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Background
It is well established that schizophrenia is associated with structural brain abnormalities, but whether these are static or progress over time remains controversial.
Methods
A systematic review of longitudinal volumetric studies using region-of-interest structural magnetic resonance imaging in patients with schizophrenia and healthy control subjects. The percentage change in volume between scans for each brain region of interest was obtained, and data were combined using random effects meta-analysis.
Results
Twenty-seven studies were included in the meta-analysis, with 928 patients and 867 control subjects, and 32 different brain regions of interest. Subjects with schizophrenia showed significantly greater decreases over time in whole brain volume, whole brain gray matter, frontal gray and white matter, parietal white matter, and temporal white matter volume, as well as larger increases in lateral ventricular volume, than healthy control subjects. The time between baseline and follow-up magnetic resonance imaging scans ranged from 1 to 10 years. The differences between patients and control subjects in annualized percentage volume change were −.07% for whole brain volume, −.59% for whole brain gray matter, −.32% for frontal white matter, −.32% for parietal white matter, −.39% for temporal white matter, and +.36% for bilateral lateral ventricles.
Conclusions
These findings suggest that schizophrenia is associated with progressive structural brain abnormalities, affecting both gray and white matter. We found no evidence to suggest progressive medial temporal lobe involvement but did find evidence that this may be partly explained by heterogeneity between studies in patient age and illness duration. The causes and clinical correlates of these progressive brain changes should now be the focus of investigation.
Are There Progressive Brain Changes in Schizophrenia? A Meta-Analysis of Structural Magnetic Resonance Imaging Studies
In an open-label study from Australian researchers presented here at the Ninth International Conference on Bipolar Disorder (ICBD), patients diagnosed with bipolar disorder and given 2000 mg of NAC in addition to their "treatment as usual" showed significantly lower symptom severity scores and increased functioning and quality-of-life scores.
Adjunctive N-Acetyl Cysteine Effective for Bipolar Depression
Excitotoxicity
Several lines of evidence suggest that glutamatergic system dysfunction (eg, N-methyl d-aspartate [NMDA] receptor complex) may play a critical role in the pathophysiology of bipolar disorder. In keeping with this view, the use of glutamatergic modulators may be predicted to alleviate symptoms and modify the disease process. Postmortem studies indicate that altered NMDA receptor complexes are observed in the brain tissue of patients with bipolar disorder. Moreover, genetic polymorphisms for genes implicated in the glutamate receptor complex have been associated with this disorder.6
Riluzole, an inhibitor of glutamate release, is approved by the FDA for the treatment of amyotrophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS).
Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.7 Results from a double-blind, randomized, placebo-controlled, crossover study indicate that a single intravenous infusion of ketamine(Drug information on ketamine) combined with lithium or valproate(Drug information on valproate) was capable of alleviating depressive symptoms within 40 minutes of administration when compared with placebo.7 The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was not associated with significant increases in hypomania or mania but was associated with dissociative symptoms.
Cyclooxygenase-2 (COX-2) inhibitors have been shown to protect against glutamate-induced neurotoxicity; to prevent normal aging-related increases of cytokines, prostaglandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis.10 The COX-2 inhibitor celecoxib(Drug information on celecoxib) was evaluated as a potential antidepressant in adults with bipolar I/II depression (N = 28).10 This drug was administered at a dosage of 400 mg daily in combination with a mood stabilizer or antipsychotic medication as part of a 6-week, randomized, double-blind, placebo-controlled study. Depressive symptoms in both the treatment group and the placebo group improved, with a statistically significant (P = .01) advantage at week 1 in patients treated with celecoxib compared with patients who received placebo. Although there was an advantage in favor of the treatment group at week 1, both the active-treatment and placebo groups had similar reductions for each of the remaining observation points.
Several case reports and case series suggest that insulin sensitizers (eg, rosiglitazone(Drug information on rosiglitazone)) may offer an antidepressant effect in persons with major depressive disorder. Studies are currently under way in bipolar disorder. For example, several studies are evaluating the antidepressant effects of intranasal insulin and insulin secretagogues (eg, incretins) in bipolar disorder. Moreover, there is ongoing research to determine whether weight loss, bariatric surgery, and dietary modification (eg, ketogenic diet) improve depressive symptoms in persons with bipolar disorder.
