Schizophrenia is a severe debilitating mental disorder characterised by distortions of
thinking, perception and blunt affect. It poses a major healthcare burden with the
prevalence of 1% worldwide. As per National Mental Health Survey of India (2016), the
prevalence of Schizophrenia and other psychotic disorders was 0.4% and the lifetime
prevalence was 1.4%. The earliest success in treating some of the symptoms of
schizophrenia came with the discovery of typical antipsychotics. Later, newer "atypical"
antipsychotics with different psychopharmacological actions promised better outcomes, but
were found similar in clinical response although with less extrapyramidal side effects.
Almost 30% patients with schizophrenia do not show clinically significant improvement
with antipsychotic medications. Treatment resistant schizophrenia (TRS) is thus, defined
as inadequate response to at least two failed antipsychotic trials of adequate dose and
duration. However, clozapine has been found to be exceptionally effective in such cases.
Therefore, multiple guidelines including FDA approve clozapine as the only
pharmacological agent in the treatment for TRS. However, its use is associated with
serious myocarditis, agranulocytosis, seizures and sudden cardiac death along with a
plethora of common side effects like sedation, weight gain, constipation,
hypersalivation, tachycardia, orthostatic hypotension. Clozapine causes dysregulation of
the autonomic nervous system possibly by anti-muscarinic effects and inhibition of vagal
neurons resulting in constipation, orthostasis, tachycardia. The side-effects of
clozapine has been notoriously the major cause behind its underutilisation under clinical
settings, therapeutic challenge due to need for constant monitoring of the physical and
blood parameters of the patients and high rates of treatment dropouts. For instance,
persistent tachycardia occurs in approximately 33% of TRS receiving clozapine ultimately
leading to treatment discontinuation in at least 10% of cases. Moreover, high heart rate
has been an independent predictor for cardiovascular diseases, stroke, sudden cardiac
death and noncardiac diseases. It has been shown that for each rise in 10 bpm from
resting heart rate the relative risk for these diseases increases linearly. Therefore,
there is a need to understand the effects of clozapine on the autonomic nervous system,
and regularly monitor the relevant parameters for early detection and intervention to
ensure treatment adherence, prevention of any serious cardiac event and improve the
overall quality of life of these patients.
One way to measure autonomic dysregulation induced by clozapine is with the help of heart
rate variability. Heart Rate Variability (HRV) is the change in time duration of adjacent
heart beats, arising from various mechanisms including but not limited to brain-heart
interaction, blood pressure, gaseous exchange, vascular tone, hormone levels. HRV can be
measured in different time periods (ultra-short-term(<5min), short-term (5min) and
24hours measurement)and described into different metrics (including time-domain,
frequency-domain and non-linear measurements). The time-domain includes interbeat
duration variation as measured by standard deviation of all interbeat duration, root mean
square of all interbeat duration etc. Frequency-domain is analysed using Power spectral
density (PSD) calculated using Fast Fourier Transformation (FFT) . When measuring for
short-term, frequency-domain should be preferred. Due to its antimuscarinic effects,
Clozapine has shown to cause high mean heart rate, low heart rate variability, high
low-frequency component when compared to other antipsychotics or control patients.
Most guidelines suggest treating persistent tachycardia in patients receiving clozapine
after excluding other causes of tachycardia. Beta blockers (like Atenolol) or Calcium
channel blockers have been recommended for clozapine associated tachycardia (20).
Patients who do not tolerate these drugs can be prescribed Ivabradine. The exact
mechanism by which Ivabradine modulates autonomic function is not known, but is
hypothesised to be its effects on the intra cardiac nervous system, which by a feedback
to the Central Nervous System via the afferent nerve fibres from the heart results in
overall increase in the parasympathetic activity.
The available literature is scarce about the effects of clozapine on the heart rate
variability. Moreover, despite the usual prescription of beta blockers/ ivabradine in the
treatment of the clozapine induced tachycardia, evidence for the same are limited in the
specific population of TRS patients. Furthermore, all studies supporting their use has
been conducted in western countries. Again, there is no clear consensus regarding the
choice of one drug over the other, given their different pharmacodynamic actions. The
specific effects of these drugs (beta blockers/ ivabradine) on the HRV caused by
clozapine therefore needs further exploration. This study is intended to compare the
effects of atenolol versus ivabradine on heart rate variability in patients of TRS on
Clozapine with tachycardia. The findings of the study will be able to guide appropriate
use of the mentioned pharmacological therapies in context of clozapine-induced autonomic
instability/tachycardia. This will help improve the overall cardiac functioning and the
tolerability and compliance in TRS scenarios.