Abuse Histories Decrease Rate of Remission to Antidepressant Treatment
Harkness et al reported in The Canadian Journal of Psychiatry (2023) “Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR]=1.68, P =0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8.”
Editors note: Response to ADs is less good in those with a history of abuse in childhood. Therefore psychotherapy should be added to medications in such situations to attempt to enhance responsiveness.
Childhood Physical Abuse Predicts Response to IV Ketamine
At a recent scientific meeting, researcher Alan Swann reported the results of a study of intravenous ketamine in people with treatment-resistant depression. The 385 participants, who received four infusions of IV ketamine at a dosage of 0.5 mg/kg, could be grouped into three based on their type of response to the treatment.
One group had moderate depression at baseline and showed little change. A second group with severe baseline depression also showed minimal improvement. A third group who also had severe baseline depression had a rapid and robust antidepressant response to the treatment. This group had high scores relating to physical abuse on the Childhood Trauma Questionnaire (CTQ), but did not differ on other clinical variables. Swann and colleagues concluded, “Our outcomes show that IV ketamine should be considered as a primary treatment option for adults presenting with severe, treatment resistant depression and a self-reported history of childhood physical abuse. IV ketamine may not be as effective for moderately depressed individuals irrespective of childhood maltreatment.”
Infliximab Helps the Subgroup of Bipolar Depressed Patients Who Faced Adversity in Childhood
At the 2019 meeting of the International Society for Bipolar Disorders, researcher Mike Cosgrove and colleagues described a study of the immune-suppressing drug infliximab in adults with bipolar disorder. The researchers found persistent significant improvements on infliximab only in those with bipolar disorder who also had a history of childhood adversity. Childhood adversity is consistently associated with elevated levels of inflammatory cytokines, and baseline inflammation may be a prerequisite for a positive effect from infliximab, which works by blocking the inflammatory cytokine TNF alpha.
Inflammatory Marker IL-6 is Elevated in People with Depression and Those with a History of Childhood Trauma
In a 2018 article in the journal Psychiatry Research, researcher Ana Munjiza and colleagues reported that the inflammatory marker IL-6 was higher in 64 depressed people than in 53 non-depressed people, and that levels of IL-6 among people in the depressed group were significantly correlated with scores on a questionnaire in which participants reported traumas experienced in childhood. They reported more physical abuse, physical neglect, and emotional abuse.
Munjiza and colleagues indicate that trauma in childhood is a risk factor for depression in adulthood, as other researchers have suggested, and that inflammation could mediate the relationship between childhood adversity and depression.
Editor’s Note: IL-6 has been associated with antidepressant treatment resistance. IL-6 is secreted from white cells in the blood and from monocytes from the bone marrow in response to stress. It enters the brain and starts an inflammatory cascade that induces depressive behaviors. Animal studies have shown that if IL-6 secretion is blocked, depressive-like behaviors do not occur.
Another indicator of inflammation is CRP, and elevations in CRP have been associated with poor response to selective serotonin reuptake inhibitor (SSRI) antidepressants, and better response to the noradrenergic tricyclic antidepressant nortriptyline and the dopamine active antidepressant bupropion.
Treatments for depressed people with histories of childhood trauma may include psychotherapy, somatic therapies such as repeated transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), and medication. More research is needed to determine the optimal treatment regimens for this subgroup of depression sufferers, including whether anti-inflammatory drugs could play a helpful role in preventing or treating depression. People with elevated inflammatory markers (such as IL-6, CRP, IL-1, or TNF-alpha) are likely to be better candidates for adjunctive anti-inflammatory treatments than those with normal or low baseline levels of inflammation.
Brain Volumes Affected by Type and Timing of Childhood Abuse
Maltreatment during childhood has been linked to brain changes and mental illness. In a study by researcher Carl M. Anderson and colleagues that was presented at the 2016 meeting of the Society of Biological Psychiatry, maltreatment at particular ages was statistically linked to deficits in the size of certain brain areas in young adulthood.
