By the time psychosis appears in someone with schizophrenia, biological changes associated with the illness may have already been present for years. A 2015 article by R.S. Kahn and I.E. Sommer in the journal Molecular Psychiatry describes some of these abnormalities and how treatments might better target them.
One such change is in brain volume. At the time of diagnosis, schizophrenia patients have a lower intracranial volume on average than healthy people. Brain growth stops around age 13, suggesting that reduced brain growth in people with schizophrenia occurs before that age.
At diagnosis, patients with schizophrenia show decrements in both white and grey matter in the brain. Grey matter volume tends to decrease further in these patients over time, while white matter volume remains stable or can even increase.
Overproduction of dopamine in the striatum is another abnormality seen in the brains of schizophrenia patients at the time of diagnosis.
Possibly years before the dopamine abnormalities are observed, underfunctioning of the NMDA receptor and low-grade brain inflammation occur. These may be linked to cognitive impairment and negative symptoms of schizophrenia such as social withdrawal or apathy, suggesting that there is an at-risk period before psychosis appears when these symptoms can be identified and addressed. Psychosocial treatments such as individual, group, or family psychotherapy and omega-3 fatty acid supplementation have both been shown to decrease the rate of conversion from early symptoms to full-blown psychosis.
Using antipsychotic drugs to treat the dopamine abnormalities is generally successful in patients in their first episode of schizophrenia. Use of atypical antipsychotics is associated with less brain volume loss than use of the older typical antipsychotics. Treatments to correct the NMDA receptor abnormalities and brain inflammation, however, are only modestly effective. (Though there are data to support the effectiveness of the antioxidant n-acetylcysteine (NAC) on negative symptoms compared to placebo.) Kahn and Sommer suggest that applying treatments when cognitive and social function begin to be impaired (rather than waiting until psychosis appears) could make them more effective.
The authors also suggest that more postmortem brain analyses, neuroimaging studies, animal studies, and studies of treatments’ effects on brain abnormalities are all needed to clarify the causes of the early brain changes that occur in schizophrenia and identify ways of treating and preventing them.
At the 2015 meeting of the International Society for Bipolar Disorders, Ben Goldstein described a study of cognitive dysfunction in pediatric bipolar disorder. Children with bipolar disorder were three years behind in executive functioning (which covers abilities such as planning and problem-solving) and verbal memory.
There were other abnormalities. Youth with bipolar disorder had smaller amygdalas, and those with larger amygdalas recovered better. Perception of facial emotion was another area of weakness for children (and adults) with bipolar disorder. Studies show increased activity of the amygdala during facial emotion recognition tasks.
Goldstein reported that nine studies show that youth with bipolar disorder have reduced white matter integrity. This has also been observed in their relatives without bipolar disorder, suggesting that it is a sign of vulnerability to bipolar illness. This could identify children who could benefit from preemptive treatment because they are at high risk for developing bipolar disorder due to a family history of the illness.
There are some indications of increased inflammation in pediatric bipolar disorder. CRP, a protein that is a marker of inflammation, is elevated to a level equivalent to those in kids with juvenile rheumatoid arthritis before treatment (about 3 mg/L). CRP levels may be able to predict onset of depression or mania in those with minor symptoms, and is also associated with depression duration and severity. Goldstein reported that TNF-alpha, another inflammatory marker, may be elevated in children with psychosis.
Goldstein noted a study by Ghanshyam Pandey that showed that improvement in pediatric bipolar disorder was related to increases in BDNF, a protein that protects neurons. Cognitive flexibility interacted with CRP and BDNF—those with low BDNF had more cognitive impairment as their CRP increased than did those with high BDNF.
Researcher Ben Goldstein reported at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry that children with bipolar disorder have levels of inflammatory markers in the same range as people with inflammatory illnesses, such as rheumatoid arthritis. In his research, increases in the inflammatory marker c-reactive protein (CRP) occurred in proportion to the severity of manic symptoms in the children.
