Early Cannabis Use and BDNF Gene Variant Increase Psychosis Risk
Normal variations in genes can affect risk of mental illness. One gene that has been implicated in psychosis risk is known as BDNF. It controls production of brain-derived neurotrophic factor, a protein that protects neurons and is important for learning and memory. Another important gene is COMT, which controls production of the enzyme catechol-O-methyltransferase, which breaks down neurotransmitters such as dopamine in the brain.
Several forms of these genes appear in the population. These normal variations in genes are known as polymorphisms. Certain polymorphisms have been linked to disease risk. A study by Anna Mané and colleagues published in the Journal of Psychiatric Research in 2017 explored links between COMT and BDNF polymorphisms, cannabis use, and age at first episode of psychosis.
Mané and colleagues found that among 260 Caucasians being treated for a first episode of psychosis, the presence of a BDNF polymorphism known as val-66-met and a history of early cannabis use were associated with younger age at psychosis onset.
The val-66-met version of BDNF occurs in 25-35% of the population. It functions less efficiently than a version called val-66-val.
The researchers also found that males were more likely to have used cannabis at a young age.
Editor’s Note: In the general population, marijuana use doubles the risk of developing psychosis. Previous data had indicated that the risk was higher for those with a COMT polymorphism known as val-158-val that leads to more efficient metabolism of dopamine in the prefrontal cortex. The resulting deficits in dopamine increase vulnerability to psychosis compared to people with the val-158-met version of the COMT gene.
The new study by Mané and colleagues suggests that a common form of BDNF may be associated with an earlier onset of psychosis. Bottom line: Pot is dangerous for young users and can induce psychosis, particularly in people at genetic risk. Pot may be legal in many places, but heavy use in young people remains risky for mental health and cognitive functioning.
The company Genomind offers genetic testing for BDNF and COMT variants as part of a routine panel.
Recent Birth Cohorts May Have More Depression and Bipolar Disorder
In medicine, the ‘cohort effect’ describes the idea that more recent birth cohorts have an increased incidence and younger age of onset of their illness. A 2016 article by this editor (Robert M. Post) and colleagues in the Journal of Clinical Psychiatry presented evidence that younger patients with bipolar disorder have an earlier age of onset of bipolar disorder and more relatives with mood disorders than older patients with bipolar disorder.
The research was carried out by the Bipolar Collaborative Network in four US cities (Dallas, Cincinatti, Los Angeles, and Bethesda) and three northern European ones (Utrecht, Freiburg, and Munich). On both continents, patients born more recently had an earlier age of onset of their bipolar disorder. Younger patients also had parents and grandparents with a greater incidence of depression, bipolar disorder, and alcohol and substance abuse compared to older patients.
Editor’s Note: Other researchers have found evidence of a cohort effect for unipolar depression, substance abuse, and attention-deficit hyperactivity disorder (ADHD). The data indicate that childhood onset of psychiatric illnesses may be becoming more common. Research aimed at earlier detection and treatment is needed to reverse these trends.
Children of Bipolar Parents in US More Ill than Those in the Netherlands
New research shows that bipolar disorder risk is higher in the US than in the Netherlands. At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researchers Manon Hillegers and Esther Mesman described a study in which they compared the offspring of mothers with bipolar disorder in the US to those in the Netherlands. The offspring ranged in age from 10–18.
In the US, the mothers had, on average, an earlier age of onset, more substance abuse comorbidity, and were more likely to have been diagnosed with bipolar II disorder. Among the US offspring, 66% had been diagnosed with a psychiatric illness compared to 44% of the Dutch offspring. This included significantly higher rates of anxiety, ADHD, and disruptive behavior disorders in the US offspring. Among the offspring who had been diagnosed with a mood disorder, 80% of those in the US had other additional psychiatric disorders, but only 34% of the Dutch did. Bipolar disorder is more rare among children under the age of 12 in the Netherlands compared to the US.
Dutch children and adolescents were typically treated with lithium and with only one drug at a time. In the US, lithium is less widely used, and simultaneous treatment with several medications (usually including atypical antipsychotics) is common.
Editor’s Note: The research by Hillegers and Mesman replicates research by this editor (Robert M. Post) and colleagues that compared bipolar disorder incidence and severity in the US, Germany, and the Netherlands. Other comparisons have been made between the US and Europe. A 2014 article by Frank Bellivier and colleagues in the World Journal of Biological Psychiatry also showed that bipolar disorder onset occurs earlier in the US than in 10 different European countries, while Bruno Etain and colleagues found that bipolar disorder onset occurs earlier in the US than in France in a 2012 article in the Journal of Clinical Psychiatry.