The brain areas under examination are critical for the regulation of emotion and behavior, and this research suggests that early experiences can stunt their development, perhaps through altered production of synapses or via the synaptic pruning process that occurs during preadolescence. The details, summarized below, are perhaps less important than the overall finding that maltreatment in childhood affects brain volume, and this effect varies based on the timing and type of maltreatment. Abuse and neglect earlier in life affected the left side of the brain, while later maltreatment affected the right side.
Severity of physical abuse at age 3 affected the volume of the ventromedial prefrontal cortex in women. Physical abuse at ages 3 and 8 in men affected left ventromedial prefrontal cortical volume, while later abuse at ages 7 and 12 predicted volume of the right side.
In women, dorsal anterior cingulate area on the left was predicted by physical abuse at age 5 and by emotional neglect at ages 7 and 11. Later emotional neglect at ages 15 and 16 and physical abuse by a peer at age 10 was associated with smaller right dorsal anterior cingulate. In men, smaller left dorsal anterior cingulate area was predicted by physical neglect at age 2 and emotional abuse by a peer and witnessing abuse of a sibling at ages 5 and 10, and right area by physical neglect at age 12.
Child Abuse Linked to Adolescent Obesity
New research clarifies how trauma in early life can lead to obesity in adolescence. In a study of 160 young people between the ages of 9 and 15, researcher Janitza Montalvo-Ortiz and colleagues identified seven sites in the genome where DNA methylation predicted body mass index (BMI) in adolescence. The researchers also collected information on family traumas that occurred during the participants’ childhoods and found that DNA methylation and family trauma such as child abuse interacted to predict BMI.
Epigenetics describes the ways life experiences can change how easily DNA is turned on or off. While the genes coded by DNA sequences one inherits from one’s parents never change, the structure of DNA can change. DNA methylation is one type of epigenetic change that refers to the addition of methyl groups to promoter regions of DNA in response to life events.
In this research, which was presented at the 2016 meeting of the Society of Biological Psychiatry, Montalvo-Ortiz and colleagues found that the site of DNA methylation with the strongest link to BMI in adolescence was a gene called MAP2K3. This gene had previously been linked to obesity, but this is the first time DNA methylation at this site has been linked to both obesity and childhood trauma. Other relevant gene sites where DNA methylation occurred include ANKRD2, CPXM2, NUBPL, and RFK.
Childhood adversity, epigenetics, and hippocampal volume
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Booij reported that in humans, there is an interaction between adversity experienced during childhood, and an epigenetic variation in the short form of the serotonin transporter (5HT-T ss, or SLC6A4), which can influence hippocampal volume during depression.
Epigenetics refers to environmental influences on the way genes are transcribed. The impact of life experiences such as stress is not registered in DNA sequences, but can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment. When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.
Booij followed 33 children who had experienced some form of adversity at a young age until they were 15 or 16, examining methylation of the serotonin transporter in their T cells and monocytes compared to 36 children who had not experienced adversity during childhood. He found that in children who had experienced abuse in childhood, the degree of that abuse was correlated with methylation of the serotonin transporter and was inversely related to the volume of the hippocampus, as measured using magnetic resonance imaging (MRI). Thus, child abuse yields lasting epigenetic effects (methylation of the serotonin transporter) and has anatomical consequences in teenagers, as seen in smaller hippocampi. These data parallel converse findings by Joan Luby et al. published in the journal PNAS in 2012, in which increased maternal warmth directed toward a child aged 4-7 was associated with increased volume of the hippocampus several years later.
Depression in Youth Is Tough to Treat and Requires Persistence and Creativity
At a symposium on ketamine for the treatment of depression in children at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, David Brent, a professor at the University of Pittsburg, gave the opening talk on the fact that as many as 20% of adolescents who are depressed fail to improve, develop chronic illness, and are thus in need of alternatives to traditional treatment. Predictors of non-improvement include substance use, low-level manic symptoms, poor adherence to a medication regimen, low blood levels of antidepressants, family conflict, high levels of inflammation in the body, and importantly, maternal depression. In adolescents insomnia was associated with poor response, but in younger children insomnia was associated with a better response.
