Better One-Year Clinical Outcomes After Four Weeks of Theta Burst Stimulation for PTSD Than After Two Weeks
In a 2019 article in the journal Neuropsychopharmacology, Nicholas J. Petrosino and colleagues described findings from one year of follow-up with veterans suffering from post-traumatic stress disorder (PTSD) who received intermittent theta burst transcranial magnetic stimulation (iTBS) in a four-week crossover study.
In the first two weeks of the study, half of the 50 participants (who were mostly male and had an average age of 51) received iTBS while the others were given a sham procedure. Then all the participants received iTBS on an open (non-blind) basis for two more weeks.
At one month, those who had received four total weeks of iTBS had better outcomes than those who had received only two weeks of active iTBS. These results were published in the American Journal of Psychiatry in 2019 in an article by Noah S. Philip and colleagues.
The researchers went on to look at longer-term outcomes, namely time until relapse (a major event such as a re-hospitalization or suicide). After one year, those who received four weeks of iTBS went 9 to 11 months without relapsing (296.0 days ± 22.1), while those who received only two weeks of iTBS went 5 to 7 months before relapsing (182.0 days ± 31.9).
It seems that more iTBS may be better than less iTBS for PTSD in both the short and long term.
Cannabis Use in Adolescence Linked to Depression and Suicidality in Young Adulthood
In a meta-analysis published in the journal JAMA Psychiatry in 2019, researcher Gabriella Gobbi and colleagues analyzed findings from 11 studies including a total of 23,317 participants and found that cannabis use in adolescence (before age 18) was associated with a significantly increased risk of depression, suicidality, and suicide attempts in young adulthood (between 18 and 32 years of age).
The researchers did not find a link between cannabis use and anxiety.
Editor’s Note: Cannabis use is not as harmless as many teens may believe.
In Animal Model, Long-Term THC Exposure Interferes with Cortical Control of the Nucleus Accumbens
In an article in the journal Biological Psychiatry, researchers Eun-Kyung Hwang and Carl R. Lupica reported that in rats, long-term use of THC (tetrahydrocannabinol) weakens input from the cortex to the reward area of the brain, the nucleus accumbens (NAc). Long-term THC use also strengthens connections to the NAc from emotional control (limbic) regions, such as the basolateral amygdala and ventral hippocampus. Hwang and Lupica reason that this shift from cortical control of the NAc to limbic control likely contributes to the cognitive and psychiatric symptoms associated with cannabis use.
Editor’s Note: Street marijuana largely contains THC rather than CBD, the beneficial, anxiety-reducing component of cannabis. Cannabis products are being decriminalized, but it is important to remember that those with THC are linked to cannabis use disorder and increased susceptibility to psychiatric illness. Patients with bipolar disorder who use marijuana also have a more adverse course of illness than those who do not use it.
One Hit of THC Tied to Psychotic Symptoms in Adults with No History of Mental Illness
In a meta-analysis published in the journal Lancet Psychiatry, researcher Guy Hindley and colleagues reported that in otherwise healthy adults, a single dose of THC (equivalent to smoking one joint) produced transient psychotic symptoms.
The meta-analysis included 9 studies with a total of 196 participants. The researchers included studies in which participants took tetrahydrocannabinol (THC, the psychoactive component in marijuana) or placebo, and psychotic symptoms were measured.
The researchers also sought out studies in which cannabidiol or CBD was given in combination with THC, but there were not enough of these to derive significant results. CBD does not produce schizophrenia-like symptoms on its own, and some think it may have anti-psychotic effects, but findings on this topic have been mixed.
Taking THC had a large effect size on total psychotic symptoms and negative symptom severity (such as emotional flatness or avolition). It also had an effect on positive symptom severity (for example, hallucinations or delusions). The effects were larger with intravenous administration than with inhaled administration, and tobacco smokers had less severe positive symptoms.
Of four studies that included CBD, only one found that CBD reduced THC-induced psychotic symptoms.
