Bipolar Disorder in Pregnancy and the Postpartum Period

July 3, 2020 · Posted in Risk Factors · Comment 

At the 2020 meeting of the International Society for Bipolar Disorders, researcher Veerle Bergink reported several findings from a recent meta-analysis of articles on pregnancy and bipolar disorder. Bergink and colleagues found that pregnant women with bipolar disorder have a 37% risk of a postpartum relapse, more than twice the risk of postpartum mental disorders in the general population.

Using lithium as a treatment in the first trimester of pregnancy increased risk of congenital malformations in the fetus, but the risk was much smaller than previously thought and could be monitored by ultrasound.

Bergink and colleagues also reported that in a sample of 645 women with first-onset postpartum psychosis who received followup over a period of 7 to 25 years, 43% had no subsequent severe episodes outside of the postpartum period.

Another finding was that women with postpartum severe depression or mania had abnormalities in T cells, which are important in immune response.

Childbirth and Bipolar Disorder

June 30, 2020 · Posted in Risk Factors · Comment 

In an abstract for virtual presentation at the 2020 meeting of the International Society for Bipolar Disorders, researcher Ian Jones presented evidence that childbirth may trigger onset of bipolar disorder.

Jones found that 15% of women who experience postpartum mood disorders shortly after childbirth will go on to develop bipolar disorder over time. A previous diagnosis of bipolar affective disorder is the biggest predictor that a woman will be readmitted for treatment of postpartum mental illness.

In addition, one of the biggest risk factors for postpartum mental disorders is a family history of bipolar disorder in first-degree relatives. The risk of postpartum mental disorders also increases when first-degree relatives have a psychiatric illness of any kind.

Editor’s Note:  These data are consistent with research on sensitization/kindling, the idea that while early mood episodes may be triggered by psychosocial stress and other endocrine factors, later episodes may emerge more spontaneously.  In this case, the stress associated with childbirth can lead to a subsequent bipolar diagnosis (with or without a precipitating stressor) in the future.

The psychosocial stress of childbirth and subsequent sleep deprivation can be severe, and those with a history of a mood disorder should seek additional support during such a time.

Neurotransmitters Can Also Function As Epigenetic Marks

June 2, 2020 · Posted in Genetics, Peer-Reviewed Published Data · Comment 
lab rat

The most common epigenetic marks involve methylation of DNA (which usually inhibits gene transcription) and the acetylation and methylation of histones. Acetylation opens or loosens the winding of DNA around the histones and facilitates transcription, while methylation of histones leaves the DNA tightly wound and inhibits transcriptional activation.

Researcher Ashley E. Lepack and colleagues have identified a surprising type of epigenetic mechanism involving neurotransmitters. They report in a 2020 article in the journal Science that neurotransmitters such as serotonin and dopamine can act as epigenetic marks. Dopamine can bind to histone H3, a process called called dopaminylation (H3Q5dop). In rats undergoing withdrawal from cocaine, Lepack and colleagues found increased levels of H3Q5dop in dopamine neurons in a part of the midbrain called the ventral tegmental area (VTA), a part of the brain’s reward system. When the investigators reduced H3Q5dop, this decreased dopamine release in the reward area of the brain (the nucleus accumbens) and reduced cocaine seeking. Thus, dopamine can be both an important transmitter conveying messages between neurons and a chemical mark on histones that alters DNA binding and transcriptional regulation.

Researcher Jean-Antoine Girault provided commentary on the article by Lepack and colleagues, writing that “[t]he use of the same monoamine molecule as a neurotransmitter and a histone modification in the same cells illustrates that evolution proceeds by molecular tinkering, using available odds and ends to make innovations.”

Editor’s Note: Epigenetic marks may remain stable and influence behavior over long periods of time. They are involved in the increased reactivity or sensitization to repeated doses of cocaine through DNA methylation. Such sensitization can last over a period of months or longer. If the methylation inhibitor zebularine is given, animals fail to show sensitization. Now a newly identified epigenetic process, dopaminylation, is found to alter histones and is associated with long-term changes in cocaine-seeking.

The clinical message for a potential cocaine user is ominous. Cocaine not only creates a short-term “high,” but its repeated use rewires the brain not only at the level of changes in neurotransmitter release and receptor sensitivity, but also at the genetic and epigenetic level, changes that could persist indefinitely.

The sensitization to motor hyperactivity and euphoria that occur with cocaine use can progress to paranoia and panic attacks and eventually even seizures (through a process known as kindling).

