HRV and Schizophrenia

Following our Yearly General Meeting of December 7, 2017, Farah Hodeib presented her work at the Assistance Publique Hôpitaux de Paris. Thanks to work on post-traumatic stress disorder (PTSD), studies on heart rate variability in psychiatry show the risk of cardiac disorders following the use of psychotropic drugs, especially for psychotic patients.

Post traumatic stress disorder (PTSD) is a psychiatric disorder that is triggered following a traumatic event.

PTSD is characterized by 4 groups of symptoms:
– reliving events (like flashbacks and nightmares)
– avoidance behavior (places and objects that recall the traumatic event)
– neurovegetative hypertonia (which includes sleep disturbances, concentration problems and hypervigilance)
– cognitive changes (of memory, of pleasure.)
In this presentation, we are particularly interested in the symptoms of vegetative hypertonia that are related to one of the physiopathological pathways of PTSD.

Following the attacks in New York in 2001, the world has faced an increase in terrorist attacks, as seen on this graph. The most disastrous and recent attacks in France were those of Paris in 2015 and Nice in 2016. The patient population still suffering from these attacks is ideal for the evaluation of new relief treatment, such as that proposed by the Paris MEM study.

Currently available treatments for PTSD include antidepressants such as SSRIs or SNRIs that are mostly abandoned by patients because of their side effects such as sexual dysfunction and weight gain. Psychotherapy, such as CBT and EMDR are also used. These techniques are also effective but often expensive and lead to a relapse in 50% of patients. This leads us to seeking new targets for therapies or for blocking memory reconsolidation as proposed by the Paris MEM study that is currently recruiting. This treatment involves six sessions of reactivation of traumatic memory through a script 75 minutes after taking 1 mg / kg of propranolol, a beta-blocker. It is this treatment that will be evaluated using HRV as I will soon explain.

The main theory concerning the pathophysiology of PTSD attempts to explain that a poorly adaptive stress response is characterized by a defective hypothalamic-pituitary axis. Under normal conditions, following a stimulus, the hypothalamus of CRH that leads to the release of ACTH which in turn stimulates the release of cortisol by the adrenal glands. Cortisol is responsible for activating the negative feedback that controls its production. In PTSD, continued secretion of CRH leads to desensitization of ACTH. More negative feedback is present with a consequent decrease in cortisol production.

The defective AHH is accompanied by a disruption of the autonomic system and therefore the balance between the inhibitory and excitatory circuits of the brain. This disruption of the autonomic nervous system leads to an increase in catecholamines, reduced heart rate, lower blood pressure and a decrease in cardiac vagal tone which eventually increases the risk of cardiovascular disease.

Basically, stress is the cause of cardiological disorders that appear in anxiety diseases such as PTSD. There is a strong connection between heart and brain with respect to psychiatric illnesses. The autonomic system directs the heart and regulates its rhythm. A disruption of this system leads to serious cardiac consequences as is the case of psychiatric diseases. A low heart rate is associated with good health. Conversely, a high HRV is an index of better health and better adaptability and resilience. But is this the case for other psychiatric illnesses?

It is this link between disorders of the nervous system and cardiovascular risk that drives us to look for a parameter for evaluation of cardiotoxicity in psychiatric diseases. The variability of heart rate is not equivalent to the heart rate. It is an index of the functioning of the cardiac system that is used as a predictor of mortality following a myocardial infarction. It can also be used to assess heart health in people with hypertension or coronary artery disease.

Under normal conditions, HRV is an index of adaptability to stress and the environment. HRV is therefore essentially considered as a measure of the functioning of the autonomic nervous system. And this is where we find the link with anxiety disorders including PTSD.

HRV is therefore the variation of the RR interval on the ECG which includes several parameters to be analyzed. The variation represents the cyclical changes in sinus rhythm following a circadian rhythm. Data is usually retrieved from an ECG record.

