Progressive losses in gray matter have been observed in the cortex of people with schizophrenia, and those at high risk for the illness. In the past, studies have shown that the amount of antipsychotics a patient is exposed to is correlated with the extent of their deficits in gray matter, suggesting that antipsychotic treatment could exacerbate gray matter loss.
A new meta-analysis by Antotonio Vita and colleagues in the journal Biological Psychiatry shows that first-generation antipsychotics were associated with greater losses in gray matter compared with atypical antipsychotics, which seemed to slow the loss of gray matter.
The meta-analysis analyzed data from 18 longitudinal studies comparing a total of 1155 patients with schizophrenia to 911 healthy control participants. Magnetic resonance imaging (MRI) scans showed that over time, patients with schizophrenia lost more cortical gray matter volume. The patients’ cumulative intake of any kind of antipsychotic between MRI scans was associated with gray matter losses. But when Vita and colleagues drilled down to find differences between patients taking first-generation antipsychotics and those taking second-generation atypical antipsychotics, they found that patients with higher average daily intake of first-generation antipsychotics had greater losses in gray matter, while patients with higher average daily intake of atypical antipsychotics had less progressive losses in gray matter.
This study is the first to compare the effects of first-generation antipsychotics, which were developed in the 1960s, with those of atypical antipsychotics, which came into frequent use in the late 1980s, on cortical gray matter loss in schizophrenia. While first-generation antipsychotics are associated with the side effect of tardive dyskinesia, involuntary movements of the face and jaw, atypical antipsychotics are most commonly associated with weight gain.
Three studies have randomly assigned patients with schizophrenia to receive either first-generation or atypical antipsychotics. In these studies as well, second-generation antipsychotics were associated with smaller losses in gray matter.
The authors speculate that either second-generation antipsychotics may have neuroprotective effects, or first-generation antipsychotics may have neurotoxic effects. They also suggest that first-generation antipsychotics may not have the capacity to interfere with the natural progression of schizophrenia in terms of gray matter losses.
Future studies may investigate differences between specific antipsychotic medications’ effects on gray matter volume. Vita and colleagues reported that in the analysis, the atypical antipsychotic clozapine was associated with the least loss of gray matter of any medication in the included studies.
Editor’s Note: This study is important because it adds to findings questioning the conclusions of a large National Institute of Mental Health–sponsored study known as CATIE and a meta-analysis by John Geddes published in the journal BMJ in 2000, in which he wrote that “There is no clear evidence that atypical antipsychotics are more effective or better tolerated than conventional (first generation) antipsychotics.” Read more
According to researcher David J. Bond at the 2014 meeting of the International Society for Bipolar Disorders, “Up to 75% of people with bipolar disorder (BD) are overweight or obese, and these patients suffer more severe psychiatric symptoms than normal-weight patients, including more frequent depressions, more suicide attempts, lower response rates to pharmacotherapy, and greater inter-episode cognitive impairment.” Obesity is a chronic inflammatory condition that damages body organs, and it appears as though the brain may be one of these. Adipose (fatty) tissue is an endocrine organ that produces substances that cause inflammation in blood vessels and that damage the heart.
Obesity is associated with decreased total brain volume, and in children, decreased gray matter volume. Obesity increases the risk of cognitive impairment, and decreases memory, attention, and executive functioning. Obesity increases the risk of Alzheimer’s disease, as well as multiple sclerosis, Parkinson’s, and depression.
In bipolar disorder, obesity decreases response to mood stabilizers and atypical antipsychotics. Bond found that in patients with a first episode of mania, body mass index (BMI) was inversely related to white matter volume and temporal lobe gray matter volume. Higher BMIs also led to neurochemical changes including increased hippocampal glutamate and reduced N-acetylaspartate. Bond also noted findings by Roger S. McIntyre that weight loss surgery in patients with bipolar disorder led to more positive treatment outcomes.
Editor’s Note: These findings speak to the importance of exercise and good diet, using medications with the least likelihood of weight gain, and treating obesity once it has developed. We have previously noted the weight loss effects of topiramate and zonisamide, and new data support the substantial weight loss with the combination of bupropion (150-300mg) and naltrexone (50mg).
Marijuana Addiction Associated with White Matter Loss and Brain Changes in Healthy People and Those with Schizophrenia
It has been established that cannabis use is associated with impairments in working memory, but researchers are still investigating how these impairments come about. A 2013 study by Matthew J. Smith et al. in the journal Schizophrenia Bulletin compared regular marijuana users both with and without schizophrenia with demographically similar people who did not use marijuana.
Using magnetic resonance imaging (MRI), the researchers were able to map each participant’s brain structures. Healthy people who were marijuana users showed deficits in white matter (axons of neurons that are wrapped in myelin) compared to healthy people who did not use the drug. Similarly, patients with schizophrenia who used marijuana regularly had less white matter than those patients with schizophrenia who did not use the drug. There were also differences in the shapes of brain structures, including the striatum, the globus pallidus, and the thalamus, between cannabis users and non-users.
Differences in the thalamus and striatum were linked to white matter deficits and to younger age of cannabis use disorder onset.
