|Year : 2016 | Volume
| Issue : 2 | Page : 108-122
Hyponatremia and psychotropics
Swapnajeet Sahoo, Sandeep Grover
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||13-Dec-2016|
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
Hyponatremia is usually defined as a plasma sodium level below 135 mmol/L (normal range 135-145 mmol/L). , It is one of the most common electrolyte abnormalities encountered not only in hospitalized patients but also in routine psychiatric clinical practice.  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. ,, The prevalence of hyponatremia is more in elderly subjects, with a prevalence rate of 22% in patients admitted to geriatric wards. ,
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|| |
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. 
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.  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|| |
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.
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.
Older studies reported incidence rate of hyponatremia with tricyclic antidepressants (TCAs) such as clomipramine to around 16%;  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%. , 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).  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.  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. ,, Some of these studies have focused on single SSRI, ,[23-26] whereas others have evaluated incidence of hyponatremia with several SSRIs. ,,,, 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). ,,,,[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%). , 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%. , However, clinic-based small sample studies have reported incidence rates to be as high as 71% [Table 2].  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.  Studies which have compared the incidence of hyponatremia between SNRIs and SSRIs suggest that the incidence rates are equal or higher with venlafaxine. ,,,, 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.  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. 
|Table 2: Studies reporting incidence rate of hyponatremia with venlafaxine|
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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. , 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. ,,, 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. 
| Antipsychotics|| |
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. , Among the atypicals, there are case reports of hyponatremia with risperidone,  olanzapine, [48-50] aripiprazole, [51-54] clozapine, , and quetiapine. , 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.  Studies which could be located for this review included four observational studies, ,[55-60] one interventional study,  and one case-control study,  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.  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.  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.  The intervention study showed that replacement of fluphenazine, haloperidol, thiothixene, and perphenazine with clozapine led to normalization of plasma osmolality.  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. 
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. , 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.  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 ,,,,,, although some case reports suggest that risperidone and olanzapine are also quite effective. ,
| Mood stabilizers|| |
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],, Data are limited for lamotrigine-induced hyponatremia. ,
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. ,,
| Etiopathogenesis of Psytrophic-Induced Hyponatremia|| |
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. , 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.  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. , 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. ,, Carbamazepine/oxcarbazepine is postulated to induce hyponatremia either by increasing ADH release centrally or by the potentiation of ADH effect.  Sodium valproate leads to hyponatremia through the mechanism of development of SIADH,  whereas lithium has been associated with development of paradoxical hyponatremia secondary to lithium-induced diabetes insipidus.  On the other hand, lamotrigine has been found to induce hyponatremia by potentiating the renal tubule effects of ADH.  Benzodiazepines have also been reported to cause hyponatremia by causing SIADH. ,,
|Table 3: Mechanism of action for development of hyponatremia by various psychotropics|
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| Risk factors for developing hyponatremia with psychotropic medications|| |
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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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.  The odds ratio for SSRI-induced hyponatremia among elderly is reported to be 6.2.  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.  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. ,, 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. ,, 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).  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. ,, 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. ,
In terms of gender, almost all the studies show that risk of antidepressant-induced hyponatremia is more in females.  However, the same is not true for carbamazepine or antipsychotic-induced hyponatremia.  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. ,, 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.
There is some evidence to suggest that incidence of hyponatremia is more among subjects with low body weight  or those weighing <60 kg (adjusted OR: 3.47, 95% CI: 1.19-10.13). 
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). 
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. ,,,,,
Among the environmental variables, risk of antidepressant-induced hyponatremia has been reported to be more common during the summer season.  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. 
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,  psychotic depression, , bipolar disorder, substance use disorders, mental retardation,  and other neuropsychiatric conditions such as epilepsy. , Psychogenic polydipsia is seen in 6-20% of psychiatric patients. , 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.  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. 