Laborde et al. 2017
The 1996 Task Force has put in place several recommendations for the measurement of HRV. Regarding ECG recording, the patient must be seated, knees 90 °, hands on thighs, eyes steady, or lie with the palms exposed. The patient should not move during recording. The duration of recording should be 5 minutes where possible and at least 1 minute.

The main parameters to evaluate are those of time and frequency. It is interesting to note that the variables to be analyzed for PTSD and other psychiatric disorders are RMSSD and HF since they give information about the parasympathetic system that is defective / overactive in PTSD.

There are no official values ​​but the Task Force made these recommendations.

In PTSD, HRV is reduced as in other anxiety disorders. Several studies have shown the change of HRV before and after an injury. But HRV has not been evaluated in the treatment of PTSD, hence the possibility of presenting HRV as a biomarker of improvement following treatment, in this case the blocking of memory reconsolidation. An overview of 34 studies on anxiety disorders (including 13 PTSD studies) showed a reduction in HRV (Chalmers et al., 2014).

Only 2 studies showed conflicting results.

In the case of schizophrenia, especially in the manifestly positive symptoms of the disease, it is interesting to look at the effect on the cardiovascular system by considering stress as the origin of the disorders of the heart.

This is related to various factors mainly pathology, but also antipsychotic agents that cause prolongation of the QT interval. Other factors may play a role such as the patient’s lifestyle (smoking, general health neglect, poor diet and reduced access to health care services) and cardiac co-morbidities. Considering their direct effect on the cardiovascular system, it seems appropriate to evaluate the effect of antipsychotics on HRV.

First of all it should be noted that HRV of a schizophrenic patient is similar to that of a patient who suffers from anxiety disorder. A reduction in parasympathetic activity is observable in patients who were on treatment but are no longer. Autonomic disorders appear to be more pronounced during acute psychotic episodes in patients with a first episode of schizophrenia.

The classification of antipsychotics is complex and is based on several factors. The most commonly used classification is the pharmacological mode of action classification. In this case we have the typical AP of the 1st generation as … and atypical antidepressants or the 2nd generation.

As can be seen from this side effect table, almost all PAs have cardiological side effects characterized by prolongation of the QT interval on the ECG.

Lower HRV in patients taking clozapine compared to olanzapine, sertindole or amisulpride. The reduction of HRV is exacerbated by antipsychotic drugs. This effect on HRV depends on the dose of the AP. Sixteen healthy male volunteers received risperidone (4 mg), olanzapine (10 mg), thioridazine (50 mg) or a placebo in a randomized crossover design. Subjective effects and psychomotor function were measured at 2 h and linear (summary statistics) and nonlinear (scatterplot) measurements of HRV were evaluated by continuous electrocardiogram over 10 h. The differential effects of single doses of the three antipsychotic drugs on HRV were found, and these were independent of their sedative effects. Olanzapine increased and thioridazine decreased HRV, while risperidone had no effect.

A study to evaluate the effect of atypical or second generation APs on HRV in bipolar individuals showed reduced RMSSD and HF were observable in patients with second generation APs but not in non-users of APs. These two parameters are parameters for evaluation of the parasympathetic system. This reinforces the idea that APs lead to hyper activation of the parasympathetic system or worsen the hyper activation already present in bipolar individuals.

If these patients are poorly adapted or have a reduced HRV, the ideal treatment agent must both decrease the symptoms and increase or even stabilize HRV. But it remains a truth that most antipsychotic medications have serious cardiac consequences because of their pharmacological mode of action. Recently, thioridazine has been the subject of restricted indications and the license for sertindole has been withdrawn due to concerns about their cardiotoxic potential.

In the development of new atypical agents, corrected heart rate QT effects are assessed, but it is unclear to what extent they are predictive of clinically significant cardiotoxicity or sudden death. Heart rate variability (HRV) is a potential index of cardiotoxicity that has been observed after the decrease in antidepressants and clozapine. We studied acute changes in HRV as a result of antipsychotic agents.