Results from a randomized, double-blind, multicenter, placebo-controlled study of adults with bipolar disorder (N = 75) indicate that N-acetylcysteine (1 g bid) adjunctive to usual medications was capable of alleviating depressive symptoms as measured by the MADRS.14 The benefit on depressive symptoms was noted at week 20 as part of this 24-week study. Benefits were noted by week 8 on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale. N-acetylcysteine did not induce hypomania or mania and was well tolerated. Adverse events reported in more than 15% of the N-acetylcysteine group included change in energy, headaches, heartburn, and increased joint pain.
Armodafinil is the longer-lasting isomer of modafinil, and its therapeutic indications are similar to those of the racemic agent modafinil. Armodafinil at a dosage of 150 mg/d was evaluated as an antidepressant in adults with bipolar disorder who received either olanzapine, lithium, or valproic acid as part of an 8-week double-blind placebo-controlled study.
Novel Treatment Avenues for Bipolar Depression
The pharmacological effects of MDMA include serotonin release; serotonin type 2 receptor stimulation; and an increase in levels of the neurohormones oxytocin(Drug information on oxytocin), prolactin, and cortisol.24-29 Serotonin release plays an important role in producing the subjective effects of MDMA.30-33 Pretreatment with SSRIs reduces most acute subjective and physiological effects of MDMA, including effects on mood and perception. Serotonin release directly or indirectly leads to an elevation in oxytocin levels, possibly by stimulating serotonin type 1A receptors.24,28,34 Studies suggest that oxytocin plays an important role in stress response, reduces the fear response, and increases social affiliation and trust35-39; thus, elevated oxytocin levels might help patients form a therapeutic alliance and revisit traumatic experiences in an emotionally engaged state.
Elevation in oxytocin levels after MDMA administration has been associated with greater sociability and more gregarious behavior.24 MDMA has recently been shown to decrease perception of negative emotions in others and perception of threat-related signals, such as fear, which might increase social approach behavior.40 It has been postulated that prolactin release following MDMA administration may contribute to a postorgasmic-like sense of relaxation and receptivity.41 The neurocircuitry model of PTSD postulates a deficit in extinction of fear conditioning mediated by the amygdala and the ventromedial prefrontal cortex, a model supported by findings of reduced hippocampal activity and volume, increased activity in the amygdala, and decreased activation of the medial prefrontal cortex in persons with PTSD.42,43
Gamma and colleagues44 used positron emission tomography to measure cerebral blood flow 75 minutes after MDMA was given to healthy volunteers. Their findings showed increases in cerebral blood flow in the ventromedial frontal and occipital cortex and decreases in the left amygdala. MDMA may produce some of its effects through these acute changes in brain activity, which may reverse abnormalities associated with PTSD and thereby allow effective processing of traumatic memories. The nature of the effects is consistent with much of what we observed in our clinical trial.
Does MDMA Have a Role in Clinical Psychiatry?
Problems with postural control may be a core feature of bipolar disorder (BD) and not just a random symptom, new research suggests.
In a small comparison study of 32 patients, those with BD showed a "greater sway magnitude" compared to healthy controls, especially when asked to close their eyes.
Off Balance? Postural Problems May Point to Bipolar Disorder
Context A number of studies have found that the use of cannabis and other psychoactive substances is associated with an earlier onset of psychotic illness.
Objective To establish the extent to which use of cannabis, alcohol, and other psychoactive substances affects the age at onset of psychosis by meta-analysis.
Data Sources Peer-reviewed publications in English reporting age at onset of psychotic illness in substance-using and non–substance-using groups were located using searches of CINAHL, EMBASE, MEDLINE, PsycINFO, and ISI Web of Science.
Study Selection Studies in English comparing the age at onset of psychosis in cohorts of patients who use substances with age at onset of psychosis in non–substance-using patients. The searches yielded 443 articles, from which 83 studies met the inclusion criteria.
Data Extraction Information on study design, study population, and effect size were extracted independently by 2 of us.
Data Synthesis Meta-analysis found that the age at onset of psychosis for cannabis users was 2.70 years younger (standardized mean difference = –0.414) than for nonusers; for those with broadly defined substance use, the age at onset of psychosis was 2.00 years younger (standardized mean difference = –0.315) than for nonusers. Alcohol use was not associated with a significantly earlier age at onset of psychosis. Differences in the proportion of cannabis users in the substance-using group made a significant contribution to the heterogeneity in the effect sizes between studies, confirming an association between cannabis use and earlier mean age at onset of psychotic illness.
