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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 108-122

Hyponatremia and psychotropics


Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication13-Dec-2016

Correspondence Address:
Sandeep Grover
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-9995.195604

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  Abstract 

Psychotropic-induced hyponatremia is one of the most common electrolyte abnormalities seen in routine psychiatric practice and is especially common in elderly subjects. Recent evidence suggests that even mild hyponatremia is associated with several detrimental effects in elderly. However, practicing clinicians often overlook hyponatremia due to lack of awareness about the incidence, presentation, and risk factors of psychotropic-induced hyponatremia. Available evidence suggests that all classes of psychotropics, i.e., antidepressants, antipsychotics, mood stabilizers, and sedative/hypnotics can lead to hyponatremia. Maximum evidence is available for antidepressant-associated hyponatremia. Various risk factors for hyponatremia include increasing age, female gender, low body weight, history of hyponatremia, low baseline sodium levels, summer season, initial phase of antidepressant use, early-onset psychiatric illnesses, longer duration of psychiatric disorder, prolonged admission, presence of comorbid medical conditions, concomitant use of diuretics, antihypertensives, and cytochrome P450 inhibitors. Awareness about this potentially life-threatening side effect and taking appropriate, timely steps can help in prevention of psychotropic-associated hyponatremia.

Keywords: Antidepressants, hyponatremia, psychotropics


How to cite this article:
Sahoo S, Grover S. Hyponatremia and psychotropics. J Geriatr Ment Health 2016;3:108-22

How to cite this URL:
Sahoo S, Grover S. Hyponatremia and psychotropics. J Geriatr Ment Health [serial online] 2016 [cited 2019 Sep 20];3:108-22. Available from: http://www.jgmh.org/text.asp?2016/3/2/108/195604


  Introduction Top


Hyponatremia is usually defined as a plasma sodium level below 135 mmol/L (normal range 135-145 mmol/L). [1],[2] It is one of the most common electrolyte abnormalities encountered not only in hospitalized patients but also in routine psychiatric clinical practice. [3] The impact of hyponatremia on the general health and well-being of an individual is significant, and if left untreated or overlooked, it can lead to serious complications. It has been reported to be independently associated with 55% increase in the risk of mortality, substantial hospital resource utilization, and costs. [4],[5],[6] The prevalence of hyponatremia is more in elderly subjects, with a prevalence rate of 22% in patients admitted to geriatric wards. [7],[8]

Hyponatremia has also been reported as a side effect of various psychotropic medications. It has been reported with antidepressants, antipsychotics, and mood stabilizers. In this review, we discuss the various types of hyponatremia, incidence of hyponatremia with various psychotropic medications, risk factors for developing hyponatremia with various psychotropics, clinical presentation of hyponatremia, and management of hyponatremia. For this review, a thorough internet search was done using the search engines of PubMed, PsycInfo, Google Scholar, Scopus, and ScienceDirect. The search terms used in various combinations included hyponatremia, antidepressants, antipsychotics, anticonvulsants, antiepileptics, sedatives, hypnotics elderly, and risk factors. An effort was made to organize the available literature as per the aim of the review.


  Types of hyponatremia Top


Hyponatremia can be classified on the basis of tonicity as hypertonic hyponatremia, isotonic hyponatremia, and hypotonic hyponatremia. Hypotonic hyponatremia is further classified as hypervolemic, euvolemic, and hypovolemic on the basis of volume status. Patients with hypertonic hyponatremia have plasma osmolality >295 mOsm/kg, and it is thought to have factitious etiology. Isotonic hyponatremia is characterized by plasma osmolality in the range of 280-295 mOsm/kg and is considered pseudohyponatremia. Hypotonic hyponatremia, which is true hyponatremia, is the most commonly encountered hyponatremia in the clinical settings, and it is characterized by plasma osmolality of <280 mOsm/kg. Patients with hypervolemic hyponatremia have expansion of both intracellular and extracellular fluid, but there is reduced effective arterial blood volume. This is often associated with azotemia and is seen in patients experiencing advanced renal failure, cirrhosis, heart failure, and nephrotic syndrome, etc. Euvolemic hyponatremia is characterized by expansion of both intracellular and extracellular fluid; however, this is characterized by the absence of accompanying edema and is seen in conditions such as psychogenic polydipsia, drug-induced hyponatremia, and syndrome of inappropriate antidiuretic hormone (SIADH) secretion and in endocrinopathies such as hypothyroidism and hypocortisolism. Hypovolemic hyponatremia is characterized by reduced extracellular fluid and occurs when there is primary natriuresis in conditions such as metabolic alkalosis, use of diuretics, and clinical conditions such as diarrhea, pancreatitis, and burns in which there are extrarenal sodium losses. [9]