Together this research shows that bipolar disorder is more serious in the US than in a number of European countries. Two-thirds of adults with bipolar disorder report that their illness began in childhood or adolescence. Most of these cases are not properly diagnosed or treated. A concerted effort must be made by the medical establishment and healthcare policymakers in the US to provide better and earlier treatment of bipolar illness.
Link Between Childhood Trauma and Difficult Course of Bipolar Disorder Clarified
A collaboration between Norwegian and French researchers led by Bruno Etain has clarified the pathway by which childhood trauma is linked to worse outcomes among people with bipolar disorder. The researchers, who presented their work in a poster at the 2015 meeting of the Society of Biological Psychiatry, replicated earlier findings by this editor (Robert Post) that patients who experienced trauma as a child had a more adverse course of bipolar disorder. Etain and colleagues found a link between childhood trauma and an earlier age of onset of bipolar disorder, rapid cycling, suicide attempts, and cannabis misuse.
The researchers identified more than 550 patients with bipolar disorder, who answered questionnaires about their history of bipolar disorder and childhood trauma. Their DNA was also analyzed, and the researchers found that the effect of childhood trauma on age of onset was mediated by the presence of common genetic variants in proteins related to stress (the serotonin transporter) and immune function (Toll-like receptors). They also found that the traits of mood lability (or moodiness) and impulsivity mediated the effects of trauma on clinical outcomes.
The lasting epigenetic effects of child maltreatment and adversity noted in the above abstract are consistent with a large literature showing more epigenetic effects in these individuals than in controls. While genetics are important, the impact of the environment is also substantial.
Verbal Abuse in Childhood, Like Physical and Sexual Abuse, Linked to Earlier Onset and More Difficult Course of Bipolar Disorder
Earlier research has shown that childhood adversity is linked to earlier age of onset of bipolar disorder and more difficult course of illness. Physical and sexual abuse are associated with both earlier age of onset and more difficulties such as anxiety disorders and substance abuse. Now, new research by this editor (Robert M. Post) and colleagues links verbal abuse (even in the absence of physical and sexual abuse) to earlier onset of bipolar disorder and to more severe and complicated course of illness.
The study, published in the journal Bipolar Disorders, was based on the self-reports of 634 adult outpatients with bipolar disorder at four sites in the US. These participants were interviewed about their history of illness and the frequency of adverse events they experienced in childhood, adolescence, and adulthood, including physical, sexual, and verbal abuse. Twenty-four percent of these participants reported having experienced verbal abuse occasionally or frequently in childhood, but not other forms of abuse, while another 35% had a history of verbal abuse as well as physical or sexual abuse, for a total of 59% with a history of verbal abuse.
The greater the frequency of verbal abuse in childhood, the earlier the average age of onset of bipolar disorder. Participants with no history of abuse had a mean age of onset of 20.6 years, but verbal abuse by itself reduced the mean age of onset to 16.5 years, and verbal abuse plus sexual abuse reduced the mean age of onset to 15.3 years. (The mean age of onset for participants who experienced sexual abuse alone was 17.5 years.) It was impossible to determine the combined effect of verbal and physical abuse because verbal abuse was almost always present when physical abuse occurred. For the 14% of the participants who had experienced verbal, physical, and sexual abuse in childhood, the mean age of onset of bipolar disorder was 13.1 years.
Those who were verbally (but not physically or sexually) abused in childhood had more anxiety disorders, drug abuse, and rapid cycling than those who were not abused, but not more alcohol abuse. Those who were verbally abused also showed increasing severity of illness, including increased frequency of cycling.
Genetics can also play a role. Having a parent with a mood disorder also contributed to an earlier age of onset of bipolar disorder.
Editor’s Note: Researcher David J. Miklowitz and colleagues have shown that family focused therapy (FFT), which emphasizes illness education and communication enhancement within the family, is more effective than treatment as usual for children with a family history of bipolar disorder and a diagnosis of depression, cyclothymia, or bipolar not otherwise specified (BP NOS).
FFT was particularly effective in reducing symptoms in children from families with high expressed emotion, suggesting that this kind of family-based intervention could reduce levels of verbal abuse.
It Appears Antidepressants and Stimulants Do Not Hasten the Onset of Bipolar Disorder in Children
It is a common clinical assumption that early treatment of depression with antidepressants may be a risk factor for hastening the onset of subsequent bipolar disorder. Accumulating evidence indicates that this may not be the case. At a symposium at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) researchers in the field shared the latest findings on antidepressant-induced manic symptoms in youth (AIMS), and there was a surprising consensus that antidepressants do not increase the risk of subsequent bipolar disorder onset when used for the treatment of childhood-onset depression.
