Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68:128-137.
This longitudinal study looked at 211 patients with first episode schizophrenia who were treated with either first and/or second generation antipsychotics. The patients had repeated MRI scans over an average period of 7.2 years (ranging up to 14 years). Brain volume changes were examined in terms of their relationship to informant reports of the duration of illness, symptom severity, the particular type of antipsychotic used, and history of substance abuse. The more exposure to antipsychotic medications, the greater the volume reductions in grey and white matter, except in the putamen. The longer the duration of illness and the more severe the symptoms, the more reductions in brain volume. Only the role of antipsychotic exposure in reducing brain volumes remained after controlling for the other predictors. Both first generation and second generation antipsychotics reduced brain volumes.
As the augmenting uses of antipsychotics grow in treatments of nonpsychotic disorders, particularly in children, the potential reduction of brain volume should encourage the use of alternative augmenting agents, when treatment augmentation is necessary.
Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen(Drug information on tamoxifen): a population based cohort study. BMJ. 2010;340:c693.
A large cohort of older women with breast cancer (2430), treated with tamoxifen and a single SSRI were examined for possible competition for cytochrome P450 2D6 (CYP2D6). Tamoxifen is a prodrug that is metabolized by the hepatic cytochrome P450 enzyme system to its clinically active metabolite, endoxifen. Conversion of tamoxifen to endoxifen is predominantly done by the enzyme CYP2D6. Consequently, drugs that inhibit the CYP2D6 enzyme may potentially interfere with the conversion of tamoxifen to its clinically active metabolite. Mortality rates were compared across different SSRIs and the proportion of time these treatments overlapped. Paroxetine(Drug information on paroxetine) was found to be the only SSRI that increased mortality rates, and the longer the overlap between paroxetine and tamoxifen, the higher the mortality rate. Paroxetine should be avoided if possible for women undergoing tamoxifen treatments.
Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry. 2010;197:266-271.
This large Danish epidemiological study compared the incidence of diabetes among 1.5 million people who did not use antipsychotic medications, and among 350,000 people who were exposed to first and/or second generation antipsychotic medications. Danish registers for prescriptions filled at pharmacies, medical disorders, psychiatric disorders, and total population from 1996 through 2005 were linked to produce the comparison cohorts and measured outcomes. Rates of diabetes per 10,000 person years ranged from 27.5 for unexposed people to 78.9 for people exposed to both first and second generation antipsychotics. As the number of prescriptions for antipsychotic medications increased, so did the rate of diabetes. As the number of antipsychotics used simultaneously in polypharmacy increased, the incidence of diabetes increased.
Comparison between different antipsychotics showed incidence rate differences although physician decision making about who to put on which medication may have biased the results. Overall, it is clear that antipsychotics in general, and especially polypharmacy, are associated with increased diabetes risk.
Serretti A, Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics. Int Clin Psychopharmacol. 2011;26:130-140.
Studies of sexual dysfunction associated with single antipsychotic use were combined in a meta-analysis. Rates of overall sexual dysfunction for different antipsychotics were compared. Rates of sexual dysfunction between 16% and 27% were found with quetiapine, ziprasidone(Drug information on ziprasidone), aripiprazole(Drug information on aripiprazole), and perphenazine(Drug information on perphenazine), while rates between 40% and 60% were found for olanzapine, clozapine(Drug information on clozapine), risperidone(Drug information on risperidone), haloperidol(Drug information on haloperidol), and thioridazine(Drug information on thioridazine). This was interpreted as reflecting different levels of prolactin raising effects. Psychiatrists can now include risk of sexual adverse effects when choosing among antipsychotic medications.
Potential to change clinical practice
These studies have the promise of improving clinical care, but require too many assumptions at this point to merit clinical application. Additional studies are needed to eliminate some of the assumptions that must be made. These are more suggestive of future directions and developments than of ways to improve treatment outcomes.
Johnson BA, Ait-Daoud N, Seneviratne C, et al. Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol(Drug information on alcohol) drinking. Am J Psychiatry. 2011;168: 265-275.
Actively drinking alcohol-dependent patients (N = 283) who sought treatment were randomly assigned to ondansetron(Drug information on ondansetron) treatment or to placebo. The patients were stratified on the basis of the type of polymorphism in the regulatory region of their serotonin transporter gene, the long type (LL), the short type (SS), or a combined long and short (LS). Patients were also categorized on the basis of an additional single nucleotide polymorphism (SNP) T or G at another region of the serotonin transporter gene. Of primary interest was whether the effects of ondansetron were different as a function of the type of polymorphism. Patients in all groups received CBT. Using intent-to-treat analyses, the long type ondansetron group showed significant reductions in drinking amount and days without drinking compared with placebo. The LS and SS types showed smaller or absent differences between ondansetron and placebo. The additional effects of the SNP TT increased the advantages of the long type polymorphism. The effects of using ondansetron to reduce alcohol dependence behaviors were greatest with the LL/TT genetic combination. If genetic screening of alcohol dependent patients allowed reliable and timely identification of this combination, these patients could be assigned to ondansetron with significantly positive effects.
Angst J, Cui L, Swendsen J, Rothen S, et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry. 2010;167: 1194-1201.
A 5692 subject subset of the 9282 original National Comorbidity Survey Replication sample included 2 groups: those identified by interview in the original survey to have any lifetime mental disorder, and those systematically chosen without history of mental disorder. The Composite International Diagnostic Interview was used to categorize patients into 4 groups: those with MDD plus mania, those with hypomania, those with subclinical hypomanic symptoms, or those with depression alone. These groups were compared on prevalence, treatment history, comorbid disorders, treatment for manic and for depressive disorders, symptom severity scores, and age of mood disorder onset. The bipolar category showed the lowest prevalence, highest probability of previous treatment, greatest probability of comorbid disorders, the highest symptom severities for both mania and depression, and earliest age of onset.