Conclusions The results of meta-analysis provide evidence for a relationship between cannabis use and earlier onset of psychotic illness, and they support the hypothesis that cannabis use plays a causal role in the development of psychosis in some patients. The results suggest the need for renewed warnings about the potentially harmful effects of cannabis.
Cannabis Use and Earlier Onset of Psychosis
OBJECTIVE: Data on the effectiveness of antipsychotics in the early phase of schizophrenia are limited. The authors examined the risk of rehospitalization and drug discontinuation in a nationwide cohort of 2,588 consecutive patients hospitalized for the first time with a diagnosis of schizophrenia between 2000 and 2007 in Finland.
METHOD: The authors linked national databases of hospitalization, mortality, and antipsychotic prescriptions and computed hazard ratios, adjusting for the effects of sociodemographic and clinical variables, the temporal sequence of the antipsychotics used, and the choice of the initial antipsychotic for each patient.
RESULTS: Of 2,588 patients, 1,507 (58.2%) collected a prescription for an antipsychotic during the first 30 days after hospital discharge, and 1,182 (45.7%, 95% confidence interval [CI]=43.7–47.6) continued their initial treatment for 30 days or longer. In a pairwise comparison between depot injections and their equivalent oral formulations, the risk of rehospitalization for patients receiving depot medications was about one-third of that for patients receiving oral medications (adjusted hazard ratio=0.36, 95% CI=0.17–0.75). Compared with oral risperidone, clozapine (adjusted hazard ratio=0.48, 95% CI=0.31–0.76) and olanzapine (adjusted hazard ratio=0.54, 95% CI=0.40–0.73) were each associated with a significantly lower rehospitalization risk. Use of any antipsychotic compared with no antipsychotic was associated with lower mortality (adjusted hazard ratio=0.45, 95% CI=0.31–0.67).
CONCLUSIONS: In Finland, only a minority of patients adhere to their initial antipsychotic during the first 60 days after discharge from their first hospitalization for schizophrenia. Use of depot antipsychotics was associated with a significantly lower risk of rehospitalization than use of oral formulations of the same compounds. Among oral antipsychotics, clozapine and olanzapine were associated with more favorable outcomes. Use of any antipsychotic was associated with lower mortality.
A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia
The study did find that treatment discontinuation was more common in the group that switched to monotherapy than in the polypharmacy group, but the symptom control and weight loss associated with the switch to monotherapy suggests that monotherapy may be an option worth trying for patients who are relatively stable.
Monotherapy After Polypharmacy Effective for Some Patients
“Metyrapone is a drug that significantly decreases the levels of cortisol, a stress hormone that is involved in memory recall,” explained lead author Marie-France Marin, a doctoral student.
Manipulating cortisol close to the time of forming new memories can decrease the negative emotions that may be associated with them, the researchers said.
“The results show that when we decrease stress hormone levels at the time of recall of a negative event, we can impair the memory for this negative event with a long-lasting effect,” said Sonia Lupien, Ph.D., who directed the research.
The Drug Metyrapone to Erase Bad Memories?
The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P=5.9e−7). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared with Caucasians (allele frequency 67 vs 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable.
Genetic variation in CYP3A43 explains racial difference in olanzapine clearance
Interferons are powerful antivirals but they have the dubious honor of being one of the few medical drugs clearly implicated in causing depression. Others include reserpine, an anti-hypertensive and rimonabant, a weight-loss drug (it got banned for this reason).
The anti-malarial mefloquine can cause a range of neuropsychiatric symptoms including depression but also hallucinations and nightmares, as can the HIV drug efavirenz which I covered recently.
Most people who take each of these drugs don't experience problems but in a non-trivial minority it happens. It obviously poses a serious problem for doctors, but it's also very interesting for people researching mood and depression. Work out why these drugs cause depression, and it might help work out why people get "normal" clinical depression.
For example, just recently it was shown that mefloquine has a unique and unusual effect on cells in the dopamine system of the brain, responsible for motivation and pleasure. Whether this explains the side-effects is an open question but without mefloquine we wouldn't even be able to ask it.
As for interferons, which are actually not drugs as such but rather molecules produced by the immune system during infections, it's given rise to the inflammation theory of depression. There's always a risk, though, that by focussing too much on just one class of depressing drug, you'll end up with a narrow theory that can't account for the others.
Antivirals and Suicide