Symposium speakers Kiki Chang, Melissa P. DelBello, and David Axelson all agreed that antidepressant treatment was not a risk factor for bipolar disorder.
DelBello shared data from a study in which antidepressant treatment was associated with a lower likelihood of mania during follow-up. Antidepressants were typically discontinued if the patient switched into manic-like symptoms or increased irritability or aggression. These symptoms tended to occur in children who were younger, who had a smaller volume of the amygdala, and in those who had a positive family history for bipolar disorder in first-degree relatives.
Axelson indicated that his data represented only a “bird’s-eye view,” but suggested that antidepressants do not cause or hasten the onset of bipolar disorder when used for treating depression in children. He also reported results from a naturalistic study in which stimulants also did not increase the risk of subsequent bipolarity.
Several of the presenters discussed how they would treat children with an early-onset depression when there is a family history of bipolar disorder. Read more
Earlier Age of Onset of Bipolar Illness in the US Compared to Europe
As we have previously reported in the BNN, the Bipolar Collaborative Network (including this editor Robert M. Post) found that patients from 4 sites in the United States had significantly earlier ages of onset of their bipolar illness compared to 3 sites in the Netherlands and Germany). These findings have been replicated by Frank Bellivier et al., who used a broader sample of European participants.
Bellivier’s research group studied two large samples of bipolar I patients from the US (n= 2275) and from 14 countries in Europe (n= 3616). The researchers found 3 different distributions of age of onset, and patients from the US had a greater representation in the early age of onset subgroup. Sixty-three percent of the sample from the US fell into the early-onset group versus 25% of those from Europe. The mean age of onset of the early-onset subgroup was significantly lower in the US sample (14.5 +/- 4.9 years) than in the European sample (19 +/- 2.7 years).
Editor’s Note: It is time that we took these geographical differences in the frequency of early age of onset of bipolar disorder seriously. While some controversy has surrounded the diagnosis of bipolar illness in children, it becomes increasingly important to recognize that this bona fide, well-diagnosed illness is more common in children from the US than from many other countries. Affected children should have careful clinical evaluation and, if the diagnosis warrants, definitive treatment. This should include both psychoeducational approaches; focused psychotherapies, including the family-focused therapy pioneered by Dave Miklowitz; and psychopharmacological intervention. When this kind of combined treatment is implemented, young patients who are treated with lithium, another mood stabilizer, or an atypical antipsychotic do much better than those who do not receive these consensus-based treatments.
Treatment algorithms for children of different ages with bipolar disorder are still being developed. However, it appears that in young and very young children, the atypical antipsychotics are often more effective than lithium or valproate monotherapy, as suggested in recent large randomized clinical trials. Initiating appropriate treatment is extremely important, since the duration of the untreated interval (that is, the time from illness onset to first treatment) is directly related to worse outcomes in adulthood. The longer the duration of untreated illness, the greater the severity of depression, the longer the duration of depression, and the greater the number of episodes an adult experiences.
As might be expected from the earlier age of onset of bipolar disorder, US patients also have a higher incidence of the major vulnerability factors for early onset—more genetic vulnerability (parents with bipolar disorder), more childhood stressors, and more stressors in the year prior to illness onset. Patients from the US also had a variety of other poor prognosis factors, including a higher degree of anxiety comorbidity, alcohol and substance abuse problems, a higher incidence of having more than 20 episodes over their lifetime, and a higher incidence of rapid cycling. All of these characteristics combine to produce worse outcomes in adult patients from the US compared to those from Europe. Earlier and more judicious treatment of the illness in the United States is needed to help ward off this more pernicious course of bipolar illness.
Sunlight Could Be a Geographic Risk Factor for Pediatric-Onset Bipolar Disorder
A number of factors appear to be associated with age of onset of bipolar disorder. Several studies have replicated the finding that those who experienced some adversity in childhood and who have a parent or parents with bipolar disorder are at increased risk for earlier onset of the illness. These risk factors are more prevalent in the US than in many western European countries, and considerable data support the observation that the age of onset of bipolar illness is earlier in the United States than in several European countries. However, childhood onsets of the illness are prevalent in Turkey and in Norway.
Researcher Mike Bauer raises another possibility in an abstract presented at the 5th Biennial Conference of the International Society for Bipolar Disorders. He examined the association between age of onset and sunlight in the environment in 24 different sites in 13 different countries. Solar insolation refers to the amount of electromagnetic energy striking the surface of the earth. Bauer found that larger springtime maximum monthly increases in solar insolation were associated with younger ages of onset of bipolar disorder (p= 0.006). These calculations were derived from NASA Surface Meteorology and Solar Energy databases for each location. The largest maximum monthly increases in solar insolation occurred in varied climates, including in Norway, Chile, and arid parts of California.