Differences between cannabis users and non-users were more dramatic across the populations with schizophrenia than across the healthy populations.
Editors note: Future research is needed to determine whether marijuana causes these brain changes, or whether the brain changes are a biomarker that shows a vulnerability to marijuana addiction (although the latter is less likely than the former).
Other data show that marijuana is associated with an increase in psychosis (with heavy use), cognitive deficits, and an earlier onset of both bipolar disorder and schizophrenia in users compared to non-users. These findings make pot begin to look like a real health hazard. With legalization of marijuana occurring in many states, ease of access will increase, possibly accompanied by more heavy use. The most consistent pharmacological effect of marijuana is to produce an amotivational syndrome, characterized by apathy or lack of interest in social activities. Particularly for those already struggling with depression, pot is not as benign a substance as it is often thought to be.
Brain-derived neurotrophic factor (BDNF) keeps neurons healthy and is critical for long-term memory and synapse formation. BDNF levels increase in the nucleus accumbens (the brain’s reward center) and decrease in the hippocampus during clinical depression and chronic cocaine use. In rodents, the same changes in BDNF levels occur during defeat stress (which resembles human depression).
Rodents who are repeatedly defeated by a larger rodent exhibit behaviors such as social withdrawal, lethargy, and decreased interest in sucrose. The increases in BDNF in the nucleus accumbens of these rodents could reflect the learning that takes place during the repeated defeat stress and the depression-like behaviors that follow it. Blocking the BDNF increases in the nucleus accumbens prevents these behaviors from developing.
Chadi Abdallah and other researchers at Yale University recently found that the left nucleus accumbens of patients with treatment-resistant depression is enlarged compared to normal controls, and the drug ketamine, which produces rapid-onset antidepressant effects, rapidly decreases the volume of the nucleus accumbens in the depressed patients. The mechanism by which it does so is unknown, but could reflect some suppression of the depressive learning.
Any relationship between the volume of the nucleus accumbens and its levels of BDNF is unknown, but ketamine’s effect on the size of this brain region could be linked to a decrease in the defeat-stress memories.
In a 2013 study of children by Luby et al. in the Journal of the American Medical Association Pediatrics, poverty in early childhood was associated with smaller white and gray matter in the cortex and with smaller volume of the amygdala and hippocampus when the children reached school age. The effects of poverty on hippocampal volume were mediated by whether the children experienced stressful life events and whether a caregiver was supportive or hostile.
The children were recruited from primary care and day care settings between the ages of three and six, and were studied for five to ten years. They were initially assessed annually for three to six years and information on psychosocial, behavioral, and developmental dimensions were collected. Then the children took part in a magnetic resonance imaging (MRI) scan and continued annual assessments that included information such as whether the children experienced stressful life events.
Previous research has shown that poverty affects children’s psychosocial development and economic success in adulthood. This research shows that poverty also affects brain development. The findings suggest important targets for intervention that could help prevent these developmental deficits.
Studies have indicated that lithium increases gray matter and the volume of the cortex and hippocampus in patients with bipolar I disorder. A poster presented by S. Selek et al. at the 5th Biennial Conference of the International Society for Bipolar Disorders described a longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment.
This study reported that patients whose illness failed to respond to lithium had smaller right amygdalas than euthymic bipolar I patients or healthy controls. After treatment with lithium, those who responded well to the drug showed significant enlargement of the left prefrontal cortex and the left dorsolateral prefrontal cortex, while those who responded poorly to lithium showed decreases in the volume of their left hippocampus and right anterior cingulate cortex.
Editor’s Note: This is one of several studies that suggest a relationship between volume of brain regions and degree of response to lithium. These data add to the remarkably consistent literature suggesting that lithium may have neurotrophic and neuro-protective effects, potentially because of the drug’s ability to increase neuroprotective factors such as BDNF and Bcl-2 while decreasing cell death factors such as BAX and p53.
There is considerable evidence that children with bipolar disorder have smaller amygdalas, and the amygdala also appears to be hyper-reactive when these children perform facial emotion recognition tasks. A symposium on longitudinal imaging studies in pediatric bipolar disorder was held at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry to shed light on other brain abnormalities in these children.
Researcher Nancy Aldeman reported that there is some evidence children with bipolar disorder have decreased gray matter volume in parts of the brain including the subgenual cingulate gyrus, the orbital frontal cortex, and the superior temporal gyrus, as well as the left dorsolateral prefrontal cortex and amygdala. At the same time there is evidence of increased size of the basal ganglia. These abnormalities do not appear to precede the onset of the illness.
Some changes occur over the course of the illness. The basal ganglia seem to increase in volume in patients with bipolar disorder, but decrease in volume in those with severe mood dysregulation and comorbid ADHD. Moreover, parietal cortex and precuneus cortex volumes appeared to increase in children with bipolar disorder while decreasing or staying the same in normal volunteer controls.
A meta-analysis of brain imaging studies indicated that in general, the size of the amygdala appears to increase from childhood to adulthood in bipolar patients, starting out smaller than that of similarly-aged normal volunteers, but becoming larger than that of adult normal volunteers as the patients age into adulthood.
