Inflammation Linked to Poor Sleep Quality and Worse Executive Functioning

January 18, 2019 · Posted in Risk Factors · Comment 

man drooling while sleeping

At a recent scientific meeting, researcher Ellen E. Lee and colleagues reported that compared to healthy volunteers, people with bipolar disorder or schizophrenia had elevated levels of inflammatory markers, which were associated with poor sleep. 

According to self-reports, people in the schizophrenia and bipolar disorder group had worse sleep quality than the control group. Those with schizophrenia or bipolar disorder also had significantly higher levels of the inflammatory markers CRP, IL-6, and TNF alpha compared to the healthy volunteers. Among people with bipolar disorder, executive functioning and sleep quality had a strong inverse association to levels of IL-6, such that lower sleep quality and worse executive functioning were associated with higher levels of IL-6. These findings suggest that sleep disturbance and inflammation may have negative consequences for cognitive functioning.

White Matter Abnormalities in Obesity

January 16, 2019 · Posted in Brain Imaging, Neurobiology · Comment 

obese man

Researcher Ramiro Reckziegel and colleagues reported at a recent scientific meeting that white matter is abnormal in obese adults with bipolar disorder. In a 2018 article in the journal Schizophrenia Bulletin, Reckziegel reported that body mass index (BMI) was associated with reduced fractional anisotropy, a measure of brain fiber integrity, in the cingulate gyrus in patients with bipolar disorder. This finding implies that obesity may play a role in white matter microstructure damage in the limbic system.

White Matter Abnormalities Linked to Irritability in Both Bipolar Disorder and DMDD

January 14, 2019 · Posted in Brain Imaging, Neurobiology · Comment 

white matterAt a 2018 scientific meeting, researcher Julia Linke of the National Institute of Mental Health reported that there were white matter tract abnormalities in young people who had irritability associated with either bipolar disorder or disruptive mood dysregulation disorder (DMDD). Thus, while these two disorders differ in terms of diagnosis, presentation, and family history, they seem to have this neurobiological abnormality in common.

Scientific Mechanisms of Rapid-Acting Antidepressants

January 10, 2019 · Posted in Neurochemistry · Comment 
pyramidal cell

A pyramidal cell (Photo by Bob Jacobs, Laboratory of Quantitative Neuromorphology Department of Psychology Colorado College)

At a recent symposium, researcher Francis McMahon provided electrophysiological evidence that several different types of rapid-acting antidepressants—low-dose ketamine, scopolamine, and rapastinel (a partial agonist of the neurotransmitter NMDA)—act by decreasing the inhibitory effects of GABAergic interneurons on excitatory neurons called pyramidal cells, thus increasing synaptic firing.

Researcher Ronald Duman further dissected these effects, showing that ketamine and its active metabolite norketamine reduce the steady firing rate of GABA interneurons by blocking NMDA receptors, while the partial agonist rapastinel acts on the glutamate neurons directly, and both increase the effects of a type of glutamate receptors known as AMPA. These effects were demonstrated using a virus to selectively knock out GluN2B glutamate receptor subunits in either GABA interneurons or glutamate neurons.

Increasing AMPA activity increases synapse number and function and also increases network connectivity, which can reverse the effects of stress. Duman and colleagues further showed that when light is used to modulate pyramidal cells (a process called optogenetic stimulation) in the medial prefrontal cortex, different effects could be produced. Stimulating medial prefrontal cortex cells that contained dopamine D1 receptors, but not D2 receptors, produced rapid and sustained antidepressant effects. Conversely, inhibiting these neurons blocked the antidepressant effects of ketamine. Stimulating the terminals of these D1-containing neurons in the basolateral nucleus of the amygdala was sufficient to reproduce the antidepressant effects. These data suggest that stimulation of glutamate D1 pyramidal neurons from the medial prefrontal cortex to the basolateral nucleus of the amygdala is both necessary and sufficient to produce the antidepressant effects seen with ketamine treatment.

Researcher Hailan Hu reported that NMDA glutamate receptors drive the burst firing of lateral habenula (LHb) neurons, which make up the depressogenic or “anti-reward center” of the brain and appear to mediate anhedonic behavior (loss of interest or enjoyment) in animal models of depression. Ketamine blocks the burst firing of the LHb neurons, which disinhibits monoamine reward centers, enabling ketamine’s rapid-onset antidepressant effects. This may occur because inhibitory metabotropic glutamate receptors (mGluR-2) are activated, decreasing the release of glutamate.

MGluR-2 may also help explain the antidepressant effects of acetyl-L-carnitine supplements. L-carnitine is an amino acid that is low in the blood of depressed patients. The supplement acetyl-L-carnitine (ACL) activates the DNA promoter for mGluR-2, increasing its production and thus decreasing excess glutamate release. The acetyl group of the ACL binds to the DNA promoter for mGluR-2, thus this process seems to be epigenetic. Epigenetic mechanisms affect the structure of DNA and can be passed on to offspring even though they are not encoded in the DNA’s genetic sequence.

Risk of Suicide in People with Bipolar Disorder: Lowest with Lithium, Highest with Antidepressants

January 7, 2019 · Posted in Current Treatments · Comment 

man in sunshine

Researcher Markku Lähteenvuo and colleagues reported in the journal JAMA Psychiatry in early 2018 that long-acting injectable antipsychotics and lithium were best at preventing re-hospitalization in 18,018 bipolar patients in Finland who received an average of more than 7 years of follow up. Lähteenvuo and colleagues have now gone on to analyze suicide data from the same cohort of patients with bipolar disorder, and report that those taking lithium had the lowest rate of suicide, while those taking valproate had the next lowest suicide rate. Those patients with bipolar disorder who were treated with antidepressants had the greatest suicide rate. The suicide rate was particularly high for those once-hospitalized patients taking the MAO inhibitor antidepressant meclobemide, which is not approved for use in the US. Increased rates of suicide were also seen with use of sedatives and benzodiazepines.

Editor’s Note: Evidence continues to mount that lithium should be the definitive first line therapy in bipolar disorder for a multitude of reasons (as this editor Robert M. Post reviewed in an open-access article in the journal Neuropsychopharmacology in 2017). Still, lithium is not often prescribed for people with bipolar disorder in the US, and this does not seem to be in these patients’ best interests.

Use of antidepressants in bipolar disorder has remained controversial, but it is common in clinical practice despite a lack of evidence that it is effective, and the presence of some evidence that it is actually harmful. Antidepressant use in a person with bipolar disorder may cause switching into mania, cycle acceleration, dysphoria induction, and even suicide.

Clinicians should take these data seriously and overcome the impulse (leftover from treating unipolar depression) to use unimodal antidepressants as first line or adjunctive therapy for bipolar depression. Antidepressants are only effective in the long term in about 15% of patients with bipolar depression, and now it appears antidepressant use also carries an additional risk of suicide.