Researcher Amanda Roten reported at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry that adolescents who stopped heavy marijuana use showed improvements in multiple areas of learning and memory. These data support previous findings that pot can cause impairments in cognitive functioning, but that abstaining from the drug can bring about improvement relative quickly.
These data contrast with some others. A 2009 study by J. Jacobus et al. in the journal Pharmacology Biochemistry and Behavior suggested that some changes in brain structure resulting from marijuana use, such as decreases in cortical volume, can persist for one to three months following abstinence.
Madeline Meier, another researcher at the meeting, reported that 1,037 participants who used marijuana persistently from about age 13 to age 38 lost an average of 8 IQ points. Controlling for years of education and other potential confounds such as alcohol and drug use did not affect these findings. Moreover, Meier found that “cessation of cannabis use did not fully restore IQ among adolescent-onset cannabis users.”
Editor’s Note: The popular view that marijuana is a benign substance overlooks some key facts. The main pharmacological effect of pot is amotivational syndrome, causing apathy and lack of drive to participate in work, study, and other activities. Heavy use of pot doubles the risk of psychosis, and this risk is further increased if a user has a common genetic variation in the enzyme catechol-o-methlyl transferase (COMT), which metabolizes dopamine. The more efficient allele of COMT (known as val-56-val, identifying two valine amino acids) lowers frontal cortex dopamine more, and increases the risk of delusions and hallucinations. Marijuana alters brain structure and impairs memory. It may now be legal in some states, and while reducing penalties for smoking marijuana may be a good idea, this does not mean the drug is a harmless substance.
The moral of the story is that avoiding marijuana use in the first place, especially for people with bipolar disorder, should make it easier to get well and stay well. For current marijuana users, N-acetylcysteine (NAC, a nutritional supplement available without a prescription from health food stores) has been shown to help adolescents decrease marijuana use more than placebo.
In a huge study of Swedes, compared to offspring of young fathers (aged 20–24), offspring of older fathers (over age 45) are 24.7 times more likely to develop bipolar disorder. Older paternal age was also associated with other risks of mental disorders, such as autism, attention deficit hyperactivity disorder (ADHD), suicide attempts, substance abuse and psychosis, but the strongest finding was of a relationship with bipolar disorder.
Mutations that occur during the production of sperm may be responsible for the increased risk of illness in the offspring of older fathers.
The population-based cohort study published by Brian M. D’Onofrio et al. in the journal JAMA Psychiatry included all individuals born in Sweden between 1973 and 2001.
New research suggests that the ratio of cortisol to C-reactive protein (CRP), a marker of inflammation, may be a biomarker of depression that affects men and women differently. In women, lower ratios of cortisol to CRP were associated with more severe depression symptoms, including poor quality sleep, sleep disturbances, and decreased extraversion. In men, higher ratios of cortisol to CRP were associated with more daytime disturbance and greater anxiety. The study by E.C. Suarez et al. was published in the journal Brain, Behavior, and Immunity.
Further work must be done to confirm whether low cortisol and high inflammation predicts depression in women, while the opposite (high cortisol and low inflammation) predicts depression in men.
In the past there has been some concern that selective serotonin reuptake inhibitor (SSRI) antidepressants taken during pregnancy could increase an infant’s risk of cardiac problems. There was particular concern that the SSRI paroxetine could lead to right ventricular outflow tract obstruction, and sertraline could lead to ventricular septal defects. A 2014 study by KF Huybrechts et al. in the New England Journal of Medicine analyzed data from 949,504 women in a Medicaid system from three months before pregnancy until one month after delivery during the years 2000-2007.
Infants born to mothers who had taken antidepressants during their first trimester were compared to infants whose mothers had not taken antidepressants. In total, 6.8% or 64,389 women had used antidepressants in their first trimester.
While the rate of cardiac defects in newborns was greater among those mothers who had taken antidepressants (90.1 infants per 10,000 infants who had been exposed to antidepressants versus 72.3 infants per 10,000 infants who had not been exposed to antidepressants), this relationship diminished as confounding variables were removed. The relative risk of any cardiac defect after taking SSRIs was 1.25, but this decreased to 1.12 when restricted to only those mothers who were diagnosed with depression, and to 1.06 when the researchers controlled for things like depression severity. (All relative risk numbers were calculated with a 95% confidence interval.)
The researchers concluded that there is no substantial risk of increased cardiac defects in children born to mothers who took antidepressants during their first trimester.