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. ,,
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. ,,, 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. , 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. , 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.  Polypharmacy-induced hyponatremia has often been found to have a fatal outcome. ,
Dose of psychotropic used
Existing literature is inconclusive in terms of relationship of hyponatremia with dose of psychotropic medication. , A few clinical studies have found a correlation between carbamazepine dosage (dose >700 mg and serum carbamazepine level >8.3 μg/μl) and hyponatremia. ,,, A few case reports have also reported association of hyponatremia with dose of various antidepressants, ,, and occasional reports suggest the reversal of hyponatremia with reduction in the dose of the offending agent. ,
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. , Hyponatremia associated with antipsychotics and carbamazepine has also been seen mostly during the first 2 weeks of treatment. ,, However, there are reports of hyponatremia during the long-term maintenance treatment with carbamazepine in elderly patients with bipolar disorder and epilepsy. 
| Clinical features|| |
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.  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. , 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. , 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.  On the other hand, chronic untreated mild hyponatremia in elderly has been found to be an important risk factor for recurrent falls,  bone demineralization or osteoporosis,  hip fractures, , and cognitive impairment. , All these abnormalities are reversible, and careful correction of hyponatremia can improve quality of life and decrease mortality. 
| Prevention|| |
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]. ,, 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.  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. ,, 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.  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.  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. , A simple algorithm which can be followed is depicted in [Figure 1].
|Figure 1: Diagnosis and management of psychotropic - induced hyponatremia|
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| Management of hyponatremia|| |
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. ,
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.  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. , 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.  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. , 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. , 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. 
|Table 7: General principles of management of hyponatremia associated with psychotropics|
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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,  demeclocycline,  lithium, , and vasopressin receptor antagonists (conivaptan/tolvaptan). , 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. , 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, , 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. ,,,,
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  and also in depressed patient who developed SIADH with improvement of the depression and serum sodium levels following ECT.  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. ,,,,,, However, in some case reports, risperidone and olanzapine had been found to be quite effective. , Regular monitoring of serum sodium levels is usually recommended if another new drug from different classes or same class is tried.
| Conclusion|| |
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.
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| References|| |
Smith DM, McKenna K, Thompson CJ. Hyponatraemia. Clin Endocrinol (Oxf) 2000;52:667-78.
Biswas M, Davies JS. Hyponatraemia in clinical practice. Postgrad Med J 2007;83:373-8.
Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia. Semin Nephrol 2009;29:227-38.
Zilberberg MD, Exuzides A, Spalding J, Foreman A, Jones AG, Colby C, et al.
Epidemiology, clinical and economic outcomes of admission hyponatremia among hospitalized patients. Curr Med Res Opin 2008;24:1601-8.
Hoorn EJ, Zietse R. Hyponatremia and mortality: Moving beyond associations. Am J Kidney Dis 2013;62:139-49.
Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med 2010;170:294-302.
Mannesse CK, Jansen PA, Van Marum RJ, Sival RC, Kok RM, Haffmans PM, et al.
Characteristics, prevalence, risk factors, and underlying mechanism of hyponatremia in elderly patients treated with antidepressants: A cross-sectional study. Maturitas 2013;76:357-63.
Hoyle GE, Chua M, Soiza RL. Prevalence of hyponatremia in elderly patients. J Am Geriatr Soc 2006;54:1473.
Parikh C, Berl T. Disorders of water metabolism. In: Feehally J, Floege J, Johnson RJ, editors. Comprehensive Clinical Nephrology. Philadelphia: Mosby Elsevier; 2007. p. 97.
Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008;52:144-53.
Spigset O, Hedenmalm K. Hyponatremia during treatment with clomipramine, perphenazine, or clozapine: Study of therapeutic drug monitoring samples. J Clin Psychopharmacol 1996;16:412-4.
Coupland CA, Dhiman P, Barton G, Morriss R, Arthur A, Sach T, et al.
A study of the safety and harms of antidepressant drugs for older people: A cohort study using a large primary care database. Health Technol Assess 2011;15:1-202, iii-iv.
Letmaier M, Painold A, Holl AK, Vergin H, Engel R, Konstantinidis A, et al.
Hyponatraemia during psychopharmacological treatment: Results of a drug surveillance programme. Int J Neuropsychopharmacol 2012;15:739-48.
De Picker L, Van Den Eede F, Dumont G, Moorkens G, Sabbe BG. Antidepressants and the risk of hyponatremia: A class-by-class review of literature. Psychosomatics 2014;55:536-47.
Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: Population based cohort study. BMJ 2011;343:d4551.
Pillans PI, Coulter DM. Fluoxetine and hyponatraemia - A potential hazard in the elderly. N Z Med J 1994;107:85-6.
Strachan J, Shepherd J. Hyponatraemia associated with the use of selective serotonin re-uptake inhibitors. Aust N Z J Psychiatry 1998;32:295-8.