Among all the causes of hyponatremia, drug-induced hyponatremia is very common. A plethora of medications (diuretics, anticancer drugs, antihypertensives, antidiabetics, anti-inflammatory drugs, antiepileptics, and psychotropics) has been reported to be associated with hyponatremia. [10] In this review, we will be specifically focusing on the psychotropics (antidepressants, antipsychotics, mood stabilizers, sedatives/hypnotics) induced hyponatremia and discuss various aspects of it.


  Risk/Incidence of Hyponatremia with Different Classes of Psychotropics Top


There is ample evidence of development of hyponatremia with different classes of psychotropics. Data for the association are available in the form of drug surveillance reports, case reports/series, retrospective studies, and there are very few prospective and observational cohort studies. Most of the studies have linked hyponatremia with selective serotonin reuptake inhibitors (SSRIs)/antidepressants, followed by carbamazepine, antipsychotic, and rarely, studies have implicated benzodiazepine/anxiolytic for development of hyponatremia.

Antidepressants

There is a large amount of data on the association of antidepressants with hyponatremia, and many studies have reported on the incidence of hyponatremia associated with antidepressants. However, it would not be possible to review all the available data. An attempt has been made to limit the review to large data sets. Hyponatremia has been reported with almost all the antidepressants.

Tricyclic antidepressants

Older studies reported incidence rate of hyponatremia with tricyclic antidepressants (TCAs) such as clomipramine to around 16%; [11] however, this data have been challenged by large-scale studies done in the United Kingdom and Germany, which suggest that incidence rate of hyponatremia with TCAs range from 0.01% to 0.33%. [12],[13] Studies which have compared the risk of developing hyponatremia with different antidepressant have consistently reported that the risk is lower with TCAs (odds ratio [OR]: 1.0-4.9) compared to SSRIs (OR: 1.5-21.6). [14] A recent head-to-head comparison study of TCAs and SSRIs in a large population-based cohort revealed an adjusted hazard ratio of 1.44 with the use of SSRIs when compared with TCAs. [15] Hence, it can be said that the incidence rate of antidepressant-associated hyponatremia is higher with SSRIs compared to TCAs.

Selective serotonin reuptake inhibitors

The incidence rate of hyponatremia with SSRIs across different studies ranges from as low as 0.06% to as high as 40% [Table 1]. Most of the studies have been retrospective in nature, [16-22] with a few prospective studies. [15],[23],[24] Some of these studies have focused on single SSRI, [16],[23-26] whereas others have evaluated incidence of hyponatremia with several SSRIs. [15],[18],[20],[21],[22] In majority of these studies, the patients were elderly (age >60 years) with a diagnosis of major depressive disorder. This discrepancy across the studies is because of the differences in the definition of the case (i.e., low incidence rates are found when hyponatremia is defined as serum sodium <130 mmol/L, in contrast to high incidence rates when cutoff is taken as serum sodium <135 mmol/L). [11],[12],[13],[14],[16-26] One thing that is evident from the existing literature is that as the sample size of the studies increases, the incidence rates go down and in general incidence rates are lower in retrospective studies when compared with prospective studies. These findings suggest that when there is active surveillance to detect hyponatremia, it is found in higher proportion of cases. However, it is important to remember that the reported incidence rate, especially in retrospective studies, may also be influenced by the frequency of use of medications in the routine clinical practice. A few studies have tried to compare the incidence rate of hyponatremia with different SSRIs. A recent large population-based cohort study and a drug surveillance Arzneimittelsicherheit in der Psychiatrie study found almost similar results with a significantly increased risk of hyponatremia with fluoxetine, citalopram, and escitalopram (i.e. 0.078-0.085%) and low risk with paroxetine and sertraline (i.e., 0.033-0.053%). [13],[15] However, further studies are needed to replicate these findings so as to confirm the same.
Table 1: Studies reporting incidence rates of hyponatremia with selective serotonin reuptake inhibitors

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Serotonin-norepinephrine reuptake inhibitors