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Rieva et al. reported that 60% of bipolar patients with comorbid alcohol abuse have attempted suicide, and 48% of bipolar patients with cocaine abuse have attempted suicide. Thus, both of these comorbidities deserve specific attention and treatment. Unfortunately there are currently no Federal Drug Administration–approved drugs for bipolar patients with these comorbidities. The most promising treatments, based on data in patients with primary addictions, are the nutritional supplement N-acetylcysteine and topiramate, which have both performed better than placebo in studies of alcohol and cocaine abuse disorders.
In a symposium at the 2014 meeting of the International College of Neuropsychopharmacology, four researchers shared insights on children who are at high risk for bipolar disorder because they have a parent with the disorder.
Researcher John Nurnberger has been studying 350 children of parents with bipolar disorder in the US and 141 control children of parents with no major psychiatric disorder, following the participants into adolescence. He found a major affective disorder in 23.4% of the children with parents who have bipolar disorder and 4.4% of the controls. Of the at-risk children, 8.5% had a bipolar diagnosis versus 0% of the controls.
Nurnberger found that disruptive behavior disorders preceded the onset of mood disorders, as did anxiety disorders. These diagnoses predicted the later onset of bipolar disorder in the at-risk children, but not in the controls. A mood disorder in early adolescence predicted a substance abuse disorder later in adolescence among those at risk.
In genome-wide association studies, the genes CACNA1C and ODZ4 are consistently associated with risk of bipolar disorder, but with a very small effect size. Therefore, Nurnberger used 33 different gene variants to generate a total risk score and found that this measure was modestly effective in identifying relative risk of developing bipolar disorder. He hopes that using this improved risk calculation along with family history and clinical variables will allow better prediction of the risk of bipolar onset in the near future.
Researcher Ann Duffy reported on her Canadian studies of children who have a parent with bipolar disorder and thus are at high risk for developing the disorder. In contrast to the studies of Nurnberger et al. and many others in American patients, she found almost no childhood onset of bipolar disorder before late adolescence or early adulthood. She found that anxiety disorders emerge first, followed by depression, and then only much later bipolar disorder. Bipolar disorder occurred with comorbid substance abuse disorders in only about 10-20% of cases in 1975, but substance abuse increased to 50% of bipolar cases in 2005. The incidence of comorbid substance disorder and the year at observation correlated strongly, indicating a trend toward increased substance abuse over the 30-year period.
Duffy found that having parents who were ill as opposed to recovered was associated with a more rapid onset of mood disorder in the offspring, usually in early adulthood. Duffy emphasized the need to intervene earlier in children of parents with bipolar disorder, but this is rarely done in clinical practice. Read more
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Booij reported that in humans, there is an interaction between adversity experienced during childhood, and an epigenetic variation in the short form of the serotonin transporter (5HT-T ss, or SLC6A4), which can influence hippocampal volume during depression.
Epigenetics refers to environmental influences on the way genes are transcribed. The impact of life experiences such as stress is not registered in DNA sequences, but can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment. When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.
Booij followed 33 children who had experienced some form of adversity at a young age until they were 15 or 16, examining methylation of the serotonin transporter in their T cells and monocytes compared to 36 children who had not experienced adversity during childhood. He found that in children who had experienced abuse in childhood, the degree of that abuse was correlated with methylation of the serotonin transporter and was inversely related to the volume of the hippocampus, as measured using magnetic resonance imaging (MRI). Thus, child abuse yields lasting epigenetic effects (methylation of the serotonin transporter) and has anatomical consequences in teenagers, as seen in smaller hippocampi. These data parallel converse findings by Joan Luby et al. published in the journal PNAS in 2012, in which increased maternal warmth directed toward a child aged 4-7 was associated with increased volume of the hippocampus several years later.
Korea, like the US, has a moderate incidence of childhood-onset bipolar disorder among children who are at high risk because they have a parent with bipolar disorder. In a recent study by Young-Sun Cho et al. presented at the 2014 meeting of the International College of Neuropsychopharmacology (CINP), 59 out of 100 children with a parent who had been diagnosed with bipolar disorder met the criteria for a mental disorder themselves.
Mood disorders were most common. Of the 59 children with mental disorders, 22 were diagnosed with bipolar disorder, and 16 were diagnosed with a depressive disorder. Others included four with attention deficit hyperactivity disorder (ADHD), four with an anxiety disorder, two with disruptive behavior disorders, one with a tic disorder, one with an autistic disorder, and one with schizophrenia and an anxiety disorder.