Bouman WP, Pinner G, Johnson H. Incidence of selective serotonin reuptake inhibitor (SSRI) induced hyponatraemia due to the syndrome of inappropriate antidiuretic hormone (SIADH) secretion in the elderly. Int J Geriatr Psychiatry 1998;13:12-5.
Wilkinson TJ, Begg EJ, Winter AC, Sainsbury R. Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people. Br J Clin Pharmacol 1999;47:211-7.
Kirby D, Harrigan S, Ames D. Hyponatraemia in elderly psychiatric patients treated with selective serotonin reuptake inhibitors and venlafaxine: A retrospective controlled study in an inpatient unit. Int J Geriatr Psychiatry 2002;17:231-7.
Wee R, Lim WK. Selective serotonin re-uptake inhibitors (SSRIs) and hyponatraemia in the elderly. Int J Geriatr Psychiatry 2004;19:590-1.
Jung YE, Jun TY, Kim KS, Bahk WM. Hyponatremia associated with selective serotonin reuptake inhibitors, mirtazapine, and venlafaxine in Korean patients with major depressive disorder. Int J Clin Pharmacol Ther 2011;49:437-43.
Fabian TJ, Amico JA, Kroboth PD, Mulsant BH, Reynolds CF 3 rd
, Pollock BG. Paroxetine-induced hyponatremia in the elderly due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Geriatr Psychiatry Neurol 2003;16:160-4.
Oslin DW, Ten Have TR, Streim JE, Datto CJ, Weintraub D, DiFilippo S, et al.
Probing the safety of medications in the frail elderly: Evidence from a randomized clinical trial of sertraline and venlafaxine in depressed nursing home residents. J Clin Psychiatry 2003;64:875-82.
Huyse FJ, Zwaan WA, Kupka R. The applicability of antidepressants in the depressed medically ill: An open clinical trial with fluoxetine. J Psychosom Res 1994;38:695-703.
Fabian TJ, Amico JA, Kroboth PD, Mulsant BH, Corey SE, Begley AE, et al.
Paroxetine-induced hyponatremia in older adults: A 12-week prospective study. Arch Intern Med 2004;164:327-32.
Roxanas M, Hibbert E, Field M. Venlafaxine hyponatraemia: Incidence, mechanism and management. Aust N Z J Psychiatry 2007;41:411-8.
Krüger S, Lindstaedt M. Duloxetine and hyponatremia: A report of 5 cases. J Clin Psychopharmacol 2007;27:101-4.
Dirks AC, van Hyfte DM. Recurrent hyponatremia after substitution of citalopram with duloxetine. J Clin Psychopharmacol 2007;27:313.
Stovall R, Brahm NC, Crosby KM. Recurrent episodes of serotonin-reuptake inhibitor-mediated hyponatremia in an elderly patient. Consult Pharm 2009;24:765-8.
Safdieh JE, Rudominer R. A case of hyponatremia induced by duloxetine. J Clin Psychopharmacol 2006;26:675-6.
Choi JS, Lee HW, Lee JY, Jung HY. Rapid-onset hyponatremia induced by duloxetine in a middle-aged male with depression and somatic symptoms. Psychiatry Investig 2012;9:83-4.
Grover S, Somaiya M, Dutta P. Use of milnacipran in a patient with hyponatremia under the cover of fludrocortisones. J Clin Case Rep 2013;3:308.
Bavbek N, Alkan R, Uz E, Kaftan O, Akcay A. Hyponatremia associated with sodium valproate in a 22-year-old male. Nephrol Dial Transplant 2008;23:410.
Cheah CY, Ladhams B, Fegan PG. Mirtazapine associated with profound hyponatremia: Two case reports. Am J Geriatr Pharmacother 2008;6:91-5.
Ladino M, Guardiola VD, Paniagua M. Mirtazapine-induced hyponatremia in an elderly hospice patient. J Palliat Med 2006;9:258-60.
Famularo G, Gasbarrone L, De Virgilio A, Minisola G. Mirtazapine-associated hyponatremia in an elderly patient. Ann Pharmacother 2009;43:1144-5.
Bagley SC, Yaeger D. Hyponatremia associated with bupropion, a case verified by rechallenge. J Clin Psychopharmacol 2005;25:98-9.
Kate N, Grover S, Kumar S, Modi M. Bupropion-induced hyponatremia. Gen Hosp Psychiatry 2013;35:681.e11-2.
Kim CS, Choi JS, Bae EH, Kim SW. Hyponatremia associated with bupropion. Electrolyte Blood Press 2011;9:23-6.