A few studies have evaluated the incidence of hyponatremia with various serotonin-norepinephrine reuptake inhibitors (SNRIs) (venlafaxine, duloxetine, and milnacipran) and report an incidence rate of SNRI-induced hyponatremia with case definition of serum sodium <130 mmol/L to be in the range of 0.08-4%. [13],[15] However, clinic-based small sample studies have reported incidence rates to be as high as 71% [Table 2]. [20] A prospective study done among geriatric patients (age >65 years) with venlafaxine revealed an incidence of hyponatremia to be 17.2% and majority of the patients developed hyponatremia within a few days of starting venlafaxine. [27] Studies which have compared the incidence of hyponatremia between SNRIs and SSRIs suggest that the incidence rates are equal or higher with venlafaxine. [13],[15],[20],[22],[24] Unlike venlafaxine, the evidence for duloxetine-induced hyponatremia comes mainly from case reports/series [28-32] and it has not been evaluated across any prospective observational study, except for the recent United Kingdom drug surveillance study which reported 11% incidence of duloxetine-induced hyponatremia in only 1% of monitored patients using duloxetine. [13] Among the SNRIs, there is a lack of data for milnacipran-associated hyponatremia. However, some of the authors have used milnacipran in patients who developed hyponatremia with other antidepressants. [33]
Table 2: Studies reporting incidence rate of hyponatremia with venlafaxine

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Other antidepressants

There are few case reports of hyponatremia associated with use of mirtazapine and bupropion, and all these case reports have described the same among elderly (age >60 years) patients. [34-40] Some observational studies have also tried to find out the incidence of hyponatremia in relation to mirtazapine, but due to very low prescription rates of mirtazapine in the study population, exact incidence could not be evaluated. [12],[22] Similarly, no conclusive inference can be derived regarding incidence of hyponatremia with bupropion due to lack of large-scale prospective study. A few case reports have also demonstrated the relative safety of use of mirtazapine and bupropion in patients who developed hyponatremia with SSRIs. [41],[42],[43],[44] Other antidepressants such as monoamine oxidase inhibitors and noradrenergic reuptake inhibitor (reboxetine) have also been associated with hyponatremia though data are limited and exact incidence rates are not clear. [14]


  Antipsychotics Top


In contrast to the data on hyponatremia with antidepressants, very few studies have tried to evaluate the incidence of hyponatremia with antipsychotics. Data are mainly in the form of case reports and few observational studies, and this data has been reviewed by some of the researchers. [45],[46] Among the atypicals, there are case reports of hyponatremia with risperidone, [47] olanzapine, [48-50] aripiprazole, [51-54] clozapine, [55],[56] and quetiapine. [57],[58] Till 2002, the US Food and Drug Administration spontaneous reporting system had information of >300 reports of hyponatremia associated with various antipsychotics during the period of 1966 and 1999. [46] Studies which could be located for this review included four observational studies, [11],[55-60] one interventional study, [61] and one case-control study, [62] and data from the WHO global individual case safety report database system (VigiBase). These studies suggest that patients receiving phenothiazines are at increased risk of hyponatremia. [59] One observational study compared the prevalence of hyponatremia among 112 patients receiving perphenazine and 56 patients receiving clozapine and showed that the prevalence rates were 25.9% for perphenazine and 13.6% for clozapine. This study further documented that there was no significant association between dosage of both the medications and serum sodium levels. [11] Another cross-sectional study included 88 patients on clozapine, 61 patients on other atypicals, 23 patients on typical antipsychotics, and 11 patients on combination of typical and atypical antipsychotics. This study reported the frequency of hyponatremia with clozapine to be 3.4%, other atypicals to be 4.9%, typicals to be 26.1%, and that with a combination of typical and atypical antipsychotic to be 9.1%. None of the patients having clozapine associated hyponatremia were on monotherapy. [55] The intervention study showed that replacement of fluphenazine, haloperidol, thiothixene, and perphenazine with clozapine led to normalization of plasma osmolality. [61] The recent case-control study used the WHO global individual case safety report database system (VigiBase) and included cases being reported as hyponatremia/SIADH (n = 912) and controls being reports of other adverse drug reactions with antipsychotics. The adjusted reporting odds ratio for the association between antipsychotic use and hyponatremia was found to be 1.58 (95% confidence interval [CI]: 1.46, 1.70) which is quite significant. [62]

A problem frequently encountered while trying to establish antipsychotic-induced hyponatremia is that most of the patients in which hyponatremia is noted or is suspected to be antipsychotic induced have associated psychogenic polydipsia at presentation. Psychogenic polydipsia has been postulated to cause dysregulation of arginine vasopressin (AVP) hormone secretion and may lead to hyponatremia. [63],[64] Very few studies have also tried to look into this aspect and have tried to exclude patients with psychogenic polydipsia or those with history of psychogenic polydipsia. In addition, the atypical presentation of hyponatremia can mimic psychiatric symptoms and this may cause antipsychotic-induced hyponatremia to go unrecognized. [45] This further creates hindrance to reach a definite conclusion in this matter.