Lithium treatment increases gray matter volume in a variety of cortical areas and in the hippocampus in multiple studies. In contrast, treatment with valproate for 6 weeks appears to decrease hippocampal volume.
At the American Academy of Child and Adolescent Psychiatry (AACAP) annual meeting in Toronto in October 2011, there was a symposium on risk and resilience factors in the onset of bipolar disorder in children who have a parent with the disorder.
Family Focused Therapy Highly Encouraged
Amy Garrett reported that family focused therapy (FFT) in those at risk for bipolar disorder was effective in ameliorating symptomatology compared to treatment as usual. Family focused therapy, pioneered by Dave Miklowitz, PhD of UCLA involves three components. The first component is education about the illness and methods of self-management. The second is enhancement of communication in the family with practice and rehearsal of new modes of conversation. The third component is assistance with problem solving.
In Garrett’s study, 50 children aged 7 to 17 were randomized to family focused treatment or treatment as usual. These children were not only at high risk for bipolar disorder, they were already prodromal, meaning they were already diagnosable with bipolar not otherwise specified (BP-NOS), cyclothymia, or major depressive disorder, and had also shown concurrent depressive and/or manic symptoms in the two weeks prior to the study. At baseline, compared to controls, these children at high risk for full-blown bipolar disorder by virtue of a parental history of the illness showed increased activation of the amygdala and decreased activation of the prefrontal cortex. Most interestingly, after improvement with the family focused therapy (FFT), amygdala reactivity to emotional faces became less prominent and dorsolateral prefrontal cortical activity increased in proportion to the degree of the patient’s improvement.
The discussant for the symposium was Kiki Chang of Stanford University, who indicated that the results of this study of family focused therapy were already sufficient to convince him that FFT was a useful therapeutic procedure in children at high risk for bipolar disorder by virtue of having a parent with a history of bipolar illness. Chang is now employing the therapy routinely in all of his high-risk patients.
Editors Note: This is an extremely important recommendation as it gives families a specific therapeutic process in which to engage children and others in the family when affective behavior begins to become abnormal, even if it does not meet full criteria for a bipolar I or bipolar II disorder.
FFT also meets all the important criteria needed for putting it into widespread clinical practice. Family focused therapy has repeatedly been shown to be effective in adults and adolescents with bipolar illness and now also in these children who are prodromal. The psychoeducational part of FFT is common sense, and dealing with communication difficulties and assisting with problem solving also have merit in terms of stress reduction. Finally, this treatment intervention appears to be not only safe but also highly effective in a variety of different prodromal presentations of affect disorders even if children do not meet full criteria for bipolar disorder. While the few studies of early intervention with psychopharmacological agents have not yet identified efficacious medications for the prodromes of bipolar disorder and in particular medications with a high degree of safety, such family focused therapy appears to be an ideal early intervention.
I would concur with Dr. Chang’s assessment. Family focused therapy (FFT) should be offered to all children with this high-risk status who have begun to be symptomatic. Early onset of unipolar depressive disorder or of bipolar disorder carries a more adverse prognosis than the adult onset variety and thus should not be ignored. If more serious illness is headed off early, it even raises the possibility that the full-blown illness will not develop at all.
Gray Matter Volume Abnormalities
Tomas Hajek of Dalhousie University in Halifax presented data indicating that in children at high risk for bipolar disorder, gray matter volume in the right inferior frontal gyrus is increased. Read more
At a symposium on new research on juvenile bipolar disorder at the meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) in 2010, the discussant Kiki Chang of Stanford University reported some recent neurobiological findings on childhood bipolar disorder. He found evidence that prefrontal cortical volume appears to decrease over the course of the illness and, conversely, there was evidence of increases in amygdala volume. He also found that the volume of the striatum (or caudate nucleus, which is involved in motor control) increased in children with bipolar illness or bipolar illness comorbid with ADHD, but decreased in children with ADHD alone.
Chang cited the study of Singh et al. (2010) who found that the subgenual anterior cingulate volume early in the course of illness was smaller in adolescent-onset bipolar disorder compared to controls. Given this evidence of prefrontal cortical and anterior cingulate deficits, Dr. Chang raised the possibility that treatment with lithium and other agents with potential neurotrophic and neuroprotective effects might be able to prevent these neurobiological aspects of illness progression in young patients.
Ish Bhalla reported at the 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) in October 2010 that children with autism have greater thalamic volume than normal controls. Other posters presented at the meeting showed that patients with autism spectrum disorders have connectivity abnormalities, with increased connectivity of neurons to other nearby neuronal groups and decreased connectivity of neurons to areas of the brain at a greater distance.
Editor’s Note: These findings echo reports that the corpus callosum, the main structure connecting neurons across the two hemispheres of the brain, is smaller in autism. In addition, other investigators have reported abnormalities in cortical column structure in autism.
Interestingly, the findings of increased volume and altered connectivity may even be reflected in measurements of brain and head size. A substantial literature supports the observations that children with autism have greater initial head size and growth of their heads compared with the normal infant population.