Malik AR, Wolf PK, Ravasia S. Recurrent paroxetine-induced hyponatremia. Can J Psychiatry 2004;49:785.
Jagsch C, Marksteiner J, Seiringer E, Windhager E. Successful mirtazapine treatment of an 81-year-old patient with syndrome of inappropriate antidiuretic hormone secretion. Pharmacopsychiatry 2007;40:129-31.
Mogi T, Yoshino A, Ikemoto G, Nomura S. Mirtazapine as an alternative for selective-serotonin-reuptake-inhibitor-induced syndrome of inappropriate secretion of antidiuretic hormone. Psychiatry Clin Neurosci 2012;66:80.
Cerimele JM, Robinson LA. Sertraline-associated hyponatremia and subsequent tolerability of bupropion in an elderly woman. Prim Care Companion CNS Disord 2011;13. pii: PCC.11l01175.
Meulendijks D, Mannesse CK, Jansen PA, van Marum RJ, Egberts TC. Antipsychotic-induced hyponatraemia: A systematic review of the published evidence. Drug Saf 2010;33:101-14.
Madhusoodanan S, Bogunovic OJ, Moise D, Brenner R, Markowitz S, Sotelo J. Hyponatraemia associated with psychotropic medications. A review of the literature and spontaneous reports. Adverse Drug React Toxicol Rev 2002;21:17-29.
Whitten JR, Ruehter VL. Risperidone and hyponatremia: A case report. Ann Clin Psychiatry 1997;9:181-3.
Dudeja SJ, McCormick M, Dudeja RK. Olanzapine induced hyponatraemia. Ulster Med J 2010;79:104-5.
Chiang CL, Lin YH, Hsieh MH. Olanzapine-induced hyponatremia in a patient with autism. J Child Adolesc Psychopharmacol 2013;23:699-700.
Bakhla AK, Guria RT, Kumar A. A suspected case of olanzapine induced hyponatremia. Indian J Pharmacol 2014;46:441-2.
Behere RV, Venkatasubramanian G, Naveen MN, Gangadhar BN. Aripiprazole-induced hyponatremia: A case report. J Clin Psychiatry 2007;68:640-1.
Kohen I, Voelker S, Manu P. Antipsychotic-induced hyponatremia: Case report and literature review. Am J Ther 2008;15:492-4.
Lecamwasam DL, Alexander J. Aripiprazole associated hyponatraemia. Aust N Z J Psychiatry 2011;45:686-7.
Yam FK, Jackson EA, Kwan BK. Syndrome of inappropriate antidiuretic hormone associated with aripiprazole. Am J Health Syst Pharm 2013;70:2110-4.
Serrano A, Rangel N, Carrizo E, Uzcátegui E, Sandia I, Zabala A, et al.
Safety of long-term clozapine administration. Frequency of cardiomyopathy and hyponatraemia: Two cross-sectional, naturalistic studies. Aust N Z J Psychiatry 2014;48:183-92.
Ogilvie AD, Croy MF. Clozapine and hyponatraemia. Lancet 1992;340:672.
Atalay A, Turhan N, Aki OE. A challenging case of syndrome of inappropriate secretion of antidiuretic hormone in an elderly patient secondary to quetiapine. South Med J 2007;100:832-3.
van den Heuvel OA, Bet PM, van Dam EW, Eeckhout AM. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) during treatment with the antipsychotic agents haloperidol and quetiapine. Ned Tijdschr Geneeskd 2006;150:1944-8.
Kimelman N, Albert SG. Phenothiazine-induced hyponatremia in the elderly. Gerontology 1984;30:132-6.
Jos CJ, Evenson RC, Mallya AR. Self-induced water intoxication: A comparison of 34 cases with matched controls. J Clin Psychiatry 1986;47:368-70.
Canuso CM, Goldman MB. Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome. J Neuropsychiatry Clin Neurosci 1999;11:86-90.
Mannesse CK, van Puijenbroek EP, Jansen PA, van Marum RJ, Souverein PC, Egberts TC. Hyponatraemia as an adverse drug reaction of antipsychotic drugs: A case-control study in VigiBase. Drug Saf 2010;33:569-78.
Ferrier IN. Water intoxication in patients with psychiatric illness. Br Med J (Clin Res Ed) 1985;291:1594-6.
Dundas B, Harris M, Narasimhan M. Psychogenic polydipsia review: Etiology, differential, and treatment. Curr Psychiatry Rep 2007;9:236-41.
