A study to understand the pattern of hyponatremia in patients using selective serotonin reuptake inhibitors and serotonin dopamine antagonists.

INTRODUCTION: Hyponatremia can be a common but often overlooked side effects of psychotropics drugs. Most patients with drug-induced hyponatremia are asymptomatic and diagnosis is made incidentally following routine blood tests.
OBJECTIVES: The aim of the study was to understand the pattern of hyponatremia in patients using selective serotonin reuptake inhibitors (SSRI) and serotonin dopamine antagonists (SDA).
MATERIALS AND METHODS: All inpatients and outpatients who were diagnosed with International Classification of Diseases-10 psychiatric disorders and undergoing treatment with SSRI, SDA, or combination of both for the same, were included in the study after simple random sampling, subject to inclusion and exclusion criteria. STATISTICAL ANALYSIS USED: Categorical variables were observed as numbers and percentages. Continuous variables were evaluated as mean ± standard deviation. A Chi-square test was done to find the association between categorical variables. SPSS (IBM) version 21 was used for data analysis.
RESULTS: In 150 patients, we found hyponatremia in 17 patients (11.33%). About 66-75 age group patients had maximum found cases of hyponatremia (66.66%). About 20.31% of females found hyponatremia. Among SSRIs, 16% of individuals had hyponatremia whereas among SDA it was 6%. Patients who were taking both SSRIs and SDA total prevalence of hyponatremia was 12%.
CONCLUSIONS: Older age groups and females had higher chances of hyponatremia while taking SSRIs and SDAs. Among SSRIs, escitalopram had maximum percentage of hyponatremia, whereas fluvoxamine had minimum. Among SDAs, risperidone had maximum percentage, whereas quetiapine had minimum percentage of hyponatremia. Patients who were taking both fluoxetine + olanzapine or fluoxetine + risperidone had higher percentage of hyponatremia. Copyright:

Sodium plays a vital role in maintaining cellular homeostasis and total sodium body content is the key determinant of extracellular fluid volume and in most circumstances, effective arterial blood volume.[1] Hyponatremia can cause significant morbidity such as lethargy, headache, confusion, convulsions, coma, and can occasionally cause death.[2] Abnormalities in serum sodium, generally defined as hyponatremia if sodium concentration is <135 mmol/l and as hypernatremia, if sodium concentration is >145 mmol/l, virtually always result from disturbances in water balance, with excess or deficit body water relative to body sodium content.[3] The prevalence of hyponatremia is associated with a wide range of medical conditions and pharmacological treatments. Drug-induced hyponatremia is commonly associated with diuretics, SSRI, antipsychotics, and antiepileptics. Most patients with drug-induced hyponatremia are asymptomatic and diagnosis is made incidentally following routine blood tests. Mild cases may be managed either by stopping the drug or by careful observation if the drug is considered essential.[4] Hyponatremia has been described in association with almost all antidepressants drugs. Some studies such as Kris et al. have shown that users of SSRIs in daily clinical practice have an approximately four times higher risk for developing hyponatremia compared with users of other antidepressant drugs. Elderly patients concomitantly using diuretics fall into the highest risk category.[5] Other risk factors for the development of hyponatremia with SSRIs include older age, female gender, and concomitant use of diuretics, low body weight, and lower baseline serum sodium concentration.[67] The mechanism by which SSRIs cause hyponatremia is thought to be secondary to the development of Syndrome of inappropriate antidiuretic hormone secretion.[8] In most of the cases, this effect appears in the first month. Early detection and evaluation of concomitant risk factors in all patients starting antidepressants are important.[9] The treatment of isovolumic hypotonic hyponatremia associated with SSRI use includes water restriction and mild diuresis with a loop diuretic.[10] More severe cases may be treated with higher doses of loop diuretics and hypertonic saline. Furthermore, rechallenge with the same or another SSRI or substitution of another agent from a different therapeutic class has been successfully attempted. In some cases, hyponatremia recurred.[8]