From the available data, it can be said that hyponatremia is seen patients receiving typical antipsychotics although it is not uncommon with atypical antipsychotic too. Data also suggest that atypical antipsychotics help in treating hyponatremia associated with psychogenic polydipsia. In this regard, clozapine has been reported to be slightly better than other antipsychotics [11],[61],[65],[66],[67],[68],[69] although some case reports suggest that risperidone and olanzapine are also quite effective. [70],[71]


  Mood stabilizers Top


Among the mood stabilizers, carbamazepine/oxcarbazepine, valproate, and lamotrigine have been found to cause hyponatremia across several studies. [72-82] Out of the classical three mood stabilizers, evidence is most robust for carbamazepine. The incidence rate of hyponatremia with carbamazepine varies from 4.8% to 41.5% depending on the patient population studied. [83-89] These studies have included patients with affective/psychotic disorders, mental retardation/intellectual disability. However, it is important to note that all these have been clinic-based studies, mostly cross-sectional in nature, with sample size varying between 12 and 60 cases.

Evidence for valproate being implicated in development of hyponatremia is only in the form of case reports/case series. Majority of these patients were elderly and had either affective illness or epilepsy. [74-79],[82],[90] Data are limited for lamotrigine-induced hyponatremia. [80],[81]

Sedative/hypnotics

There have been isolated case reports of benzodiazepine/hypnotic-induced hyponatremia. Several benzodiazepines such as lorazepam, alprazolam, oxazepam, clonazepam, triazolam, temazepam, clorazepate, and zolpidem (nonbenzodiazepine hypnotic) have been linked with development of hyponatremia. [46],[91],[92]


  Etiopathogenesis of Psytrophic-Induced Hyponatremia Top


Kidneys maintain the normal homeostasis by regulating a balance between body fluids and serum sodium levels and thereby preventing development of hyponatremia in normal physiological conditions. ADH, produced by the hypothalamus, plays a major role in controlling fluid balance in our body by promoting thirst and water retention and upregulating reabsorption of water and sodium ions in the distal tubule of the nephron. Inappropriate and continuous secretion or action of ADH (SIADH), despite the normal or higher plasma volume, results in hyposmolality and hyponatremia. The proposed mechanisms by which various psychotropics cause hyponatremia are different for different groups of drugs [Table 3]. Antidepressants induce hyponatremia by either increasing hypothalamic production of ADH, potentiating the effect of endogenous ADH at the renal medulla, or resetting the osmostat mechanism by lowering the threshold for ADH secretion. [46],[93] SSRIs have been reported to mainly cause hyponatremia by potentiating the effect of endogenous ADH at the renal medulla and increasing hypothalamic production of ADH. The hypothesis behind antipsychotic-induced hyponatremia is development of SIADH. It has been suggested and proved from animal studies that both typical and atypical antipsychotics stimulate and facilitate ADH release in the brain. [94] Atypical antipsychotics (aripiprazole, quetiapine, clozapine) cause hyponatremia due to their serotonin-mediated effects on central 5-HT2 and 5-HT1c receptors which lead to excess release of ADH. Furthermore, serotonin is known to reset the osmostat and thereby lowers the threshold for ADH secretion. [52],[95] Typical antipsychotics (chlorpromazine, haloperidol, fluphenazine, trifluoperazine, thioridazine) on the other hand have been postulated to cause hyponatremia by inducing severe polydipsia by stimulating the thirst center. [46],[96],[97] Carbamazepine/oxcarbazepine is postulated to induce hyponatremia either by increasing ADH release centrally or by the potentiation of ADH effect. [72] Sodium valproate leads to hyponatremia through the mechanism of development of SIADH, [90] whereas lithium has been associated with development of paradoxical hyponatremia secondary to lithium-induced diabetes insipidus. [98] On the other hand, lamotrigine has been found to induce hyponatremia by potentiating the renal tubule effects of ADH. [80] Benzodiazepines have also been reported to cause hyponatremia by causing SIADH. [46],[91],[92]
Table 3: Mechanism of action for development of hyponatremia by various psychotropics