Verghese C, Abraham G, Nair C, Stanilla JK, de Leon J, Phillips MI, et al.
Absence of changes in antidiuretic hormone, angiotensin II, and atrial natriuretic peptide with clozapine treatment of polydipsia-hyponatremia: 2 case reports. J Clin Psychiatry 1998;59:415-9.
Eleméry M, Döme P, Faludi G. Successful clozapine treatment of primary polydipsia associated with hyponatraemia in a schizophrenic patient. A case report. Neuropsychopharmacol Hung 2007;9:209-13.
de Leon J, Verghese C, Stanilla JK, Lawrence T, Simpson GM. Treatment of polydipsia and hyponatremia in psychiatric patients. Can clozapine be a new option? Neuropsychopharmacology 1995;12:133-8.
Henderson DC, Goff DC. Clozapine for polydipsia and hyponatremia in chronic schizophrenics. Biol Psychiatry 1994;36:768-70.
Munn NA. Resolution of polydipsia and hyponatremia in schizophrenic patients after clozapine treatment. J Clin Psychiatry 1993;54:439.
Rao N, Venkatasubramanian G, Korpade V, Behere R, Varambally S, Gangadhar B. Risperidone treatment for polydipsia and hyponatremia in schizophrenia: A case report. Turk Psikiyatri Derg 2011;22:123-5.
Phull J, Davies S. Life-threatening hyponatraemia and intramuscular olanzapine: The world′s longest therapeutic trial. BMJ Case Rep 2011;2011. pii: Bcr0820114671.
Gandelman MS. Review of carbamazepine-induced hyponatremia. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:211-33.
Van Amelsvoort T, Bakshi R, Devaux CB, Schwabe S. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: A review. Epilepsia 1994;35:181-8.
Gupta E, Kunjal R, Cury JD. Severe hyponatremia due to valproic acid toxicity. J Clin Med Res 2015;7:717-9.
Patel KR, Meesala A, Stanilla JK. Sodium valproate-induced hyponatremia: A case report. Prim Care Companion J Clin Psychiatry 2010;12. pii: PCC.09l00941.
Beers E, van Puijenbroek EP, Bartelink IH, van der Linden CM, Jansen PA. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatraemia associated with valproic acid: Four case reports from the Netherlands and a case/non-case analysis of vigibase. Drug Saf 2010;33:47-55.
Herment N, Herlem E, Germain ML, Trenque T. Hyponatremia induced by sodium valproate. A case report. Therapie 2006;61:544-7.
Miyaoka T, Seno H, Itoga M, Kishi T, Ishino H, Horiguchi J. Contribution of sodium valproate to the syndrome of inappropriate secretion of antidiuretic hormone. Int Clin Psychopharmacol 2001;16:59-61.
Branten AJ, Wetzels JF, Weber AM, Koene RA. Hyponatremia due to sodium valproate. Ann Neurol 1998;43:265-7.
Mewasingh L, Aylett S, Kirkham F, Stanhope R. Hyponatraemia associated with lamotrigine in cranial diabetes insipidus. Lancet 2000;356:656.
Tsuru T, Akiyama R, Kohashi K, Okumura K. Case of a 13-year-old boy with hyponatremia due to lamotrigine-induced syndrome of inappropriate secretion of antidiuretic hormone. No To Hattatsu 2012;44:73-4.
Bève E, Beck E, Pinto E, Ansseau M. Inappropriate antidiuretic hormone secretion induced by sodium valproate. Rev Med Liege 2010;65:6-9.
Uhde TW, Post RM. Effects of carbamazepine on serum electrolytes: Clinical and theoretical implications. J Clin Psychopharmacol 1983;3:103-6.
Lahr MB. Hyponatremia during carbamazepine therapy. Clin Pharmacol Ther 1985;37:693-6.
Joffe RT, Post RM, Uhde TW. Effects of carbamazepine on serum electrolytes in affectively ill patients. Psychol Med 1986;16:331-5.
Vieweg V, Glick JL, Herring S, Kerler R, Godleski LS, Barber J, et al.
Absence of carbamazepine-induced hyponatremia among patients also given lithium. Am J Psychiatry 1987;144:943-7.
Yassa R, Iskandar H, Nastase C, Camille Y. Carbamazepine and hyponatremia in patients with affective disorder. Am J Psychiatry 1988;145:339-42.
