Stimulants are one of the most common medications prescribed to children and adolescents, typically for attention deficit hyperactivity disorder (ADHD). In children of parents with major depression, bipolar disorder, or schizophrenia, stimulant use may come with a risk of psychotic symptoms. A 2016 study by L.E. MacKenzie and colleagues in the journal Pediatrics reported that among children and youth whose parents had one of these psychiatric illnesses, 62.5% of those who had taken stimulants had current psychotic symptoms, compared to only 27.4% of those who had not taken stimulants. The participants with psychotic symptoms tended to have hallucinations that occurred while they were taking stimulants. Doctors may want to consider whether parents have a history of psychiatric illness when deciding whether to prescribe stimulants to children and adolescents with ADHD. Activation is a common side effect of antidepressants in children who have a parent with bipolar disorder. Young people taking stimulants for ADHD should be monitored for psychotic symptoms, particularly if they have a parent with a history of depression, bipolar disorder, or schizophrenia.
A gene that plays a role in the pruning of synapses has been linked to schizophrenia. The gene encodes an immune protein called complement component 4 (C4), which may mediate the pruning of synapses, the connections between neurons. Researchers led by Aswin Sekar found that in mice, C4 was responsible for the elimination of synapses. The team linked gene variants that lead to more production of C4A proteins to excessive pruning of synapses during adolescence, the period during which schizophrenia symptoms typically appear. This may explain why the brains of people with schizophrenia have fewer neural connections. The researchers hope that future therapies may target the genetic roots of the illness rather than simply treating its symptoms.
The long-acting aripiprazole is administered every 4 to 6 weeks as an injection in the arm or buttocks. The company announced that it would begin releasing the drug immediately. The drug preparation for maintenance treatment is named Maintena while the preparation for acute treatment is named Aristada.
In a recent BNN article on potential drugs for memory loss, we omitted two conventional classes of drugs used to treat Alzheimer’s Disease—acetylcholine esterase inhibitors (AChE-Is) and the blocker of glutamate NMDA receptors memantine (Namenda). This was intentional, as we hoped to suggest possible approaches prior to the use of these drugs for full-blown dementia. However, we neglected to cite a 1999 study by Fred Jacobsen in the Journal of Clinical Psychiatry that indicated that the AChE-I drug donepezil (Aricept) was effective in improving drug-induced memory dysfunction in patients without dementia. Side effects included insomnia, nausea, vomiting, and diarrhea.
Jacobsen has used AChE-Is to improve memory in over 80 patients with unipolar or bipolar depression, aged 19-85. In a 2016 personal communication to the BNN, he indicated that doses of 5mg/day are typically enough to improve memory. Higher doses of 10mg/day may be more effective, but increase the risk of switching into mania for patients with bipolar depression. Some of Jacobsen’s patients have used AChE-I drugs for 10–15 years without the drugs losing effectiveness. For some patients, Jacobsen has switched from prescribing donezepil to prescribing rivastigmine (Exelon or Exelon patch), which he finds they can more easily tolerate.
We should also remind readers of the BNN of our previous report on memantine (Namenda) for bipolar depressed patients with cognitive impairment. We wrote, “In an abstract presented at the 67th Annual Meeting of the Society of Biological Psychiatry in 2012, Dan V. Iosifescu reported that in a randomized 12-week study in which the anti-Alzheimer’s drug memantine was given to 72 euthymic bipolar subjects experiencing cognitive deficits, the drug was associated with improvement in spatial and working memory, verbal and episodic memory, and other indices that included measurements of attention and language skills. In conjunction with this treatment, a subgroup of subjects had increases in left hippocampal NAA (a measure of neuronal viability) and increases in choline in the right hippocampus. The initial improvements in these neuropsychological test results remained over 12 weeks of open follow-up.”
In an earlier proof-of-concept study published in the journal CNS Neuroscience and Therapeutics in 2009, Iosifescu had also reported that among nineteen subjects with bipolar disorder that was in remission, but who had residual cognitive deficits, open-label treatment with the AChE-I galantamine (extended release) at doses of 8–24 mg/day led to improvement in those cognitive symptoms after 4 months.
Agitation is common among people with Alzheimer’s dementia. A 2015 phase 2 clinical trial by Jeffrey L. Cummings and colleagues, which was published in the journal JAMA, found that a combination of the drugs dextromethorphan hydrobromide and quinidine sulfate called Nuedexta reduced agitation significantly compared to placebo in patients with probable Alzheimer’s disease over a period of 10 weeks. Dextromethorphan-quinidine was dosed at 20mg/10mg in the morning for one week, then twice daily in weeks 2 and 3, then increased to 30mg/10mg twice daily for weeks 4 and 5. Side effects included falls, diarrhea, and urinary tract infections. Dextromethorphan-quinidine did not cause cognitive impairment, sedation, or irregularities in heart rate.
A change in a person’s sense of humor could be an early indicator of dementia, according to a 2015 article by Jason Warren and colleagues in the Journal of Alzheimer’s Disease. The changes can appear as early as 10 years before a diagnosis of dementia. Almost all participants who would go on to be diagnosed with frontotemporal dementia showed an increased preference for slapstick humor over satirical or absurdist compared with those who would not. In contrast, changes in sense of humor appeared in less than half of those who would go on to be diagnosed with Alzheimer’s disease, indicating that changes in sense of humor may allow doctors to distinguish between different types of dementia.