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  Risk factors for developing hyponatremia with psychotropic medications Top


Various risk factors [Table 4] have been implicated for development of hyponatremia due to psychotropics. These include demographic variables, environmental variables, physical characteristics, psychiatric illness variables, comorbid medical conditions, history of hyponatremia, contaminant medications, and dose and duration of implicating agents.
Table 4: Risk factors for development of hyponatremia with psychotropics

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Demographic variables

Age is an important risk factor for the development of hyponatremia associated with antidepressants, and it has been evaluated across several studies. Most of the literature on psychotropic-induced hyponatremia suggests that older age is a significant risk factor for development of drug-induced hyponatremia although it has also been reported in young subjects. [99] The odds ratio for SSRI-induced hyponatremia among elderly is reported to be 6.2. [14] Higher risk of hyponatremia is attributed to the compromised age-related physiology, multiple comorbidities, and use of concomitant medications. In addition, elderly subjects are often dehydrated, which increases the risk of hyponatremia. [100] Prevalence of hyponatremia among elderly subjects receiving SSRIs varies between 0.5% and 25%, with an incidence rate of 4.7/1000 treated patients per year. [18],[19],[101] However, studies on hyponatremia associated with antipsychotics and carbamazepine have failed to demonstrate any significant correlation between age and hyponatremia associated with use of these medications. [45],[72],[102] When hyponatremia occurs in elderly, it is usually mild, mostly asymptomatic, devoid of any noticeable neurological sign and symptom and chronic (i.e., serum sodium ranging between 130 and 134 mmol/L). [103] Hence, it is often overlooked. However, recent studies show that even mild chronic hyponatremia can increase the risk of osteoporosis and subsequent falls and hip fracture, cognitive impairment (attentional deficits), can prolong hospitalization and cause medical complications. [104],[105],[106] However, some of the studies suggest that if all other confounding factors (such as comorbid medical conditions - diabetes mellitus, hypertension, and decreased glomerular filtration rate) are controlled for, then age alone does not appear to be an independent risk factor for development of hyponatremia. [107],[108]

In terms of gender, almost all the studies show that risk of antidepressant-induced hyponatremia is more in females. [93] However, the same is not true for carbamazepine or antipsychotic-induced hyponatremia. [72] Some authors suggest that the higher incident rates reported among females could be due to higher prevalence rates of certain psychiatric disorders among females, especially depression, which has been reported to be more common in females. [109],[110],[111] Hence, it can be said that higher exposure to psychotropics in females leads to increased incidence of psychotropic-induced hyponatremia. In addition, females have higher longevity as compared to males which further adds up to the increased rates of hyponatremia in females.

Physical characteristics

There is some evidence to suggest that incidence of hyponatremia is more among subjects with low body weight [112] or those weighing <60 kg (adjusted OR: 3.47, 95% CI: 1.19-10.13). [7]

History of hyponatremia in the past

Studies suggest that if a patient has a history of hyponatremia, then the chances of developing antidepressant-associated hyponatremia increase (adjusted OR: 11.17, 95% CI: 2.56-40.41). [7]

Baseline sodium level

Even though majority of the studies have tried to exclude patients with baseline low sodium concentration and concurrent administration of psychotropics so as to prevent any bias/confounding factor for development of hyponatremia, there is evidence to suggest that patients who have low baseline sodium levels (<138 mmol/L) are at higher risk of developing hyponatremia associated with antidepressants. [19],[20],[26],[113],[114],[115]

Environmental factors

Among the environmental variables, risk of antidepressant-induced hyponatremia has been reported to be more common during the summer season. [116] A retrospective study from India which tried to study the seasonal variation in the incidence of hyponatremia due to metabolic causes in a sample size of 353 patients revealed that incidence of hyponatremia was higher during the peak southwest monsoon season (June to August) and proposed that humidity and temperature might have important role in the manifestation of hyponatremia. [117]