Kastner T, Friedman DL, Pond WS. Carbamazepine-induced hyponatremia in patients with mental retardation. Am J Ment Retard 1992;96:536-40.
Kelly BD, Hillery J. Hyponatremia during carbamazepine therapy in patients with intellectual disability. J Intellect Disabil Res 2001;45(Pt 2):152-6.
Ikeda K, Moriyasu H, Yasaka M, Oita J, Yamaguchi T. Valproate related syndrome of inappropriate secretion of antidiuretic hormone (SIADH) - A case report. Rinsho Shinkeigaku 1994;34:911-3.
Engel WR, Grau A. Inappropriate secretion of antidiuretic hormone associated with lorazepam. BMJ 1988;297:858.
Priya SS, Dl B, TS. Zolpidem induced hyponatremia: A case report. J Clin Diagn Res 2014;8:HD03-4.
Liu BA, Mittmann N, Knowles SR, Shear NH. Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: A review of spontaneous reports. CMAJ 1996;155:519-27.
Anderson IK, Martin GR, Ramage AG. Central administration of 5-HT activates 5-HT1A receptors to cause sympathoexcitation and 5-HT2/5-HT1C receptors to release vasopressin in anaesthetized rats. Br J Pharmacol 1992;107:1020-8.
Collins A, Anderson J. SIADH induced by two atypical antipsychotics. Int J Geriatr Psychiatry 2000;15:282-3.
Vincent FM, Emery S. Antidiuretic hormone syndrome and thioridazine. Ann Intern Med 1978;89:147-8.
Cordoba OA, Chapel JL. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) secondary to antipsychotic drug therapy: Case report. Mo Med 1978;75:177-8, 181.
Fasanello RA, Vu TM. Paradoxical hyponatremia and polyurodipsia in a patient with lithium-induced nephrogenic diabetes insipidus. J Am Osteopath Assoc 2012;112:588.
Goldstein L, Barker M, Segall F, Asihene R, Balser S, Lautenbach D, et al.
Seizure and transient SIADH associated with sertraline. Am J Psychiatry 1996;153:732.
Soiza RL, Talbot HS. Management of hyponatraemia in older people: Old threats and new opportunities. Ther Adv Drug Saf 2011;2:9-17.
Cury LH, Kitadai FT, Helou CM. Antidepressant-induced hyponatremia. Clinics (Sao Paulo) 2006;61:579-80.
Kuz GM, Manssourian A. Carbamazepine-induced hyponatremia: Assessment of risk factors. Ann Pharmacother 2005;39:1943-6.
Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al.
Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014;170:G1-47.
Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 2006;119:71.e1-8.
Cumming K, McKenzie S, Hoyle GE, Hutchison JD, Soiza RL. Prognosis of hyponatremia in elderly patients with fragility fractures. J Clin Med Res 2015;7:45-51.
Gankam Kengne F, Andres C, Sattar L, Melot C, Decaux G. Mild hyponatremia and risk of fracture in the ambulatory elderly. QJM 2008;101:583-8.
Siegler EL, Tamres D, Berlin JA, Allen-Taylor L, Strom BL. Risk factors for the development of hyponatremia in psychiatric inpatients. Arch Intern Med 1995;155:953-7.
Siegel AJ. Hyponatremia in psychiatric patients: Update on evaluation and management. Harv Rev Psychiatry 2008;16:13-24.
Berah EF. Sex differences in psychiatric morbidity: An analysis of Victorian data. Aust N Z J Psychiatry 1983;17:266-73.
Bijl RV, Ravelli A, van Zessen G. Prevalence of psychiatric disorder in the general population: Results of the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Soc Psychiatry Psychiatr Epidemiol 1998;33:587-95.
Blehar MC. Women′s mental health research: The emergence of a biomedical field. Annu Rev Clin Psychol 2006;2:135-60.
Kirby D, Ames D. Hyponatraemia and selective serotonin re-uptake inhibitors in elderly patients. Int J Geriatr Psychiatry 2001;16:484-93.
Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother 2006;40:1618-22.
Fisher A, Davis M, Croft-Baker J, Purcell P, McLean A. Citalopram-induced severe hyponatraemia with coma and seizure. Case report with literature and spontaneous reports review. Adverse Drug React Toxicol Rev 2002;21:179-87.
Rosner MH. Severe hyponatremia associated with the combined use of thiazide diuretics and selective serotonin reuptake inhibitors. Am J Med Sci 2004;327:109-11.