Brent suggested using melatonin and sleep-focused cognitive behavioral therapy for insomnia in youth, but not using trazodone (which is commonly prescribed). Trazodone is converted to a compound called Meta-chlorophenylpiperazine or MCPP, which induces anxiety and dysphoria. MCPP is metabolized by hepatic enzymes 2D6, and fluoxetine and paroxetine inhibit 2D6, so if trazodone is combined with these antidepressants, the patient may get too much MCPP.
Surprisingly and contrary to some data in adults about the positive effects of therapy in those with abuse histories, in the study TORDIA (Treatment of SSRI-Resistant Depression in Adolescents), if youth with depression had experienced abuse in childhood, they did less well on the combination of cognitive behavioral therapy and selective serotonin reuptake inhibitors (SSRIs) compared to SSRIs alone.
Adversity May Increase Risk of Mood Disorders
In adults with bipolar disorder, adversity in childhood has been associated with an earlier onset of bipolar disorder compared to those who did not experience some form of adversity such as verbal abuse, physical abuse, sexual abuse, loss of a parent, abandonment, or neglect. At the 2013 meeting of the Society of Biological Psychiatry, Nancy Low et al. reported that the number of these stressful life events a child experienced was associated with the number of their anxiety symptoms, psychiatric disorders, and lifetime substance abuse. Having experienced 3 or more adversities was associated with a 3.5-fold increased risk for developing a mood disorder and a 3-fold increase in anxiety disorders and alcohol or drug abuse.
While the study has not yet been published in a peer-reviewed journal, the abstract (#194) may be found in the meeting supplement, Volume 73, Number 9S of the journal Biological Psychiatry.
Editor’s Note: Low’s study is the first to report that childhood adversity is a risk factor for the onset of bipolar disorder in the general population.
Given the increasing evidence for the persistence of epigenetic marks on DNA and histones (which can’t change the sequence of genes but can change their structure) in those who have experienced such stressors in childhood, this could provide a mechanism for the long-term vulnerability of these children to the development of mood disorders and a variety of physical illnesses.
U.S. Patients with Bipolar Disorder Have More Stressors in Childhood and Prior to Illness Onset
In research published since 2008, our Editor-in-Chief Robert M. Post and colleagues in the Bipolar Collaborative Network have compared patients with bipolar disorder in the United States to those in Germany and the Netherlands. Compared to the European sample, patients in the US have more genetic vulnerability to bipolar disorder (by having a parent with bipolar disorder), earlier onsets of their illness, more complicated courses of illness, greater treatment resistance, and more medical comorbidities. Patients in the US also have more psychosocial stress.
The researchers are now turning their attention to these psychosocial vulnerabilities, and in a new paper that will be published in Psychiatry Research (late in 2013 or early in 2014), the authors show that patients in the US had more stressors both in childhood and just prior to the onset of their illness. Childhood stressors analyzed in the study were verbal abuse, physical abuse, and sexual abuse. Stressors in adulthood included indicators of a lack of social support, troubles with finances or employment, lack of access to health care, and medical comorbidities.
The stressors patients experienced just prior to their most recent episode of bipolar illness were related to: stressors in childhood, an earlier age of illness onset, anxiety and substance abuse comorbidity, lower income, both parents having an affective illness such as depression, and feeling more stigma.
The new research suggests that for patients with bipolar disorder in the US, adverse life events in childhood and later in life are more prevalent than they are for patients in the Netherlands or Germany. Earlier and more effective approaches to these stressors, such as the Family-Focused Therapy developed by David Miklowitz and Kiki Chang, could potentially slow the onset or progression of bipolar illness in this country.
