Drug Used for Fluid Retention May Be Useful in Autism
Bumetanide has been used for decades to treat fluid retention in those with heart failure or liver or kidney disease. In the brain, it allows chloride ions to leave cells more easily. Scientists researching pediatric seizures think that reducing the chloride inside brain cells helps GABA neurons’ inhibitory functions work better. This led to speculation that bumetanide could be useful in neonatal epilepsy and autism.
In a 2012 study by French researchers including Eric Lemonnier that was published in the journal Translational Psychiatry, 60 patients aged 3 to 11 who had been diagnosed with autism or Asperger’s syndrome were given either placebo or 1mg of bumetanide daily for 3 months. By the end of the study, the children who received bumetanide showed an average reduction of 5.6 points on the Childhood Autism Rating Scale (CARS), which is assessed from observing behavior during videotaped sessions of children playing with their caregiver and questioning the child’s parents. Children taking placebo showed a reduction of 1.8 points (a statistically significant difference). Clinicians in the study rated almost twice as many children who took bumetanide as having made a significant or a small improvement. Stereotyped behavior and restricted interest were the areas of behavior that seemed to improve most after treatment with bumetanide. Patients with milder autism when the study began tended to improve more than those who started out with more severe symptoms. Symptoms returned to previous levels within a month the study’s end.
Bumetanide’s side effects are well known. It can sometimes cause decreases in potassium in the blood (hypokalemia), so the children’s potassium levels were monitored closely. One child was withdrawn from the study for hypokalemia, which can predispose one to cardiac arrhythmias.
Harsh Physical Punishment is Associated with Mood and Other Disorders
Physical punishment of children has long been a controversial subject. A 2012 article by Afifi et al. in the journal Pediatrics suggests that having experienced harsh physical punishment during childhood is associated with mood disorders, anxiety disorders, substance abuse and dependence, and personality disorders in adulthood.
In this study harsh physical punishment included pushing, grabbing, shoving, slapping, or hitting. Participants who had experienced more severe maltreatment in childhood (including physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect, and exposure to violence between intimate partners) were excluded from the study, and the results were adjusted for sociodemographic variables and family history of dysfunction, suggesting that physical punishment was the mediator of these effects.
Intermittent SSRI Treatment Helps PMS
Research has shown that serotonin-selective reuptake inhibitor (SSRI) antidepressants can be useful for severe premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). According to a 2006 article by Steiner et al. in the Journal of Women’s Health, there are various ways that SSRIs can be used to treat PMS symptoms such as irritability, depressed mood, dysphoria, bloating, breast tenderness, appetite changes, and psychosocial function, including intermittent dosing just in the two weeks prior to PMS. Usually doses for PMS are lower than those used to treat depression.
For those with mood symptoms that continue throughout the month, continuous (daily) dosing may improve PMS symptoms. For those whose mood symptoms worsen during PMS, continuous dosing can be intermittently increased from around the time of ovulation to a few days after the period begins. For those women with mood symptoms only during PMS, intermittent dosing only during those weeks between ovulation and the period seems to be helpful and minimizes side effects of the SSRIs.
Editor’s Note: While SSRIs sometimes take weeks to reach maximum benefit for those with depression, intermittent dosing for women with severe PMS seems to be helpful. This may be because SSRIs acutely increase the neurosteroid allopregnanolone, which enhances GABA-A receptor activity, associated with improvement in mood and anxiety.
Women with Bipolar Disorder at Higher Risk for Postpartum Depression
The risk of having a depressive episode during pregnancy compared to afterward have not often been studied. A 2011 review article by Viguera et al. in the American Journal of Psychiatry compared rates of affective episodes among women with bipolar I and II disorders and recurrent major depressive disorder, both during pregnancy and the postpartum period. Risks were higher for women with bipolar disorder.
Among women with bipolar disorder, 23% experienced mood episodes during the pregnancy, while 52% had an episode in the months after giving birth. Among women with unipolar depression, 4.6% had a mood episode during pregnancy, while 30% did during the postpartum period, which is about double the risk seen in the general population. Depression was the most common type of morbidity the women experienced before and after giving birth.