Editor’s Note: In contrast to studies in Germany, Switzerland, the Netherlands, and Canada, where few children are diagnosed with bipolar disorders (even among those who are at high risk because of a family history of bipolar disorder), 22% of high-risk children in Korea were diagnosed with bipolar disorder. This is comparable to or higher than rates at which high-risk children in the US are diagnosed with bipolar disorder. Studies from both the Bipolar Collaborative Network (in which this editor Robert Post is an investigator) and researcher Boris Birmaher et al. found that parents with bipolar disorder often had a variety of other disorders, such as anxiety, alcohol abuse, or substance abuse. These other illnesses also increase the risk of early-onset bipolar disorder in offspring, and this may account for the higher incidence of early-onset bipolar disorder among high-risk children in the US.
A decade ago the Federal Drug Administration (FDA) released several warnings that children, adolescents (ages 10–17), and young adults (ages 18-29) taking antidepressants were at increased risk for suicidal ideation and behavior. A recent study found that following these warnings, antidepressant use among adolescents, young adults, and adults dropped, and psychotropic drug poisonings (a validated measure of suicide attempts) increased among adolescents and young adults. Numbers of completed suicides did not change for any age group.
The decision to place the warnings on antidepressant packaging was somewhat controversial because it was based on studies that were not necessarily designed to measure suicide risk. The relationship between depression, medication, and suicide is complicated. Medication can improve mood, but patients may seek out medication because of pre-existing suicidal thoughts, and the medication may not reduce these in young people.
The reduction in antidepressant use that occurred after the warnings was accompanied by a drop in depression diagnoses in children and adults. Studies have suggested that the decreases in antidepressant were not accompanied by increases in other treatments, such as psychotherapy or atypical antipsychotics, among young people. Increased monitoring of patients was called for in the FDA’s box warning, but did not take place.
The study of the aftermath of the FDA warnings, published by Christine Y. Lu et al. in a 2014 article in the journal BMJ, used data from 11 insurance networks throughout the US. The researchers used an interrupted time series study design, which is used to show whether a policy causes an abrupt change in the expected slope of study outcomes. Data covered the pre-warning period (first quarter of 2000 to third quarter of 2003), the warning “phase-in” period (last quarter of 2003 to last quarter of 2004) and the post-warning period (first quarter of 2005 to last quarter of 2010). The study cohorts included around 1.1 million adolescents, 1.4 million young adults, and 5 millions adults per quarter.
Among adolescents, the previously upward trend in antidepressant use declined by 31.0% in the second year after the warnings, and psychotropic drug poisonings increased by 21.7% (a figure that was statistically significant for males). Poisonings by any drug increased by 13.9% in the second year after the warnings. After 2008, the downward trend in antidepressant use reversed, indicating that either the initial effects of the warning had worn off or that modifications to the warnings in May 2007, which encouraged patients and doctors to consider the risk of antidepressants alongside the risk of leaving mood disorders untreated, led to increased use.
Among young adults, the upward trend in antidepressant use declined by 24.3% in the second year after the warnings, and psychotropic drug poisonings increased by 33.7%, a statistically significant change for both male and female patients.
Among adults, to whom the warnings were not directed, antidepressant use decreased by 14.5% in the second year after the warnings.
The study by Yu et al. is the first to show that suicide attempts actually increased after the FDA warnings. The authors suggest that the increase in suicide attempts might be a consequence of undertreating mood disorders, since antidepressant use dropped simultaneously. The warnings and related media attention may have led to these unintended consequences, since media reports can sometimes be oversimplified.
Type 2 diabetes can damage the brain, particularly by reducing volume of the hippocampus, and frequently occurs in patients with bipolar disorder. A recent study of patients with bipolar disorder and abnormal glucose metabolism showed that patients with bipolar disorder who also had insulin resistance, glucose intolerance, or type 2 diabetes had smaller hippocampi than both patients with bipolar disorder and normal glucose function and normal control participants without a psychiatric disorder. In those with bipolar disorder and glucose abnormalities, age was associated with lower hippocampal volume to a greater extent than in bipolar patients with normal glucose function.
In the study, published by Tomas Hajek et al. in the journal Neuropsychopharmacology, not only did diabetes or prediabetes reduce the size of the hippocampus, but also reduced gray matter in the cerebral cortex, including the insula.
The researchers hope that treating diabetes, or possibly even its initial symptoms, more effectively may prevent these gray matter losses and slow brain aging in patients with bipolar disorder.