Nature of psychiatry disorder

Apart from being commonly reported in patients with psychogenic polydipsia (due to development of SIADH in these patients following water intoxication), hyponatremia has also been reported in patients with schizophrenia, anorexia nervosa, [118] psychotic depression, [119],[120] bipolar disorder, substance use disorders, mental retardation, [121] and other neuropsychiatric conditions such as epilepsy. [108],[122] Psychogenic polydipsia is seen in 6-20% of psychiatric patients. [64],[123] Polydipsia in patients with schizophrenia leading to hyponatremia has been hypothesized to be mediated partly by a reduced osmotic threshold for the release of AVP and partly by a defect in the osmoregulation of thirst. [108] An epidemiological study done on hyponatremia in psychiatric patients in mental hospitals in Japan revealed that early-onset psychiatric illnesses, longer duration of psychiatric disorder, and prolonged admission appear to be statistically significant factors associated with the development of hyponatremia. [124]

Comorbid medical conditions

Studies and case reports which have found hyponatremia associated with various psychotropics, especially antidepressants, suggest that the patients who develop hyponatremia with psychotropics often have medical comorbidities such as diabetes mellitus, hypertension, hypothyroidism, chronic obstructive pulmonary disease, cardiac failure, circulating volume depletion, hormonal imbalances, head injury, cerebrovascular accidents, liver cirrhosis, and various cancers. [113],[125],[126]

Use of other concomitant medications

Evidence suggests that risk of psychotropic-associated hyponatremia increases with concomitant use of other medications such as antihypertensives, antidiabetics, diuretics, proton pump inhibitors, antibiotics, antiepileptics, and nonsteroidal anti-inflammatory drugs. [10],[127],[128],[129] Among the various concomitant medications, maximum risk has been reported for use of diuretics, with 11.2-13.5 folds increase in the risk of hyponatremia when combined with SSRIs. [14],[130] The concomitant medications can also influence the serum levels of the agent implicated for development of hyponatremia, by inhibiting the metabolism of the drug at the cytochrome 450 level. [46],[93] Polypharmacy is also very common in the elderly population, and the various medications may stimulate AVP release and/or enhance the hormone's action to increase water absorption leading to hyponatremia/SIADH. [131] Polypharmacy-induced hyponatremia has often been found to have a fatal outcome. [132],[133]

Dose of psychotropic used

Existing literature is inconclusive in terms of relationship of hyponatremia with dose of psychotropic medication. [46],[93] A few clinical studies have found a correlation between carbamazepine dosage (dose >700 mg and serum carbamazepine level >8.3 μg/μl) and hyponatremia. [72],[75],[134],[135] A few case reports have also reported association of hyponatremia with dose of various antidepressants, [35],[136],[137] and occasional reports suggest the reversal of hyponatremia with reduction in the dose of the offending agent. [138],[139]

Duration of treatment

Almost all psychotropic-induced hyponatremia usually develop during the initial phase of treatment. Review of all case reports of antidepressant-induced hyponatremia, particularly SSRIs, has found that hyponatremia generally develops during the 1 st month of therapy with a broad range of 3-120 days and it reverses between 2 and 28 days after the removal of offending agent. [10],[93] Hyponatremia associated with antipsychotics and carbamazepine has also been seen mostly during the first 2 weeks of treatment. [45],[46],[72] However, there are reports of hyponatremia during the long-term maintenance treatment with carbamazepine in elderly patients with bipolar disorder and epilepsy. [72]


  Clinical features Top


Hyponatremia in patients with mental illness is often discovered incidentally on routine blood testing (except in cases of delirium due to hyponatremia). It is classically divided into mild (130-134 mmol/l), moderate (125-129 mmol/l), and severe (<125 mmol/l) hyponatremia. [100] Most of the time, it is asymptomatic initially; however, as the serum sodium decreases, patients start to experience headache, confusion, muscle cramps, lethargy and can have severe agitation. [140],[141] Drop in serum sodium level below 120 mmol/l can lead to severe signs/symptoms such as seizures, stupor, Cheyne-Stokes breathing, diminished deep tendon reflexes and may lead to coma. [140],[141] Most of the patients with hyponatremia can be diagnosed to be having delirium if properly evaluated. The mental state of a patient with hyponatremia worsens with the rate of decrease of serum sodium. It is because of the fact that all these symptoms are caused chiefly by excessive entry of water into brain cells. Brain cells can adapt to changes in plasma tonicity initially, but over time, failure to adaptation in the brain cells leads to more severe symptoms such as seizures, coma. [2] On the other hand, chronic untreated mild hyponatremia in elderly has been found to be an important risk factor for recurrent falls, [104] bone demineralization or osteoporosis, [142] hip fractures, [106],[143] and cognitive impairment. [144],[145] All these abnormalities are reversible, and careful correction of hyponatremia can improve quality of life and decrease mortality. [144]