Risk factors associated with mood episodes during pregnancy included (in descending order): younger age at illness onset, previous postpartum episodes, fewer years of illness, bipolar disorder, fewer children, and not being married. Risk factors associated with postpartum episodes included: younger age at illness onset, illness during pregnancy, bipolar disorder, fewer children, and more education.
Editor’s Note: The risk of postpartum depression increases from 15% in the general population, to 30% among women with unipolar disorder, to 50% in women with bipolar disorder. Special precautions should be taken to monitor and treat depression during and after pregnancy, in all women but particularly in those with a prior history of unipolar or bipolar disorder.
Rats Exposed to Jet Fuel Pass Epigenetic Changes on to Third Generation
A recent study of rats showed that exposure to hydrocarbons (jet fuel JP-8) can bring about disease not just in the rats who were exposed, but also in subsequent generations. Epigenetics is the study of how environmental events or biochemical changes can affect the structure of DNA, e.g. by attaching extra methyl groups. (These kinds of “epimutations” are separate from the inherited genetic makeup we receive from our parents, but new evidence suggests that some can be passed on to future generations.)
When first generation female rats were exposed to jet fuel, third generation rats showed 33 different examples of DNA methylation as well as obesity.
Previous research has shown similar signs of transgenerational transmission of disease resulting from first generation exposure to chemicals such as bisphenol A, phthalates, dioxins, and pesticide mixtures.
Arbaclofen May Improve Social Behavior in Fragile X Syndrome and Irritability in Autism
Fragile X syndrome is a genetic condition that is the most common single-gene cause of autism and inherited cause of intellectual disability. In addition to mental disabilities it is also characterized by certain physical characteristics (elongated face, protruding ears, and large testes in boys), stereotypic movements such as hand-flapping, and social anxiety.
When autism is associated with Fragile X, a mutation in the Fragile X gene is responsible for the autism. (It is also possible to have autism without Fragile X, or to have Fragile X without autism.) Fragile X is a genetic disorder like Downs Syndrome, while autism is a complex behavioral disorder, likely involving multiple genetic and environmental vulnerabilities.
A new drug called arbaclofen seems to improve social avoidance and problem behaviors in adults and children with Fragile X. Researchers hypothesize that normal social stimuli overwhelm a Fragile X patient because of a defect in inhibition, and arbaclofen acting on presynaptic GABA-B receptors reduces glutamate release, thereby reducing the overactive signaling associated with this defect.
In a 6-week placebo-controlled study of arbaclofen among 63 patients with Fragile X ranging in age from 6 to 39, patients 11 years old and younger received 10mg twice a day and patients 12 and up received 10mg three times a day. The drug was well-tolerated, with only a few reports of sedation or headache. While problem social behaviors and neurobehavioral function improved, irritability did not. The study considered irritability because that is the aspect of autism most often improved by other Federal Drug Administration-approved drugs for autism, such as risperidone and aripiprazole. In another study of arbaclofen in autism spectrum disorders, it did improve irritability and agitation.
Editor’s Note: The GABA-B agonist arbaclofen has previously shown positive effects in motor spasticity. The positive effects noted here in the social domain of autism spectrum disorders and Fragile X are very promising.
Chromium Picolinate May Be Worth Another Look In Atypical Depression
Atypical depression is characterized by overeating and oversleeping.
Atypical depression is characterized by overeating and oversleeping compared to the loss of appetite and early morning awakening associated with melancholic depression. A recent placebo-controlled study of chromium picolinate (600?g of elemental chromium) for atypical depression was not initially successful, but researcher Maurizio Fava and colleagues re-analyzed the data using a “population-enrichment strategy” to control for excessively high or low placebo response rates. Their analysis looked more positive than the initial analysis, but remained non-significant, possibly due to the small size of the study. However, the positive trend they saw made the researchers think that chromium picolinate is still worthy of future study.
Editor’s Note: Chromium picolinate had previously been shown (in one study by John Docherty et al.) to have positive effects in reducing carbohydrate craving when compared to placebo. If it only did that, it would still be useful for those struggling with overeating, even if it failed to improve other aspects of atypical depression.
