To analyze the relationship between seizure threshold (ST) and psychotropic drugs in patients treated with ECT.
We examined clinical data from 43 patients. ST was titrated at each treatment session. We examined associations between ST and psychotropic drugs using multivariate correlation analyses. Data are presented as initial ST, the difference in ST between the first and 10th sessions (ΔST10th), and the mean difference in ST between the first and last sessions (mean ΔSTlast).
Multivariate regression analyses showed associations between initial ST and the total chlorpromazine-equivalent dose of antipsychotics (β=0.363, p<0.05). The total fluoxetine-equivalent dose of antidepressants was associated with ΔST10th (β=0.486, p<0.01) and mean ΔSTlast (β=0.472, p<0.01).
Our study elucidated possible effects of psychotropic drugs on ST shifts. Larger doses of antipsychotics were associated with higher initial ST, whereas higher doses of antidepressants were associated with stronger shifts in ST.
Various kinds of brain stimulation therapies are widely used to treat discrete psychiatric disorders. Deep brain stimulation, repetitive transcranial magnetic stimulation, and vagus nerve stimulation are just a few of the tools used to stimulate the brain's neurons in the hope of achieving beneficial effects for patients with psychiatric diseases. Electroconvulsive therapy (ECT) is one of the oldest and most popular ways to achieve therapeutic effects by stimulating the brain with the help of electrical currents.
ST varies greatly by individual and can be affected by many factors.
We performed a retrospective study to investigate the effects of psychotropic drugs on ST among patients who received ECT at Korea University Guro Hospital (KUGH) between February 2009 and June 2015. Patients with a history of seizure disorders or other medical emergent conditions were excluded. A total of fifty-eight subjects received ECT during the study period. Patients were excluded if treatment was aborted due to side effects or any other reasons before the 10th session (n=12) because we intended to investigate the ST shift during the course of consecutive ECT sessions. We included 43 subjects in the final data analysis. Among them, 5 had hypertension, 7 had diabetes, and 3 patients had subclinical hypothyroidism as medical comorbidities. Patients' psychiatric disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-R) by at least two experienced psychiatrists in the usual clinical settings at KUGH. ECT was administrated with concurrent antipsychotics and antidepressants. Benzodiazepine, mood stabilizers with anticonvulsant effects such as lithium and valproic acid, and z-drugs such as zolpidem were tapered out before initiating ECT and not used until all treatment sessions ended. We documented ECT variables (including the time interval between the last and current titration sessions) and concomitant medication using medical records. The study protocol was approved by the Institutional Review Board of KUGH, and we obtained written informed consent from all participants for use of their clinical data. Consent was taken from guardians if the participant was thought to be unable to make clear decisions himself.
All patients were admitted to KUGH at least one week before starting ECT procedures. We used a MECTA SpECTrum 5000Q apparatus for seizure induction. Patients were hyperventilated with 100% oxygen for 10 seconds and anaesthetized using propofol (1–2 mg/kg). We used succinylcholine (0.5 mg/kg) to induce muscle relaxation and conducted clinical monitoring, including electrocardiographic and electroencephalographic (EEG), throughout the whole procedure. Propofol and succinylcholine doses were kept consistent throughout all treatment sessions. We placed ECT electrodes at the bilateral temporal areas and applied the electrical stimulus as soon as the patient reached the deepest stage of anesthesia. Initial stimulus strength varied between 10J and 15J, converted from the recommended initial 50 mC at 220 ohm patient impedance.
We present the following data: initial ST is the amount of electrical energy used to induce a successful seizure at the first session; ΔST10th is the difference in ST between the first and 10th sessions; mean ΔSTlast is the mean difference in ST between the first and last sessions. We used stepwise multivariate regression analyses to find associations between those data and the doses of psychotropic medication, adjusting for age, sex, and BMI. We performed univariate regression analyses to find associations between laboratory test results and ST. We used covariance analyses to find differences in variables between clinical subgroups divided by types of prescribed medication, adjusting for age, sex, and BMI. All statistical analyses were performed using the SPSS 19 statistical package (IBM Corp., Armonk, NY, USA).
Of the 43 patients included in the study, 20 were male, and the other 23 were female. The mean age of all participants was 41.44 years (SD=15.89), with a total range from 15 to 71 years old. 29 patients were diagnosed with schizophrenia, 4 with schizoaffective disorder, 9 with major depressive disorder, and 1 with bipolar disorder, according to DSM-IV-R criteria. All medication was prescribed by psychiatrists. Use of benzodiazepines, z-drugs, and anticonvulsants was avoided during ECT administration. Patients were taking the following antipsychotics and antidepressants: clozapine (n=6), amisulpride (n=9), aripiprazole (n=5), olanzapine (n=18), risperidone (n=1), quetiapine (n=20), haloperidol (n=1), paliperidone (n=5), chlorpromazine (n=1), blonanserin (n=1), escitalopram (n=7), sertraline (n=1), mirtazapine (n=2), duloxetine (n=1), venlafaxine (n=3), amitriptyline (n=1), trazodone (n=1), bupropion (n=1). Participants took an average of 1.91 (SD=1.02, range 0–5) different psychotropic drugs during ECT. The mean number of types of antipsychotics and antidepressants used were 1.53 (SD=0.74, range 0–3) and 0.37 (SD=0.76, range 0–4), respectively. We converted the dose and types of antipsychotics and antidepressants into chlorpromazine (CPZ) and fluoxetine (FXT) equivalences, respectively.