Editor’s Note: Longer-term use of marijuana in adolescents and young adults doubles the risk of psychosis, and other data suggest that chronic use of marijuana at high doses can be associated with new onset of a diagnosis of bipolar disorder or schizophrenia. As cannabis products are being decriminalized around the US, it is worth noting some of the risks of marijuana use, particularly marijuana with a high level of THC.
Dr. Post’s Recommendations For Treating Youth with Bipolar Symptoms
Our Editor-in-Chief, Dr. Robert M. Post, shares his personal recommendations for the treatment of children and adolescents with symptoms of bipolar disorder. Remember: Patients and family members must consult a physician about all information conveyed in the BNN. With the exception of lithium, none of the medications or supplements discussed above have been approved by the US Food and Drug Administration for use in children under 10. The findings reported here are in many cases preliminary and cannot be taken as recommendations based on the short summaries provided here. All treatment decisions must be made in conjunction with a patient’s treating physician, who is solely responsible for initiating any treatment discussed in the BNN or elsewhere.
In symptomatic and functionally impaired children, medication is almost always necessary. Many treating psychiatrists would start with an atypical antipsychotic, since there is clear evidence of the efficacy of such treatments. The side effects profile should be considered, as there is a considerable difference in the degree of weight gain associated with different atypical antipsychotics. The largest weight gains occur with olanzapine and clozapine, intermediate gains occur with aripiprazole and quetiapine, and the least gains occur with ziprasidone and lurasidone (and the latter has the advantage of being approved by the US Food and Drug Administration for the treatment of bipolar depression in children who are 10–17 years old). The addition of the diabetes drug metformin to decrease weight gain in people taking atypical antipsychotics is increasingly common.
The addition of an anticonvulsant medication (such as lamotrigine, carbamazepine/oxcarbazepine, or valproate) or the mood stabilizer lithium may be needed, as multiple studies indicate that combination treatment is typically needed in children (as in adults) to achieve a more complete response or remission.
Interestingly, oxcarbazepine was effective in younger but not older children with mania in a previous placebo-controlled study by Karen D. Wagner and colleagues published in the American Journal of Psychiatry in 2006.
Conversely, in a 2015 article in the journal JAACAP, researcher Robert Findling reported that in a placebo-controlled study of lamotrigine, 13–17-year-olds responded better than 10–12-year-olds.
Lithium treatment deserves consideration in children with classical presentations of bipolar disorder and those who have family members who have responded well to lithium treatment.
Lithium has the benefit of improving the white matter abnormalities seen in the brains of patients with early-onset bipolar disorder. Hafeman and colleagues reported in a 2019 article that children with bipolar disorder who were treated with lithium had better long-term results upon follow up than those treated with atypical antipsychotics or anticonvulsants.
There is much less scientific consensus about other adjunctive treatments for young people with additional bipolar symptoms and comorbidities, but this editor often uses several. Vitamin D3 is often low in children with psychiatric illness, and may improve mood and cognition.
The antioxidant N-acetylcysteine (NAC) helps depression, anxiety, and irritability, and is effective at treating habit-related behaviors such as trichotillomania (compulsive hair-pulling), obsessive-compulsive disorder (OCD), and drug use, including specifically reducing marijuana use in adolescents. A typical dose is 500–600 mg capsules, one capsule twice a day for one week, then two capsules in the morning and two in the evening thereafter.
Folate or folic acid may enhance antidepressant effects and those of lithium. In patients who have a particular low-functioning variant of a gene known as MTHFR, L-methylfolate is required instead of folate.
The widely-used supplement acetyl-L-carnitine (ALC) is poorly studied in children, but deserves consideration as a supplemental treatment for patients with histories of childhood adversity. In adults with depression, blood levels of ALC may be low, particularly in those with an early onset of bipolar symptoms and a history of childhood adversity (see a 2018 article by Carla Nasca in the journal PNAS). There is a modicum of evidence that ALC produces antidepressant effects in adults. ALC may also sensitize insulin receptors and normalize blood pressure.