Goldstein also discussed cognitive dysfunction, which is often seen early in the course of childhood onset bipolar disorder. Goldstein described studies showing that this type of cognitive dysfunction consists of a decrease in reversal learning, a measure of cognitive flexibility. Elevated CRP was significantly associated with deficits in a child’s composite score for reversal learning.
Together these data suggest that inflammation could play a role in disease disability and cognitive dysfunction in childhood bipolar disorder.
Bipolar disorder is associated with cognitive dysfunction, and no definitive treatment has yet been found to reverse these problems with memory and attention. A new study by M. Kamilla presented at the 2014 meeting of the International Society of Bipolar Disorders explored the use of erythropoietin, a hormone that induces the production of red blood cells, as a treatment for cognitive dysfunction in bipolar disorder.
Participants in the double-blind study were randomized to receive either eight weekly erythropoietin infusions (40,000 IU) or eight weekly saline infusions. While there was only a trend toward improvement in verbal memory, there were other statistically significant outcomes: erythropoietin improved sustained attention, recognition of happy faces, and speed of complex information processing across learning, attention, and executive function. These outcomes were not related to changes in reaction time or mood, and lasted as long as six weeks after the eighth erythropoietin infusion, by which time red blood cell production had normalized.
Many patients with bipolar disorder experience cognitive deficits that impede their recovery and that persist during times of wellness. In a double-blind placebo-controlled study by K. N. Roy Chengappa et al. published in the Journal of Clinical Psychiatry in 2013, the herb Withania somnifera (WSE, commonly called ashwagandha and sold under the name Sensoril) was significantly better than placebo at improving patients’ performance on three different cognitive tasks.
In the eight-week study, 53 patients took either 500 mg of WSE or placebo in addition to their regular medications.
The herb, which has traditionally been used in Ayurvedic medicine in India as an aid to resisting stress and disease, improved performance on digit span backwards (a test of short-term memory in which the subject must repeat a sequence of numbers backwards), Flanker neutral (a test of response time in which a subject must repress their instinct to give an incorrect response), and the Penn Emotional Acuity Test (which requires subjects to correctly identify facial emotions depicted in photographs).
Mood and anxiety levels were not different for the group taking WSE and the group taking placebo.
The researchers hope to continue their investigation of WSE with larger and longer-term studies that will explore the effects of different doses of WSE.
Metformin, one of the most popular drugs to treat type 2 diabetes, interferes with uptake of vitamin B12, which can in turn lead to some neuronal dysfunction resulting in cognitive dysfunction. Several studies have sought to clarify this link, which may affect up to 30% of patients taking the drug.
Most recently, an Australian analysis of 1354 aging patients found that those with type 2 diabetes performed less well on tests of cognitive abilities, and those diabetic patients with low vitamin B12 levels (below 250 pmol/L) scored lower than those diabetic patients with adequate levels.
Because of the malabsorption problem caused by metformin, patients taking the drug may not be able to get enough B12 from a balanced diet alone and may need supplemental B12. Those who follow a vegetarian diet, have had bowel surgery, have certain complications with the stomach, or who take other medications that depress stomach acid may be at special risk.
Physicians should carefully monitor B12 levels in patients taking metformin, particularly those who have been taking the drug for more than 3 years or those who already suffer from some sort of cognitive impairment.
We’ve written before that the dietary supplement citicoline improved depression in both unipolar and bipolar patients with methamphetamine dependence, reduced cocaine use in bipolar depressed patients with cocaine dependence, and improved cognition in healthy middle-aged women. Findings from a 2013 Italian study by Gareri et al. published in Clinical Interventions in Aging suggests that citicoline improves mild vascular cognitive impairment in older adults, though the study was not randomized, so its results may not be reliable. Citicoline is a natural substance found in the brain and the liver that can also be taken as a nutritional supplement.
The study examined 349 patients over age 64 (mean age 79.9) who had memory impairment and evidence of vascular lesions in the brain (but not Alzheimer’s disease). Participants who received citicoline (500mg twice daily for 9 months) scored better on a memory examination at 3 months and at the completion of the study, while participants who did not receive citicoline performed worse on the exam. Those who received citicoline also saw some statistically non-significant improvement in mood.