  Prevention Top


Psychotropic-induced hyponatremia can be prevented if it is detected early and monitored appropriately. Most clinicians are unaware how commonly psychotropics can induce hyponatremia in elderly individuals because associated symptoms are nonspecific and are usually interpreted as either symptoms of depression (e.g., fatigue, anorexia, confusion) or medication side effects (e.g., gait disturbances, vomiting, fatigue) [Table 5]. [140],[141],[145] Knowledge about the established risk factors is of paramount importance for early identification of hyponatremia in vulnerable individuals. It is advisable to look for potential drug-drug interactions, and polypharmacy should be avoided as far as possible. Prescription should be rationalized with use of minimum number of medications [Table 6]. The principle of "start low, go slow" should be followed in elderly to prevent any adverse side effect and the same holds true to prevent hyponatremia too. [126] Steps such as evaluating the history for potential risk factors including history of hyponatremia, serum sodium level before starting of antidepressants, starting at the low dose, and slowing increasing the dose of antidepressant and monitoring of serum sodium levels during the initial few weeks can be useful. It is worthwhile to get the baseline serum sodium levels, because many patients may have undetected hyponatremia, which may worsen with the prescription of psychotropics, particularly antidepressants. Hence, it is recommended to get the baseline sodium levels and serum sodium levels must be done at week 1 and 2 weeks after initiation of treatment and subsequently at each increment of dose. [113],[125],[146] Stricter monitoring is to be followed if the individual is receiving concurrent diuretic therapy. In vulnerable individuals, serum and urine osmolality should also be monitored. [147] If a patient is found to have low sodium levels at the first instance, it is also advisable to repeat and recheck the serum sodium levels to confirm hyponatremia more accurately and to prevent overcorrection/undercorrection based on common laboratory errors. Changes of up to 5 mmol/l can reflect nonsignificant variation and usually do not warrant any urgent/rapid correction. [148] In addition, the patient and family members should be educated about the signs and symptoms of hyponatremia, and what steps need to be taken to avoid hyponatremia. Any change in behavior and cognition should be immediately reported to the treating clinician. Fluid overload is one of the most important factors contributing to the development of hyponatremia, and hence, excessive fluid intake should be avoided. Daily dietary sodium intake should not be compromised and rather an addition of low sodium in the form of salt can be advised in case of low baseline serum sodium. [100],[126] A simple algorithm which can be followed is depicted in [Figure 1].
Table 5: Clinical manifestations of hyponatremia

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Table 6: Steps to prevent psychotropic-associated hyponatremia

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Figure 1: Diagnosis and management of psychotropic - induced hyponatremia

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  Management of hyponatremia Top


Although hyponatremia due to psychotropics is not so commonly encountered, it should not be neglected when detected as early identification and prompt treatment can ward off serious life-threatening complications. In addition, mild but chronic hyponatremia, particularly in elderly, should be taken seriously as it has severe deleterious effect on the cognitive functions and physical health of an elderly individual with mental illness. Routine serum sodium monitoring in elderly receiving various psychotropic medications is often not done, which actually leads to lack of recognition of hyponatremia in this high-risk population. Clinical assessment of elderly individuals should be done seriously as an incorrect assessment can result in fluid depletion/dehydration being wrongly treated with fluid restriction leading to further worsening the hyponatremia. [100],[149]