Female Rodents Are More Sensitive to Defeat Stress and Its Cross-Sensitization to Cocaine
Among rodents, being subjected to defeat stress (when an intruder mouse is threatened by a larger mouse defending its territory) can make an animal more susceptible to cocaine. This is referred to as cross-sensitization.
Researcher Elizabeth Holly and colleagues have found that compared to males, female rodents are more sensitive to defeat stress and have greater reactions to cocaine and cocaine sensitization following this type of stress. This is probably related to a neuropeptide called corticotropin releasing factor (CRF), which is associated with cross-sensitization. When the mice were exposed to cocaine, there were increases in CRF in a part of the brain called the ventral tegmental area (VTA), which contains cell bodies of dopamine neurons that travel to the nucleus accumbens, the brain’s reward center. Blocking the CRF receptors in the VTA prevented the sensitization to cocaine from occurring in the mice.
Editor’s Note: These data in animals resemble clinical observations in humans that women are more sensitive to stress and are more prone to depression, and can have an exceedingly difficult time stopping cocaine use if they become addicted.
Choline Treatment For Pregnant Mothers And Newborns Improves Babies’ Cognition and Normalizes a Risk Factor for Schizophrenia
Deficiencies in GABA inhibition have been linked to the risk of schizophrenia (and perhaps bipolar disorder). GABA receptors are initially excitatory but switch to being inhibitory early in life. Choline derived from phosphatidylcholine or from eggs and meat in the diet is important in increasing GABA receptor development and maturity.
Ross et al. reported this year in the American Journal of Psychiatry that in a placebo-controlled study in which mothers took phosphatidylcholine in the last 2 trimesters of pregnancy (at doses of 3,600mg in the morning plus 2,700mg in the evening) and infants took 100mg/day for 12 weeks, the infants who received choline showed better neuronal inhibition than infants who did not receive choline on a P50 test of auditory evoked potential, in which the brain’s response to a series of beeps is recorded. An overactive P50 response is a sign of deficiencies in GABA inhibition.
In infants with a common gene variant in the alpha 7 nicotinic receptor that makes it function less well (which also may be a risk factor for the development of schizophrenia), the choline regimen normalized the P50 test, while placebo had no effect. However, in a recent study by Cabranes et al. published in Psychiatry Research, there was no association of the alpha 7 gene variant and schizophrenia or bipolar disorder, although patients with bipolar disorder and patients with schizophrenia did perform differently on the P50 evoked potential test than controls did.
Editor’s Note: In an editorial by Judy Rapoport that accompanied the Ross et al. study, the difficulty of using the findings in clinical practice are discussed. Meck et al. showed in 1999 that choline supplementation enhanced spatial memory, and in several cases nutritional supplements can have beneficial effects on the brain. Rapoport notes the success of perinatal folate in preventing neural tube defects and the likelihood that Vitamin D supplementation can prevent some cases of schizophrenia.
However, extrapolating the choline findings of Ross et al. to clinical practice, especially given the lack of association of the alpha 7 gene variation to psychiatric illness in the study by Cabranes et al., might be premature. Instead, Rapoport recommends a good diet and prevention of infection as first steps for treatment. Choline supplementation would be roughly equivalent to three eggs a day.
No Relationship Between SSRIs in Pregnancy and Stillbirths or Neonatal Mortality
Much has been written about the use of selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy. In a review of 920,620 births in Denmark (1995 to 2008) that Jimenez-Solem published this year in the American Journal of Psychiatry, no link was found between any of the SSRIs used in any trimester and risk of stillbirth or neonatal mortality. The only exception was a possible association of three-trimester exposure to citalopram and neonatal mortality.
Editor’s Note: These new data may be of importance to women considering antidepressant continuation during pregnancy when there is a high risk for a depressive relapse. A maternal depressive episode (like other stressors such as anxiety or experiencing an earthquake) during pregnancy does convey adverse effects to the child, so appropriate evaluation of the risk/benefit ratio or staying on an antidepressant through a pregnancy is important.