The study has some limitations. It was small (48 patients) and relied on patients’ memory of what kind of humor they enjoyed 15 years earlier. More research is needed to clarify the link between changes in humor preferences and dementia.
Warren suggests that changes in humor appear before other warning signs of dementia, such as memory loss. He called humor a type of “stress test” for the brain, since getting a joke can require a quick shift in perspective.
In a 2015 article in Nature Neuroscience, Stefan Bonn and André Fischer reported that when mice were prompted to use their long-term memory to recognize a specific environment, epigenetic changes occurred in their neurons and glia. Epigenetic changes refer to chemical alterations in DNA or histones (which give DNA structure) that increase or decrease the expression of certain genes. Sometimes environmental factors lead to a methyl or acetyl group joining a strand of DNA or histones, changing how easily the genes are turned on or off.
When the mice used their long-term memory, the main change that occurred was DNA methylation in their neurons. There were also changes to histones that were linked to memory acquisition but resulted in few changes in gene expression. The DNA methylation changes, on the other hand, changed neural pathways, leading to “rewiring” of the brain.
Doctors have known for some time that treatment with high-intensity light (7,000–10,000 Lux) can improve seasonal depression. In an 8-week study published in the journal JAMA Psychiatry in 2015, researcher Raymond Lam compared four different treatment options for non-seasonal major unipolar depression: bright light therapy for 30 minutes per day first thing in the morning, 20 mg of the antidepressant fluoxetine per day, combined bright light therapy and fluoxetine, and a placebo device paired with a placebo pill.
The combination of bright light therapy and fluoxetine produced remission in 58.6% of the participants who received it, compared to remission rates of 43.8% for bright light alone, 19.4% for fluoxetine alone, and 30% for placebo. It is notable that the effects of fluoxetine did not exceed those of placebo, but the effects of light alone did. There were few side effects in any group.
These data provide convincing evidence of the efficacy of light therapy in the treatment of non-seasonal unipolar depression. Use of light therapy for non-seasonal depression should now be more routinely considered, particularly when combined with antidepressant treatment.
Patients who had previously failed to respond to two or more antidepressants and patients with bipolar depression were excluded from the study. Bright light therapy administered in the morning can sometimes bring about mixed states in people with bipolar disorder. A 2007 case study by D. Sit and colleagues in the journal Bipolar Disorders found that midday light led to more improvement and less risk of mixed states than morning light among women with bipolar disorder.
Psychiatrists should take the lead in endorsing general wellness and encouraging healthy behaviors, says researcher James Hudziak. He suggests that opportunities to practice music, mindfulness, and exercise should be made available to all school children to increase brain health, and that more intensive efforts are necessary for children in families that are at risk for mood and behavioral difficulties or in children who show some dysfunction in these areas. Hudziak has implemented a statewide program in Vermont that encourages families to engage in these healthy practices.
Hudziak and colleagues analyzed brain scans of 232 children ages 6 to 18, looking for relationships between cortical thickness and musical training. They found that practicing an instrument such as the piano or violin increased working memory, gray matter volume in the brain, and the ability to screen out irrelevant noise. Practicing mindfulness increased white matter volume and reduced anxiety and depression. Exercise also increased brain volume and neuropsychological abilities.
Now Hudziak urges parents to advocate for the teaching of music, mindfulness, and exercise in schools as a way of improving general health, especially since music and gym are often the first programs to be cut when schools face budget shortages. Hudziak suggests that opportunities for athletics should be provided to all children, independent of their skill level, rather than only for the best athletes who “make the team.” Intramural teams should be open to all children, including those with less ability or minimal athletic skills. Exercise, teamwork, and friendships benefit all children.
For more information about the programs Hudziak implemented in Vermont, use the internet to search for the Vermont Family Based Approach, see his book Developmental Psychopathology and Wellness: Genetic and Environmental Influences, or call the University of Vermont Medical Center at (802)847-0000 or (800)358-1144.
Another tool that may be useful to parents of children aged 2 to 12 who are at risk for mood disorders is our Child Network, a secure online portal where parents can complete quick weekly ratings of their child’s mood and behavior, which is then graphed over time and can be used to show the child’s doctors how his or her symptoms are fluctuating and how well any treatment is working.
Raising body temperature by a few degrees may produce antidepressant effects as the body’s cooling mechanisms kick in. At the US Psychiatric and Mental Health Congress in 2015, researcher Charles Raison described a study comparing the effects of exposing participants to a special heating coil in a tent that retained the heat until their body temperatures increased by a few degrees to those of a sham procedure that did not raise body temperature. Those participants whose body temperature was increased had a lower body temperature the following day, and their depression improved as their bodies cooled. These improvements lasted six weeks or more.
Depressed patients tend to have elevated body temperatures. Raison suggests that raising body temperatures even more prompts the body’s cooling mechanisms to compensate, bringing cooling activity to normal levels from the skin to the brain and improving depression.