Antipsychotics are also associated with reporting hyponatremia. Sometimes, antipsychotic-associated hyponatremia is underreported due to concomitant use of other medications associated with hyponatremia.[11] Atypical antipsychotic use compared to nonuse was associated with an increased risk of hospitalization with hyponatremia within 30 days.[11] The incidence of hyponatremia induced by antipsychotics may be much higher than is currently thought. Both the newer atypical antipsychotics and the older drugs have been associated with the development of hyponatremia.[12] A number of studies have suggested a possible association between atypical antipsychotics and hyponatremia.[13] Older antipsychotics too contribute to hyponatremia but owing to their side effect profiles, their use has been declining in routine care.[14] Like other psychotropic medications, it is suspected that atypical antipsychotics can induce hyponatremia by either stimulating antidiuretic hormone release from the brain or enhancing antidiuretic hormone activity in the kidneys.[15]

MATERIALS AND METHODS

This is an analytical study conducted in the Psychiatry Department of a tertiary level hospital located in Kolkata, West Bengal. The study was carried out over 15 months. It was started in December 2014 and data collection was completed in February 2016. The aim of the study was to understand the pattern of hyponatremia in patients using selective serotonin reuptake inhibitors (SSRI) and serotonin dopamine antagonists (SDA). Informed consent was obtained from the selected 150 patients. The approval of the institutional ethics committee was taken for the study.

Three groups were studied separately:

Patients on SSRI

Patients on SDA

Patients on both SSRI and SDA.

The assessment of serum sodium was done at 0, 7, 21, 60, 120, 180, and 240 days using an Eschweiler Electrolyte Analyser in the laboratory of the hospital.

Sample size

Assuming hyponatremia to be present in 10% of the study subjects as brought out by various studies and margin of error of 5% (95% confidence interval: 15%–25%) we calculated sample size to be 139 however for the ease of the study we included 50 patients in each arm. All inpatients and outpatients fulfilling the inclusion criteria, diagnosed with psychiatric illness and undergoing treatment with SSRI, SDA, or combination of both were included in the study. After simple random sampling using a lottery method, a total of 150 patients were finally included in the study comprising 50 patients from each study group as mentioned below:

Patients on SSRI

Patients on SDA

Patients on both SSRI and SDA.

Inclusion criteria

All diagnosed psychiatric cases as per the International Classification of Diseases-10 diagnostic criteria for research, who were adult and receiving SSRI, SDA, or combination of both

Patients who have participated willingly throughout the study.

Exclusion criteria

Patients unwilling to participate or lost to follow-up during the study period

Patients who were suffering from medical illnesses which might cause hyponatremia

Patients who were on medicines which might cause hyponatremia, other than psychotropic drugs

Patients who discontinued treatment before the completion of the study.

Data analysis

Categorical variables were observed as numbers and percentages. Continuous variables were evaluated as mean ± standard deviation. Chi-square test was applied for categorical variable to study their association. Five percentage error of margin has been taken for this study. Hence, any P < 0.05 has been considered to be statistically significant. IBM SPSS statistics V21.0 (Chicago, IL) was used for data analysis.

RESULTS

In this study, 57.3% were male and 42.7% were female. Majority (30.66%) were in the age group of 36–45 years as shown in Table 1. In our study population who were taking SSRI, escitalopram was taken by maximum number of cases (9.3%) as shown in Table 2. Among patients who were taking SDA, maximum patients (10.7%) were on risperidone as shown in Table 3. The most common combination of SSRI with SDA was fluoxetine with olanzapine or risperidone (8.7%) as shown in Table 4. Out of total of 150 patients in this study, 17 patients (11.3%) developed hyponatremia [Table 5]. Sixteen percent of patients on SSRI, 6% on SDA, and 12% on combination (SSRI + SDA) developed hyponatremia as shown in Table 6. Thirteen females (20.31%) developed hyponatremia, whereas only 4 males (4.65%) developed hyponatremia as shown in Table 7. Majority of the cases (66.66%) of hyponatremia were significantly higher in the age group 66–75 (P = 0.000) [Table 8].