There is increasing evidence of the role of inflammation in depression, mania, post-traumatic stress disorder (PTSD), and schizophrenia. Checking for abnormalities in inflammatory markers in the blood (especially Il-6 and CRP) may point the way to appropriate therapy with anti-inflammatory drugs such as minocycline (100 mg twice a day) or celecoxib (200 mg twice a day) in patients who do not respond fully to first-line medications.
Treating Symptoms of Bipolar Disorder in Children at Risk
At the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, one symposium was devoted to new research on predicting onset of bipolar disorder in children who have a family history of the disorder. Below are some of the findings that were reported. See previous articles for more on this symposium.
Sub-Threshold Bipolar Disorder or BP-NOS is Impairing and Requires Treatment
In research Danella M. Hafeman’s research, children with BP-NOS were almost as ill as those with bipolar I disorder (BP I) and experienced equal incidence of suicide attempts, substance abuse, other simultaneous psychiatric diagnoses, and functional impairment, clearly indicating that they were in need of treatment. About 50–65% of participants with a family history of bipolar disorder converted from diagnoses of BP-NOS to BP I, while those with BP-NOS and no family history of bipolar disorder converted to BP I at rates of about 30–48%.
Several presenters presented data showing that those with sub-threshold bipolar disorder had severe functional impairment, a high incidence of suicide attempts, and additional diagnoses including ADHD, conduct disorder, anxiety, and substance abuse.
Diagnostic Tool Can Help Identify Children with Bipolar Disorder
Researcher Amy Yule indicated that a tool called the Child Behavior Checklist (CBCL) is effective for making the diagnosis of conduct disorder in children with bipolar disorder, while researcher Joseph Biederman showed that the CBCL can also identify children with bipolar I disorder and is faster and simpler to use in clinical practice than are full structured diagnostic interviews.
Researcher Janet Wozniak found that there was a high incidence of bipolar disorder in first-degree relatives of children with sub-threshold bipolar disorder, suggesting the validity of identifying youth with sub-threshold bipolar symptoms.
As discussed above, there is also a high incidence of children with BP-NOS progressing to a full diagnosis of bipolar I or II disorder (as many as 50% of those with a family history of bipolar disorder). However, the point is not to wait for the negative effects of a full diagnosis before beginning treatment: BP-NOS itself requires treatment.
Discussion and Emerging Consensus on Treatment, Particularly of BP-NOS
Experts in the field agree that family focused therapy (FFT) or its equivalent is a crucial first step to treatment of depression, cyclothymia (cycling between depressive and hypomanic symptoms that do not meet the threshold for a diagnosis of bipolar disorder), and BP-NOS in children who are at high risk of bipolar disorder because they have a parent with the disorder.
A second area of agreement is that young people with BP-NOS should have a positive therapeutic coach (which could be a treating physician if no other person is available), who can emphasize important early steps that can improve short- and long-term health. These include maintaining a healthy diet, exercise (such as participation in school sports), the practice of mindfulness and/or meditation, and playing and practicing a musical instrument. Parental support is also critical to decreasing negative expressed emotion.
Early interventions and wellness programs that focus on these factors are part of the successful Vermont Family Based Approach, led by psychiatrist Jim Hudziak, Director of the Vermont Center for Children, Youth, and Families. Since programs like these are not widely available, treating physicians must create their own teams to provide such encouragement, and teach families how to find or establish such a support network.
School teachers should be engaged in support of the treatment of a child with bipolar disorder. Teachers should pay special attention to behavioral symptoms of an ill child. It also may be important for physicians to connect directly with teachers to ensure that children recovering from an episode of bipolar disorder receive extra time for assignments, a decreased academic burden, and other support. Researcher Manon H. Hillegers indicated that intervention by a physician will likely be listened to and believed, while parental requests alone to teachers or to the school may go ignored.
Hillegers, like researcher Lakshmi Yatham and colleagues, have found that it takes a year after a first manic episode for a child’s cognition to return to normal, so that special allowances should be made for such students even many months after they have recovered from their mania.