The researchers believe that citicoline’s effects may also extend to Alzheimer’s dementia because citicoline contributes to the synthesis of acetylcholine. (Most Alzheimer’s drugs inhibit the breakdown of acetylcholine).
Side effects were minimal, and included occasional excitability or restlessness, digestive intolerance, and headaches.
This editor (RM Post) in collaboration with Jacqueline Fleming and Flavio Kapczinski published the article “Neurobiological mechanisms of illness progression in the recurrent affective disorders” in the Journal of Psychiatric Research this year. The article built on several themes about the progression of bipolar illness that had been explored in previous research.
These themes include:
- The likely acceleration of repeated episodes as a function of the number of prior episodes (episode sensitization)
- The increased responsivity of the illness to repeated stressors (stress sensitization)
- The increased behavioral reactivity to repeated use of psychomotor stimulants such as cocaine (stimulant-induced behavioral sensitization)
Not only are these observations well documented in the scientific literature, but recent observations also suggest that each type of sensitization can show cross-sensitization to the other two types. That is, individuals exposed to repeated stressors are more likely both to experience affective illness episodes and to adopt comorbid substance abuse. In a similar way, episodes of an affective disorder and stressors may also be associated with the relapse into drug administration in those who have been abstinent.
In addition to these mechanisms of illness progression in the recurrent affective disorders, the new article reviews the literature showing that the number of affective episodes or the duration of the illness appear to be associated with a variety of other clinical and neurobiological variables.
The number of affective episodes a patient experiences is associated with the degree of cognitive dysfunction present in their bipolar illness, and experiencing more than 4 episodes of unipolar or bipolar depression is a risk factor for dementia in late life. A relative lack of response to most treatments is also correlated with the number of prior episodes, and this holds true for response to naturalistic treatment in general. While most of these data are correlational and the direction of causality cannot be ascertained for certain, it is likely that the number of affective episodes and/or their duration could account for and drive difficulties with treatment and with cognitive function.
If this were the case, one would expect to see a variety of neurobiological correlates with the number of prior episodes or duration of illness, and in the article we summarize those that have been found in unipolar and bipolar disorder. Considerable data indicate that cortical volume and degrees of prefrontal cortical dysfunction can vary as a function of number of prior episodes. There is evidence that increased activity of the amygdala and the nucleus accumbens are also related to episodes or duration of illness. In those with unipolar depression, the volume of the hippocampus is decreased with longer duration of illness. Read more
Anti-Alzheimer’s Drug Memantine (Namenda) Has Positive Effects On Cognitive Dysfunction In Patients With Bipolar Disorder
Many patients with bipolar disorder experience cognitive dysfunction, but few treatments are available for this aspect of the illness. 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.
Editor’s Note: These data are of considerable importance. Many studies indicate that the severity of the cognitive dysfunction patients experience while euthymic varies directly as a function of the number of prior episodes of mania or depression they have experienced. The degree of cognitive dysfunction in patients with bipolar disorder is also correlated with disability in social and economic functioning. Thus, the data that memantine can lead to improvement in several types of memory tests suggest that the drug could be useful in treating these deficits in some patients with bipolar disorder.
Memantine acts in part by blocking glutamate NMDA receptors and provides a different mechanism of action compared to the other drugs used to treat Alzheimer’s, which increase acetylcholine by blocking acetylcholinesterase.
Memantine has also shown promising effects in enhancing the antidepressant effects of lamotrigine, a drug that inhibits glutamate release. Thus, the similar target of action by which lamotrigine (blocking glutatmate release) and memantine (blocking glutamate receptors) operate suggest that the two drugs used in conjunction might produce additive effects in decreasing glutamate function. The current data suggest that memantine compared to placebo as an add-on to other agents in euthymic bipolar patients improves several measures of cognition as well.
New data published by Koukopoulos in the Journal of Affective Disorders in 2012 suggest that memantine (10-30mg/day) is an effective add-on treatment in severely ill patients with treatment-resistant bipolar disorder. Among those in Koukopoulos’ study, 72.5% were much or very much improved, thus there is a strong rationale for considering this drug.
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