Table 1

Age distribution

Age groups	Frequency (%)
15-25	13 (8.66)
26-35	36 (24)
36-45	46 (30.66)
46-55	26 (17.33)
56-65	17 (11.33)
66-75	12 (8)
Total	150 (100)

Table 2

Frequency of various selective serotonin reuptake inhibitors drugs intake

SSRI	Frequency (%)
Fluoxetine	12 (8.0)
Sertraline	12 (8.0)
Escitalopram	14 (9.3)
Paroxetine	7 (4.7)
Fluvoxamine	5 (3.3)
Total (SSRI)	50 (33.3)

SSRI Selective serotonin reuptake inhibitors

Table 3

Serotonin dopamine antagonists frequency table

	Frequency (%)
Risperidone	16 (10.7)
Olanzapine	13 (8.7)
Aripiprazole	9 (6.0)
Quetiapine	5 (3.3)
Clozapine	7 (4.7)
Total (SDA)	50 (33.3)

SDA Serotonin dopamine antagonists

Table 4

Both selective serotonin reuptake inhibitors and serotonin dopamine antagonists intake frequency table

	Frequency (%)
Fluoxetine+Olanzapine	13 (8.7)
Fluoxetine+Risperidone	13 (8.7)
Escitalopram+Quetiapine	6 (4.0)
Escitalopram+Aripiprazole	9 (6.0)
Sertraline+Quetipine	9 (6.0)
Total	50 (33.3)

Table 5

Number of cases of hyponatremia

	Frequency (%)
Hyponatremia	17 (11.3)
Normal	133 (88.7)
Total	150 (100.0)

Table 6

Frequency of hyponatremia with selective serotonin reuptake inhibitors, serotonin dopamine antagonists and combination of both

	Hyponatremia (n=50), n (%)
SSRI	8 (16)
SDA	3 (6)
Both (SSRI and SDA)	6 (12)
Total	17 (11.3)

SSRI Selective serotonin reuptake inhibitors; SDA Serotonin dopamine antagonists

Table 7

Gender and hyponatremia

Sex	Hyponatremia	Normal	Chi-square value significant
Female	13	51	0.003*
Male	4	82

*P<0.005

Table 8

Age and hyponatremia

Age groups	Output		Percentage of hyponatremia (%)	Chi value Sig
	Hyponatremia	Normal
15 to 25	0	13	0	0.000**
26 to 35	0	36	0
36 to 45	1	45	2.17
46 to 55	1	25	3.84
56 to 65	7	10	41.17
66 to 75	8	4	66.66
	17	133	100

**P<0.001

DISCUSSION

There has been widespread use of psychotropic drugs due to increase in prevalence and incidence of mental illnesses. Treatment with combination of two different classes of drugs and polypharmacy has become a common norm as treatment modalities among clinicians. The use of these psychotropic medicines is variable among all age groups and varied side effects of the treatment have come to light. Side effects often lead to poor drug compliance and failure of treatment. There have been studies mentioning about the hyponatremia due to the use of antidepressants and antipsychotics among psychiatric patients. However, to the present knowledge of authors, there are very few studies which have analyzed the pattern of hyponatremia among psychiatric patients with respect to sex, age, duration of treatment, and combination of different classes of drugs. Furthermore, there is dearth of such studies in the Indian setting. This study clearly brings out the pattern of hyponatremia in target population with relation to gender profile, type of drug used, and age of the patient.

