Journal Articles of Note

Some recent articles of interest have appeared in the literature I would like to alert you to. Some are directly involved clinical care, while others are in the neurosciences that may become relevant in the not too distant future.

SSRIs in Autism Spectrum Disorders (ASD)

Selective Serotonin Reuptake Inhibitors for Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. The similarity of repetitive behaviors to obsessive-compulsive behaviors and the high rates of social anxiety in higher functioning people with ASD make SSRIs a go-to drug for many clinicians, despite very weak evidence. Trinari et al. performed a meta-analysis of 9 studies involving SSRI’s in about 300 participants. They found no effects of SSRIs on any of the measures of including global functioning, repetitive or obsessive-compulsive behavior or irritability. In contrast to anti-depressant trials, this failure to find a difference between placebo and active drug appears to due to negative trials- that is neither the placebo nor the active drug groups improves. This is shown very clearly in one of the major trials reviewed, that of King et al. (Arch Gen Psychiatry. 2009;66(6):583-590). Given that SSRIs have done better in anxiety trials than depression trials , this is surprising and suggests that “anxiety” in ASD is not same as anxiety in neurotypical populations. SSRIs should not be seen as a treatment for core symptoms of ASD. Ironically, if the ASD diagnosis broadens to include more people previously defined as neurotypical, SSRIs might work, confusing the situation. The King et al study also showed disinhibition with SSRIs in their study, something consistent with my clinical experience. DON’T take a person with ASD off their SSRI abruptly and continue it if you really feel it is working but consider taper if you are not seeing results. I am interested to hear people’s views.

The GLP-1s are Coming to Psychiatry!

Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial. The authors conclusion says it all: “In this multicenter, double-blinded randomized clinical trial, 30 weeks of administration of semaglutide, up to 1.0 mg/week, was safe, lowered blood glucose (as measured by HbA_1c) and weight, and improved physical quality of life in SGA-treated patients with schizophrenia, prediabetes, and obesity without worsening mental health.” This comes on the heels of a major review in Lancet Psychiatry showing no worsening of mental health in people with both mental disorders and diabetes treated with GLP-1s. Given initial work showing GLP-1s may have efficacy in additive disorders, psychiatry will need to develop a greater awareness of neuroendocrine factors in mental disorders. Until studies are in (and maybe even after they are) get ready to fight with the insurance companies!

Psychiatric Genetics is Marching Forward!

Two papers on the genetics schizophrenia and anxiety are very technical and not for the faint of heart but are important. Humans have hundreds of thousands of single nucleotide polymorphisms (SNPs) in their DNA where a nucleotide pair is switched in the DNA (i.e., an A-T is swapped for a G-C). Often these have no effect at all or help identify your ancestry (but still have no functional use). Some can, however, very minutely increase your risk for a mental disorder. By current estimates, 8000-10,000 SNPs can influence each of the major psychiatric disorders and they can overlap (pleiotropy) meaning a risk-SNP can increase the risk for multiple disorders. So far, scientists have not found enough SNPs to account for the full symptom variability in any given disorder. (There is another class of genetic risk that deletions and duplications in the DNA [Copy Number Variants], but I will leave them aside for now.) The paper on anxiety looked at over 600,000 people and found 80 independent genome-wide significant variants within 74 locations on the chromosomes, 39 of which are new! Still, the variance of anxiety symptoms explained is only 5.9%, but each study like this will eventually find more and more of these SNPs to account for more variance.

Rossi et al. looked at regions of the DNA that regulate other genes. They looked not only at regulatory sites close to and in line with genes (cis) but trans acting variants, that is regulatory proteins that work on the DNA away from the gene itself. By looking at postmortem brains, the authors examined the amount of RNA that is transcribed with the different variants in patients vs controls. The authors speak: “Applying this framework to Psychiatric Genomics Consortium wave 3 genotypes identified 766 genes associated with schizophrenia (P_FDR < 0.01), including 641 not previously reported by transcriptome-wide analyses.” Many of these genes are involved in synaptic density and autoimmune processes. This is where the new pharmacological treatment will come from. I expect genetic studies to keep progressing to the point that genetic testing for diagnostic subtyping and predicting treatment response will become a reality.