The next highest in each of these characteristics were those with depression with hypomania, followed by those with depression with subclinical hypomanic symptoms, followed by those with depression alone. These ordered trends were consistent and support the concept of a mood disorder spectrum with depression and bipolar disorders at opposite ends of the spectrum.
The clinical implication is that many patients with MDD have hypomanic and subclinical hypomanic symptoms that are not relevant to current diagnostic categories but suggest that additional diagnostic effort be made to recognize the presence of hypomanic symptom history. When this history is present, consider the addition of mood stabilizers. However, no data are presented that show that adding mood stabilizers to the treatment or maintenance regimens for patients with MDD and subclinical hypomanic symptoms improves treatment outcomes.
De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol. 2010;67:949-956.
Three cerebrospinal fluid derived biomarkers were tested for their capacity to discriminate between participants with a clinical diagnosis of Alzheimer’s disease (AD), participants with mild cognitive impairment (MCI), and normal participants with no cognitive impairments. A diagnostic model that combined beta-amyloid protein 1-42 and phosphorylated tau181 was developed to best discriminate the three training populations and validated against both a population of autopsy confirmed patients with AD (n = 68) and a group of patients with MCI) who were followed for 5 years (n = 57) to gauge conversion to AD. The model identified 94% of the autopsy confirmed AD patients and 100% of the patients with MCI that worsened into AD.
These findings suggest that diagnosis of AD, and discrimination from alternatives, such as pseudo-dementia, will be improved with the use of these biomarkers. Some exceptional clinical settings could find the model useful in providing early information on risk for AD and for stronger confirmation of AD; however, the need for lumbar punctures negates their usefulness in a general clinical setting. Furthermore, distinctions between AD and other types of dementia have not been demonstrated.
Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry. 2011;68:444-454.
In 2003, Caspi and colleagues reported that the serotonin transporter promoter polymorphism (5-HTTLPR) moderates the relationship between stress and depression. They were the first to offer a specific quantitative model for the nature-nurture interaction. Two subsequent meta-analyses concluded that the evidence did not support the presence of this interaction. The current meta-analysis by Karg and colleagues supports the Caspi findings by pointing out that even the larger of the two negative meta-analyses included only 14 of the 56 studies that have assessed the relationship between 5-HTTLPR, stress, and depression. The Karg et al. meta-analysis included all relevant studies that explored the interaction and found that the studies published to date support the hypothesis that 5-HTTLPR moderates the relationship between stress and depression. This lends support to the hypothesis that, rather than stressful life events that occur just before the onset of depression, maltreatment and early childhood adversities in conjunction with 5-HTTLPR polymorphisms increase the likelihood of future depression.. Once questions of how the serotonin transporter gene polymorphism plus early stress histories relate differently to treatment outcomes and relapse, the recognition of this combination might be used to tailor treatment strategies.
Stevenson J, Sonuga-Barke E, McCann D, et al. The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children’s ADHD symptoms. Am J Psychiatry. 2010;167:1108-1115.
This study links the effect of food additives and ADHD symptoms on a genetic level. The findings indicate a link between histamine and ADHD symptoms, with polymorphisms in the HNMT gene-moderating behavioral responses to food additives. In a double-blind, placebo-controlled crossover trial, an aggregate ADHD symptom measure was the main outcome variable. Children aged 3 years (n = 153) and 8/9 years (n = 144) were given a fruit drink with 2 food color additives and sodium benzoate (preservative) in the drink.
The adverse effect of food additives on ADHD symptoms was moderated by histamine degradation gene polymorphisms HNMT T939C and HNMT Thr105Ile in 3- and 8/9-year-old children and by a DAT1 polymorphism (short versus long) in 8/9-year-old children only. The authors concluded that histamine may mediate the effects of food additives on ADHD symptoms, and variations in genes influencing the action of histamine may explain the inconsistencies in previous studies. The study explains the frequent claim that food allergy/intolerance is a cause of ADHD symptoms and the effects of infections in aggravating aberrant behavior. It supports a potential target for therapeutic intervention in ADHD focused on the H3 receptor. It shows that histamine release and its effects on the CNS may play a crucial role in mediating the effects of artificial food colors on ADHD symptoms.
These findings may indicate that dietary modifications can have some effect on hyperactivity and distractibility in children with ADHD. This important confirmation of the effects of food dyes has potential implications for identifying the connections between genetic deficits in histamine metabolism and symptoms consistent with ADHD. The lack of connection to classic dopamine(Drug information on dopamine)-based genetic variants creates an entirely new category of ADHD that may explain many of the atypical cases and potentially the otherwise challenging to understand “adult onset” ADHD-like presentations. Identifying the subgroup of children with the histamine degradation gene polymorphism will allow more targeted dietary interventions with a higher likelihood of positive outcomes.
Others would very likely choose different reports to include or exclude, so that the notion that these are definitively the “top” papers cannot be defended. However, these are papers of high quality with direct clinical application. This view of clinical research also provides insight into highly dynamic areas of clinical investigations, which again can be hidden by the mass of studies available. For example, many of the papers included here were on child and adolescent disorders. The percentage of papers included in this sample on child and adolescent disorders far exceeds the percentage of total psychiatric research papers on child and adolescent disorders. This suggests that research on child and adolescent disorders is producing a relatively high level of clinically applicable findings, which could have policy, funding, and hiring implications. The papers on cannabis also suggest this area of research is producing useful and implementable clinical changes. At the same time, implementable clinical changes related to genetic and biological markers seem to be getting closer on disorders ranging from depression to ADHD.