Various psychotropic agents including SSRIs, tricyclic antidepressants, monoamine oxidase inhibitors, and antiepileptic drugs can cause hyponatremia. The most common mechanism is by inducing SIADH.[16] Various antipsychotic drugs, both typical and atypical, have been known to cause SIADH. The mechanism by which antipsychotics cause SIADH is not yet clear. There have been various postulated hypotheses in this regard, including long-term D2 receptor blockade leading to D2 receptor supersensitivity, that results in ADH release.[1718] There is also antipsychotic-induced hypotension causing ADH release through baroreceptor reflex, along with serotonin-mediated effects on central 5-hydroxytryptamine (5-HT) 2 and 5-HT1c receptors stimulating ADH secretion.[1920]

Most of the older patients have multiple comorbidities and often prescribed multiple drugs results in polypharmacy. Few commonly prescribed drugs have hyponatremia as known adverse effects such as thiazide diuretics, and ACEI. Due to changes in kidney functions as a result of aging, there is decreased excretion of drugs leading to increased incidence of hyponatremia.[21]

The majority of hyponatremia cases in the elderly and most of the cases occurring in psychiatric patients have been attributed to SIADH. Causes of SIADH are (a) CNS diseases such as CVA, head injury, and psychosis (b) lung pathologies such as pneumonia, bronchial asthma, atelectasis, pneumothorax, and respiratory failure (c) malignancies such as lung tumors, especially small cell carcinoma, produce ADH ectopically. (d) Other tumors such as cancers of, the duodenum, pancreas, head, and neck may also produce ADH occasionally (e) Hormone administration such as oxytocin, vasopressin, or desmopressin can cause SIADH by enhancing the activity of vasopressor-2 (V2) vasopressin receptor (f) surgical procedures, such as GI and thoracic surgeries and pituitary surgery can also increase the risk of SIADH (g) Both HIV infection and acquired immune deficiency syndrome are associated with SIADH (h) various drugs such as ciprofloxacin, cyclophosphamide, sodium valproate, oxcarbazepine, vincristine, opiate, and nonsteroidal anti-inflammatory drugs , can cause SIADH.[22]

Incidence of hyponatremia in psychiatry patients on SSRI ranges between 0.5% and 25%.[23] The most common SSRIs, predisposing to hyponatremia, reported are citalopram and escitalopram. Risk of hyponatremia is highest, more commonly seen in women than in men.[24] Our study results are consistent with these researches and bring out the same results. Bourgeois et al., have shown that escitalopram-induced hyponatremia is very commonly reported in clinical practices which are in favor of this study.[25] Our study shows that older age groups are more susceptible to the development of hyponatremia with the use of psychotropic drugs. The above results are similarly reported in lots of previous studies such as a study done by Jacob and Spinler reported incidence of SSRI-associated hyponatremia has been variable, ranging from 0.5% to 32%, and was most often observed in older adults.[4] Studies done by Kirby et al., have also suggested that SSRI use is strongly associated with the presence of hyponatremia in a population of elderly psychiatric patients.[26]

CONCLUSIONS

Hyponatremia is a life-threatening medical condition that can occur in patients with mental illness on psychotropic medications during treatment. Condition is usually unrecognized, overlooked, and untreated in psychiatric patients. When these drugs are prescribed then patients should be made aware of adverse side effects and sign and symptoms of this condition. If psychotropic-induced hyponatremia occurs, we should withdraw causative drug along with correction of condition with hypertonic saline and other measures. Our recommendation is that monitoring of serum sodium level should be done at regular intervals to diagnose cases with hyponatremia and prevent this life-threatening condition, especially in high-risk population.

Limitations of the study

Psychiatric diagnosis was not featured in this study

Dose of medications was not mentioned

Multiple samples for a single patient for serum sodium assessment at the fixed time interval led to increase in drop-out cases

As the study was conducted in a tertiary care setup and the patients had participated from far-flung areas so drug compliance of outpatients has always been a concern especially with those having poor family support. Therefore, possible irregular drug compliance also posed a challenge and risk of estimation error.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.