Of the 43 patients, 40 used at least one antipsychotic drug, 12 used more than one antidepressant, and 3 did not take any psychotropic medication while undergoing ECT (
We divided the subjects into four subgroups to further analyze the effects of drug combinations: 11 patients took only one antipsychotic medication, 6 patients took one antipsychotic in combination with antidepressants, 17 patients took multiple antipsychotics, and 6 patients took multiple antipsychotics in combination with antidepressants (
Lab results were significant. Initial ST was positively associated with serum triglyceride levels (B=0.390, p<0.05). ΔST10th showed positive associations with serum low density lipoprotein (LDL) (B=0.412, p<0.05), and serum triiodothyronine levels showed associations with mean ΔSTlast (B=0.326, p<0.05). See
Optimal electrical stimulus is critical for inducing therapeutic seizures in ECT. As previous studies suggest, energy levels exceeding ST are necessary to achieve proper therapeutic effects.
It was traditionally thought that dopamine agonists could provoke and modulate seizures, increasing the number and severity of attacks.
The exact mechanisms by which antipsychotics affect ST remain unknown, but some plausible explanations are possible.
First, dopamine itself is known for its possible seizure-evoking properties. Dopamine, mainly through D1 receptors in the midbrain, has been shown to have proconvulsant effects.
Second, antipsychotics might have anticonvulsant effects via regulation of gamma-aminobutyric acid (GABA) transmission. GABA is already known to play an important role in elevating ST, as shown by medications such as barbiturates or benzodiazepines.
Third, the choice of antipsychotic medication might have affected outcomes directly. Previous reviews suggest that chlorpromazine and clozapine have higher risks for inducing seizures, whereas newer drugs such as risperidone, quetiapine, and olanzapine have relatively low risks.
Another major finding of our study is the effect of antidepressants on ST during ECT. We discovered that antidepressants alter the shift of ST during the course of ECT sessions, resulting in larger and more drastic ST rises. Previous reports on the topic were controversial to some extent, showing mixed results. Antidepressants were traditionally thought to have the rare consequence of increased seizure risks.
Although the exact mechanisms are unknown, there are possible explanations for the effects of antidepressants on ST. GABAergic regulation caused by changes in serotonin levels might be the first plausible reason. SSRIs, among other classes of antidepressants, were reported to upregulate GABA receptors in animal models and clinical studies.
Second, norepinephrine (NE), a neurotransmitter commonly modulated by antidepressants, also seems to contribute to seizure control. Previous studies indicated that NE target areas, such as the stria terminalis or hippocampus, show increased GABAergic activity when exposed to chronic stress.
Third, evidence suggests that NE can affect seizures in other ways than by mediating GABA levels. An animal study reported that mice engineered to lack NE showed greater seizure susceptibility than control groups, also displaying higher severity and mortality rates from induced seizures.
Apart from the effects of psychotropic drugs, our study also found that higher levels of serum triglycerides correlated with higher initial ST, and higher serum LDL levels correlated with higher ΔST10th values. Related ideas can be traced back to the classical ketogenic diet designed for children with intractable epilepsy. A diet of high fats and low carbohydrates is expected to be ketogenic and increase serum ketone levels. Ketosis is anticipated to activate the tricarboxylic acid cycle and increase GABA synthesis, leading to increased antiepileptic effects.
Modern drugs offer treatment choices of great efficacy to most clinicians. However, the number of treatment-resistant cases is increasing, making ECT an attractive, if not mandatory, treatment option.
The strength of this study is that we considered both antipsychotics and antidepressants in our search for possible effects on ST during ECT. Our research also has several limitations. First, the population size was small, and the proportion of patients taking antidepressants was smaller than that of patients taking antipsychotics. Larger populations could lead to more precise results. Second, we used equivalent dose calculations to compensate for the variety of psychotropic medications, but no universal guideline for such conversions has been published. Nevertheless, those conversions are widely used in clinical practice. Third, one of our participants was taking bupropion as an antidepressant although there are studies claiming that bupropion lowers seizure threshold. The small dose (300 mg) is less likely to make a big difference but this might have affected our results. Fourth, previous studies described about the correlations between age and seizure thresholds. Our study also showed positive correlations between age and seizure threshold shifts, but the results were not shown to be significant. We believe that a larger number of participants would have resulted in more significant outcomes.
In conclusions, this study identified factors that affect ST during ECT, specifically focusing on the effect of psychotropic drugs. We found that larger doses of antipsychotics are associated with higher initial ST, whereas antidepressants are associated with stronger shifts of ST, resulting in a steeper increase. The number and amounts of concomitantly used psychotropic drugs should always be kept in mind because titrating for ST is crucial for optimal outcomes. Higher drug doses might demand higher initial energy levels and even larger titration intervals to obtain the best treatment results. Our findings provide a basis for creating safer and more efficient ECT protocols.
This study was supported by a grant from the Korea University, Republic of Korea (K1512631).
Data presented as chlorpromazine-equivalent dose for antipsychotics; fluoxetine-equivalent dose for antidepressants
ECT: electroconvulsive therapy, SD: standard deviation
Data presented as mean±standard deviation. Adjusted for age, sex, and BMI. Variables: ΔST10th, difference in seizure thresholds between first and 10th sessions, mean ΔSTlast: mean difference in seizure thresholds between first and last sessions. ANCOVA: analysis of covariance, AP: antipsychotic, AD: antidepressant, ST: seizure threshold in jaules, BMI: body mass index
Variables: ΔST10th, difference in seizure thresholds between first and 10th sessions, mean ΔSTlast: mean difference in seizure thresholds between first and last sessions. *p<0.05, †p<0.01. ST: seizure threshold in jaules, BMI: body mass index, LDL: low density lipoprotein, B: regression coefficient, SE: standard error, β: standardized regression coefficient, T3: triiodothyronine