The dopaminylation of histones in the VTA could lead to persistent increases in drug craving and addiction that may not be easily overcome. Thus, the appealing short-term effects of cocaine can spiral into increasingly adverse behaviors and drug-seeking can become all consuming. While these adversities do not emerge for everyone, the best way to ensure that they do not is to avoid cocaine from the start.

Manic episodes that include a feeling of invincibility, increased social contacts, and what the DSM-5 describes as “excessive involvement in pleasurable activities that have a high potential for painful consequences” are a time that many are at risk for acquiring a substance problem. For the adolescent who has had a manic episode, ongoing counseling about avoiding developing this type of additional long-term, difficult-to-treatment psychiatric illness could be lifesaving. Describing the epigenetic consequences of substance use may or may not be helpful, but may be worth a try.

Environment Can Leave “Molecular Scars” Via Epigenetic Processes

May 29, 2020 · Posted in Genetics, Peer-Reviewed Published Data · Comment 
DNA

A 2020 review article by researchers Julia Richetto and Urs Meyer in the journal Biological Psychiatry provides a good overview of the role epigenetic modifications play in schizophrenia and related disorders.

The article provides a powerful understanding of how the environment can induce long-lasting changes in the structure of DNA (not only in schizophrenia, but also in bipolar disorder). This process, known as epigenetics, can have life-long influences on brain chemistry and behavior, and remarkably, some of these epigenetic changes can even be transmitted to the next generation.

While the sequence of DNA that one inherits from one’s parents does not change over the course of one’s life, what can change is how loosely or tightly the DNA is wound around proteins called histones, making it easier or harder to transcribe the genetic material held there. The addition of a methyl group to DNA usually inhibits transcription, while the addition of an acetyl group to histones usually facilitates transcription. These alterations in the shape of the DNA that result from environmental exposures or behavior can be passed on through generations.

Richetto and Meyer describe these chemical changes to DNA as “molecular scars,” which are left when environmental stress occurs during sensitive developmental periods. For example, patients with schizophrenia who experienced stressors in early life have higher levels of the enzyme histone deacetylase than patients who had stress or trauma later in life. Histone deacetylase would remove the acetyl groups on histones, which would inhibit gene transcription.

Other factors that have been implicated in epigenetic modifications in schizophrenia, such as DNA methylation of key developmental pathways, include pre- or post-natal stress, a challenge to a mother’s immune system during pregnancy, pre- and post-natal nutrition, exposure to drugs or toxic substances, and cannabis use in adolescence.

Richetto and Meyer suggest that epigenetics may explain why schizophrenia (and we would add bipolar disorder) can differ so much across individuals, and may help researchers and clinicians determine how best to treat different individuals.

Editor’s Note: This editor has written about how epigenetic changes can mediate sensitization to the recurrence of life stressors, episodes of mood disorder, and bouts of substance abuse, each of which can drive illness exacerbation and progression in bipolar disorder (see the 2016 article by Robert M. Post in the journal Bipolar Disorders, “Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention”).

The chemical changes to our DNA, histones, and microRNA emphasize how important it is to begin long-term preventative treatment starting after a first episode of mania. This not only helps limit episode recurrence and the accumulation of stressors and bouts of substance use that can cause illness deterioration, but also limit the placement of these “molecular scars” on our DNA. The key to treating bipolar disorder is: prevent episodes, protect the person and the brain.

Transcranial Direct Current Stimulation Improved OCD in Controlled Trial

May 26, 2020 · Posted in Potential Treatments · Comment 
tDCS

In an abstract of a paper that was to be presented at the 2020 meeting of the Society of Biological Psychiatry in May, researcher Roseli Gedanke Shavitt described a study of transcranial direct current stimulation (tDCS) in people with treatment-resistant obsessive-compulsive disorder (OCD). TDCS is a treatment in which electrodes applied to a patient’s scalp provide a constant low level of electricity that can modulate neuronal activity.

Shavitt and colleagues gave 30 minutes of either active or sham tDCS for 20 days to patients with treatment-resistant OCD. They positioned the cathode over the supplementary motor area of the brain, and the anode over the left deltoid. Those patients who received active tDCS achieved significantly greater reductions in OCD symptoms than did those in the sham group.

New Type of Antipsychotic Drug for Schizophrenia Looks Promising

Photo by The-Lore.com on Unsplash

In a 2020 article in the New England Journal of Medicine, researcher Kenneth S. Koblan and colleagues described a new type of antipsychotic drug treatment for schizophrenia. Almost all other antipsychotic drugs block dopamine D2 receptors, while atypical antipsychotics also block the serotonin 5HT2 receptor. They are described as antagonists at these receptors.