General considerations

Both extremes of treatment should be avoided. Acute hyponatremia even if mild should not be neglected as it can cause mortality as a result of osmotically induced cerebral edema as well as excessively rapid correction of chronic hyponatremia can cause severe neurologic impairment, i.e., central pontine myelinolysis and mortality. [150] Practical difficulties can be encountered in reaching to an optimum balance as many a times correction of hyponatremia leads to overcorrection resulting in further supplementation with hypotonic fluids. [100],[151] Ideally, such problems can be avoided by periodic monitoring of serum sodium levels on multiple occasions in a day till optimization. The general principles as listed in [Table 7] must be followed. As soon as hyponatremia is detected in an individual receiving psychotropic medication, a rapid search for the possible etiology of hyponatremia should be done to rule out all other possible/contributing causes of hyponatremia such as heart failure, dehydration, and cirrhosis before attributing the same to psychotropic medication only. Studies have shown that hyponatremia in older people is often multifactorial rather than attributable to a single entity. [152] Prescription of the patient must be reviewed and the medications known to cause hyponatremia should preferably be discontinued. For example, concurrent use of diuretics and SSRIs can both lead to low serum sodium. Thiazide diuretics and nonsteroidal anti-inflammatory drugs increase the risk of developing hyponatremia in older people. [100],[153] If one is sure that hyponatremia/SIADH is due to a psychotropic, then mere stopping the offending agent can lead to restoration of sodium levels in body. If the patient does not have any clinical symptom of hyponatremia, less aggressive measures may be followed. If discontinuation of the drug does not lead to an increment in the serum sodium level, water restriction (0.5-1 L/day) may be necessary. If the condition worsens with neurological signs and symptoms, then correction with hypertonic saline is indicated in coordination with physicians. The rapidity of correction depends on the chronicity of the condition as well as the presence or absence of symptoms. [46],[154] If the serum sodium level is <125 mmol/L and/or there is worsening of neurological signs and symptoms irrespective of serum sodium level, then hyponatremia should be regarded as a medical emergency. The patient should be given inpatient care in a hospital, and hypertonic saline infusion may be required after proper evaluation followed by furosemide administration to prevent the kidney from concentrating urine even in the presence of high levels of ADH. [100]
Table 7: General principles of management of hyponatremia associated with psychotropics

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Other measures

There is minimal evidence for use of other medications for management of hyponatremia. Some of the authors have suggested the beneficial effect of medications such as phenytoin, [155] demeclocycline, [156] lithium, [155],[157] and vasopressin receptor antagonists (conivaptan/tolvaptan). [100],[158] However, the evidence is preliminary to make any recommendation.

Can antidepressants be used again in a patient who develops hyponatremia?

Some of the earlier case reports suggested that patients could be rechallenged with the same psychotropic medication after normalization of serum sodium levels. [159],[160] However, with the broadening of psychopharmacological options, rechallenge with the same agent is not recommended unless there is no other alternative psychotropic available to treat the patient's condition. Based on available literature, i.e., mainly case reports of patients developing hyponatremia with various antidepressants again if any other drug from the same class is tried, [161],[162] it is suggested to avoid using a drug from the same class. Available case reports suggest that switching to an antidepressant of another class may be beneficial and there is less chance of developing hyponatremia with new drug from different class. Usually, if there is a history of hyponatremia with SSRI/SNRI or if patient develops hyponatremia with a SSRI/SNRI, antidepressant known to have lower potential to cause hyponatremia such as bupropion, mirtazapine, and milnacipran may be considered. [33],[41],[42],[43],[44]

Electroconvulsive therapy (ECT) has also been postulated to cause hyponatremia/SIADH by deregulating thirst mechanisms and stimulating the release of ADH and thereby causing SIADH by some authors in the past. [163-165] However, there have been recent case reports of successful use of ECT in a patient with catatonia induced by hyponatremia [166] and also in depressed patient who developed SIADH with improvement of the depression and serum sodium levels following ECT. [167] Hence, ECT may be considered if clinically indicated for management of primary disorder.

Antipsychotics vary in their structure and receptor affinity among the same class to a very wide extent. Hyponatremia with one atypical antipsychotic does not usually pose risk of developing hyponatremia with another atypical. Rather another atypical, especially clozapine has been found to improve serum sodium levels. However, it is better to avoid typical antipsychotic if an individual develops hyponatremia with typical or an atypical antipsychotic. Most of the evidence suggests that if there are no contraindications, then clozapine may be considered as an option for management in patients who develop hyponatremia while receiving various antipsychotics. [11],[61],[65],[66],[67],[68],[69] However, in some case reports, risperidone and olanzapine had been found to be quite effective. [70],[71] Regular monitoring of serum sodium levels is usually recommended if another new drug from different classes or same class is tried.


  Conclusion Top


Hyponatremia is an untoward and life-threatening adverse effect which commonly occurs in elderly patients with mental illness receiving various psychotropic medications. It is usually overlooked and unrecognized. Almost all psychotropics have potential to induce hyponatremia in elderly individuals. However, antidepressants have been more commonly implicated. One must evaluate the potential risk factors for development of hyponatremia in an elderly before prescribing a psychotropic and should be cautious enough to monitor during the initial phase of treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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