (or sequence of nucleotides) T-G-G-T was the one associated with risk. Genetic risk scores were also associated with early onset of illness.
Editor’s Note: In research by Michael McCarthy and colleagues, CACNA1C has been linked to abnormal circadian rhythms in bipolar disorder and to responsiveness to lithium treatment. Together, these data suggest the importance of studying the calcium channel blocker nimodipine (which blocks calcium influx through CACNA1C) in childhood-onset bipolar disorder. A 1999 case report by Pablo A. Davanzo and colleagues described a teenager with ultra rapid cycling bipolar disorder (multiple mood switches/day) that did not respond to a host of conventional medications, who improved dramatically on nimodipine, reaching remission. This author (Robert M. Post) has also seen confirmed responsivity in adults with rapid cycling bipolar disorder (reported in the 2008 book Treatment of Bipolar Illness: A Casebook for Clinicians and Patients, by Post and Gabriele S. Leverich).