In contrast, the new drug is an agonist or activator of two different receptors. The drug SEP-363856 (also called SEP-856) activates the trace amine–associated receptor 1 (TAAR1) and 5-hydroxytryptamine (or serotonin) type 1A (5-HT1A) receptors.

Blocking D2 receptors can cause Parkinson’s-like symptoms (such as tremor, masked faces, and impaired movement or speech) and other extrapyramidal side effects (such as slurred speech, slow movements, or restless legs.) In contrast, SEP-856 seems to have a better side effects profile than these types of drugs while also being highly effective.

Patients with an acute exacerbation of schizophrenia were assigned to receive either placebo or once-daily treatment with SEP-856 (either 50mg or 75mg) for four weeks. A total of 120 patients received SEP-856 while 125 received placebo.

Compared to the placebo group, the SEP-856 group showed significantly greater reductions on a scale of positive and negative symptoms of schizophrenia by the end of the four weeks. Side effects included some sleepiness and gastrointestinal symptoms, but the incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in both groups. There was one sudden death from cardiac causes in the SEP-856 group, which was not thought to be drug-related.

Editor’s Note: This drug acting on trace amine–associated receptor 1 (TAAR1) and 5HT1A receptors could herald a new and better tolerated type of antipsychotic. It is also being studied for psychosis in Parkinson’s disease. Since all of the antipsychotics that treat schizophrenia have also shown antimanic efficacy, we look forward to future studies of this unique drug in patients with mania.

Endocannabinoid System May Help Explain Tourette Syndrome

May 19, 2020 · Posted in Neurochemistry, Peer-Reviewed Published Data · Comment 
Photo by Roman Bilik on Unsplash

Endocannabinoids are neurotransmitters produced by the human body that attach to cannabinoid receptors in the brain, the same receptors that are affected by the consumption of cannabis products.

Tourette syndrome, a neurodevelopmental disorder characterized by tics and psychological symptoms, is probably caused by some dysfunction involving the neurotransmitter dopamine. The syndrome is usually treated with dopamine receptor blockers but is also eased by cannabis use and treatment with THC, the main psychoactive component in cannabis. Recently, researchers set out to determine whether concentrations of endocannabinoids in the cerebrospinal system are related to Tourette syndrome.

In an article published in the journal Neuropsychopharmacology in 2020, researcher Kirsten R. Müller-Vahl and colleagues report that endocannabinoid concentrations were significantly higher in the cerebrospinal fluid of 20 people with Tourette’s syndrome than in 19 control participants without Tourette’s.

The researchers found elevations in the endocannabinoids AEA and 2-AG, the endocannabinoid-like ligand PEA, and the metabolite AA in the participants with Tourette’s syndrome. Levels of 2-AG in the cerebrospinal fluid correlated with severity of attention-deficit hyperactivity disorder symptoms, an aspect of the syndrome.

It is possible that higher concentrations of endocannabinoids are present in the syndrome because they compensate for the overactive influence of dopamine. This explanation would fit with the effectiveness of cannabis in treating Tourette’s. However, that has not yet been determined, and it is also possible that the endocannabinoids are a reaction to dysfunction involving other neurotransmitters, are incidental to the syndrome, or in the best case that they are a direct cause of the syndrome.

Müller-Vahl and colleagues suggest that based on the effectiveness of cannabis in treating Tourette’s, it may turn out that the syndrome is a sort of endocannabinoid deficiency. They believe this hypothesis is not counteracted by the high levels of cannabinoids they found in Tourette’s patients in this study, because these high levels may be accompanied by a reduced number or reduced sensitivity of the cannabinoid receptors or overactivity in the enzymes that break down endocannabinoids, such that it is difficult to maintain normal levels of these neurotransmitters.

Cannabis Withdrawal Syndrome Occurs in Almost Half of Regular Users

May 15, 2020 · Posted in Peer-Reviewed Published Data · Comment 
Photo by Thought Catalog on Unsplash

A recent systematic review and meta-analysis by researcher Anees Bahji and colleagues in the open access medical journal JAMA Network Open describes the symptoms and prevalence of cannabis withdrawal syndrome.

The most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) indicates that cannabis withdrawal syndrome “requires the presence of at least 3 of the following symptoms developing within 7 days of reduced cannabis use: (1) irritability, anger, or aggression; (2) nervousness or anxiety; (3) sleep disturbance; (4) appetite or weight disturbance; (5) restlessness; (6) depressed mood; and (7) somatic symptoms, such as headaches, sweating, nausea, vomiting, or abdominal pain.”