Predicting Onset of Bipolar Disorder in Children at High Risk: Part II
At the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, one symposium was devoted to new research on predicting onset of bipolar disorder in children who have a family history of the disorder. Below are some of the findings that were reported.
Early Recognition and Treatment Needed
Researcher Boris Birmaher, the discussant of the symposium, described a sample of 100 children between the ages of 2 and 5; half had a parent with bipolar disorder, and these were compared to community controls. Those children who had a parent with bipolar disorder had a high incidence of attention-deficit hyperactivity disorder (ADHD) and ODD, and their conversion to a diagnosis of bipolar disorder was predicted by early age of onset of bipolar disorder in the parent (again) and by the presence of family conflict.
Birmaher emphasized that a delay before children and adolescents with bipolar disorder received their first treatment for the illness had terrible effects—more suicide attempts, completed suicides, substance abuse, and school failure. Birmaher urged early recognition of bipolar disorder and adequate treatment in order to delay onset of the disorder and to render its course more benign.
Childhood-Onset Bipolar Disorder Incidence
Researcher Anna Van Meter and colleagues showed that the incidence of bipolar disorder in children is about 2% worldwide. Researcher Kathleen Merikangas and colleagues report that 80% of adolescents with a bipolar spectrum disorder are not receiving any kind of treatment. Researcher Ben Goldstein indicated that about 50% of those with a full diagnosis of bipolar disorder receive treatment in Canada (where such treatment is cost-free).
Delayed Treatment Leads to Compounding Challenges
Since longer intervals without treatment predict poorer outcomes in bipolar disorder and schizophrenia, and early onset bipolar disorder has been linked to longer delays before first treatment, a significant number of children, particularly in the US, are at risk for disastrous outcomes. Earlier recognition and treatment is imperative, especially since even bipolar disorder not otherwise specified (BP-NOS) can be severe, impairing, associated with multiple simultaneous comorbid diagnoses, and has a familial (genetic) basis.
Predicting Onset of Bipolar Disorder in Children at High Risk: Part I
At the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, one symposium was devoted to new research on predicting onset of bipolar disorder in children who have a family history of the disorder. Below are some of the findings that were reported.
Symptom Progression
In offspring of parents with bipolar disorder, researcher Anne Cecilia Duffy found that symptoms in the children tended to progress in a typical sequence. Childhood sleep and anxiety disorders were first to appear, then depressive symptoms, then bipolar disorder.
Different Types of Illness May Respond Best to Different Medications
Duffy’s research also suggested links between illness features and a good response to specific medications. Those offspring who developed a psychotic spectrum disorder responded best to atypical antipsychotic medication. Those with classical episodic bipolar I disorder responded well to lithium, especially if there was a family history of lithium responsiveness. Those offspring with bipolar II (and anxiety and substance abuse) responded well to anticonvulsant medications.
If parents with bipolar disorder had experienced early onset of their illness, their children were more likely to receive a diagnosis of bipolar disorder.
The offspring of lithium-responsive parents tended to be gifted students, while those from lithium non-responders tended to be poorer students.
Comparing Risk Factors for Bipolar Disorder and Unipolar Depression
Researcher Martin Preisig and colleagues also showed that parental early onset of bipolar disorder (before age 21) was a risk factor for the offspring receiving a diagnosis of bipolar disorder. Parental oppositional defiant disorder (ODD) was also a risk factor for bipolar disorder in the offspring. The emergence of depression, conduct disorder, drug use, and sub-syndromal hypomanic symptoms also predicted the onset of mania during childhood.
Conversely, sexual abuse and witnessing violence were strong risk factors associated with a diagnosis of major (unipolar) depressive disorder. Being female and experiencing separation anxiety were also factors that predicted unipolar depression.
Predicting Conversion to Mania
Researcher Danella M. Hafeman reported that mood swings (referred to in the literature as “affective lability”), depression/anxiety, and having a parent who had an early onset of bipolar disorder were linked to later diagnoses of mania. Immediate risk factors that predicted an imminent onset of mania included affective lability, substance abuse, and the presence of sub-threshold manic symptoms.