According to Bahji and colleagues, cannabis withdrawal syndrome occurred in 47% of regular users. Higher rates of withdrawal were found among those in clinical settings, those who also used tobacco or other substances, and those who used cannabis daily.

Bahji and colleagues write that while many people believe that cannabis is relatively harmless, it actually has a variety of associated risks. Short-term risks include impaired short-term memory and motor coordination, altered judgment, paranoia, and psychosis. Long-term effects include addiction, altered brain development, poor educational outcomes, cognitive impairment, diminished quality of life, increased risk of chronic respiratory tract and psychotic disorders, injuries, motor vehicle collisions, and suicide.
The researchers warned that users of cannabis may resume cannabis use to allay the depression and anxiety symptoms that are part of the withdrawal syndrome, perpetuating the long-term withdrawal cycle.

Bahji and colleagues suggest that because of the high prevalence of the withdrawal syndrome, doctors should screen patients for cannabis withdrawal, particularly men and frequent cannabis users. They write, “Clinicians should be aware of CWS as it is associated with clinically significant symptoms, which can trigger resumption of cannabis use and serve as negative reinforcement for relapse during a quit attempt.” Doctors can offer support for those reducing their cannabis consumption.

AiTBS Superior to ECT in Small Study

May 12, 2020 · Posted in Potential Treatments · Comment 

Researchers Erica Jensen and Nolan Williams reported in abstracts of a paper that they were to present at the 2020 meeting of the Society of Biological Psychiatry in May that daily sessions of accelerated intermittent theta burst transcranial stimulation (aiTBS) over five or more days produced better results in 15 patients hospitalized for depression and suicidality than in matched patients who received electro-convulsive therapy.

AiTBS is a form of repeated transcranial magnetic stimulation (rTMS), in which a magnetic coil is applied to a patient’s scalp, producing electrical changes in the brain.

The aiTBS treatment was delivered to the left dorsolateral prefrontal cortex. It consisted of 1800 pulses per session, at 80% of a patient’s resting motor threshold with a 50-minute inter-session interval.

The patients in the study were matched (for age, gender, and treatment resistance) to patients who were hospitalized and given ECT. Among patients who received aiTBS and were discharged after an average of 8.4 days, there was an 86% response rate and a 73% remission rate. Among the patients who received ECT, who were discharged after an average of 22.3 days, there was a 53% response rate and a 40% remission rate. With further ECT, response and remission rates increased to 73% and 67%. Time to remission was 3.5 days with aiTBS and 31.3 days for ECT. The investigators concluded conservatively, “Our results suggest that aiTBS could have comparable efficacy to ECT, with potentially faster resolution of acute severe depression.”

Editor’s Note: ECT has been the gold standard treatment for severe depression and suicidality and now we may have a platinum comparator. If these findings are replicated, they could represent a paradigm shift in the treatment of severe depression. Hopefully, this novel form of rTMS will be fast-tracked for approval by the Food and Drug Administration (FDA).

Fish Oil Monotherapy on Depression in Adolescents at High Risk for Bipolar I Disorder: Ambiguity Persists

omega-3 fatty acids
Fish oil supplements

Researcher Robert K. McNamara and colleagues reported in the Journal of Child and Adolescent Psychopharmacology in a 2020 article that 12 weeks of treatment with omega-3 fatty acids in the form of fish oil did not reduce depression symptoms in adolescents at risk for bipolar disorder when compared to placebo. The primary outcome measured was the results of the Childhood Depression Rating Scale-Revised (CDRS-R).

Fish oil did perform better than placebo on two parts of the rating scale: symptom severity and symptom improvement, especially in weeks 11 and 12 of the study. Omega-3 fatty acids increased creatine and choline in the anterior cingulate, and also increased polyunsaturated fatty acids in red blood cells. The treatment was safe and well-tolerated.

A total of 42 patients between the ages of 9 and 21 who had been diagnosed with depression and had at least one parent with bipolar I disorder received either placebo or 3 fish oil capsules per day. Each capsule contained 450?mg EPA, 40?mg docosapentaenoic acid (DPA), and 260?mg DHA for a total daily dose of 2130?mg EPA + DHA.

Editor’s Note: Ambiguity persists about whether omega-3 fatty acids can improve unipolar or bipolar depression, attention-deficit hyperactivity disorder (ADHD), or prevent the progression of schizophrenia symptoms to the full syndrome. Given the lack of side effects, and the documented effects on red blood cells and brain choline, clinical use of these compounds could be considered in some circumstances.

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