Spigset O, Hedenmalm K. Hyponatremia in relation to treatment with antidepressants: A survey of reports in the World Health Organization data base for spontaneous reporting of adverse drug reactions. Pharmacotherapy 1997;17:348-52.
Chakrapani M, Shenoy D, Pillai A. Seasonal variation in the incidence of hyponatremia. J Assoc Physicians India 2002;50:559-62.
Radojevic N, Bjelogrlic B, Aleksic V, Rancic N, Samardzic M, Petkovic S, et al.
Forensic aspects of water intoxication: Four case reports and review of relevant literature. Forensic Sci Int 2012;220:1-5.
Lewis WH. Iatrogenic psychotic depressive reaction in hypertensive patients. Am J Psychiatry 1971;127:1416-7.
Sato T, Igarashi N, Minami S, Okabe T, Hashimoto H, Hasui M, et al.
Recurrent attacks of vomiting, hypertension and psychotic depression: A syndrome of periodic catecholamine and prostaglandin discharge. Acta Endocrinol (Copenh) 1988;117:189-97.
Poirier S, Legris G, Tremblay P, Michea R, Viau-Guay L, Mérette C, et al.
Schizophrenia patients with polydipsia and water intoxication are characterized by greater severity of psychotic illness and a more frequent history of alcohol abuse. Schizophr Res 2010;118:285-91.
Boyd MA. Polydipsia in the chronically mentally ill: A review. Arch Psychiatr Nurs 1990;4:166-75.
Verghese C, de Leon J, Josiassen RC. Problems and progress in the diagnosis and treatment of polydipsia and hyponatremia. Schizophr Bull 1996;22:455-64.
Ohsawa H, Kishimoto T, Hirai M, Shimayoshi N, Matsumura K, Oribe H, et al.
An epidemiological study on hyponatremia in psychiatric patients in mental hospitals in Nara Prefecture. Jpn J Psychiatry Neurol 1992;46:883-9.
Shetty HM, Manimekalai K, Sivaprakash B, Jagan Mohan R, Shetty PH. Hyponatremia secondary to antidepressant therapy - A post marketing safety study. J Pharmacovigil 2015;3:167. Available from: http://www.esciencecentral.org/journals/hyponatremia-secondary
-to- antidepressant-therapy--a-post-marketing-safety-study- 2329-6887-1000167.pdf. [Last cited on 2016 Apr 02].
Soiza RL, Cumming K, Clarke JM, Wood KM, Myint PK. Hyponatremia: Special considerations in older patients. J Clin Med 2014;3:944-58. Available from: http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC4449639/. [Last cited on 2016 Apr 03].
Peyro Saint Paul L, Martin J, Buon M, Gaillard C, Fedrizzi S, Mosquet B, et al.
New frequent adverse reaction of PPI in older adults: Mild hyponatremia. Therapie 2014;69:157-62.
Bahat G. Risk of proton pump inhibitor-induced mild hyponatremia in older adults. J Am Geriatr Soc 2014;62:1206-7.
Cumming K, Hoyle GE, Hutchison JD, Soiza RL. Prevalence, incidence and etiology of hyponatremia in elderly patients with fragility fractures. PLoS One 2014;9:e88272.
Movig KL, Leufkens HG, Lenderink AW, van den Akker VG, Hodiamont PP, Goldschmidt HM, et al.
Association between antidepressant drug use and hyponatraemia: A case-control study. Br J Clin Pharmacol 2002;53:363-9.
Schrier RW, Sharma S, Shchekochikhin D. Hyponatraemia: More than just a marker of disease severity? Nat Rev Nephrol 2013;9:37-50.
Vucicevic Z, Degoricija V, Alfirevic Z, Vukicevic-Badouin D. Fatal hyponatremia and other metabolic disturbances associated with psychotropic drug polypharmacy. Int J Clin Pharmacol Ther 2007;45:289-92.
Musham CK, Jarathi A, Pedraza G. A rare case of fatal hyponatremia due to a combination of psychotropic polypharmacy and hypothyroidism. Prim Care Companion J Clin Psychiatry 2010;12. pii: PCC.09l00897.
Flegel KM, Cole CH. Inappropriate antidiuresis during carbamazepine treatment. Ann Intern Med 1977;87:722-3.
Kalff R, Houtkooper MA, Meyer JW, Goedhart DM, Augusteijn R, Meinardi H. Carbamazepine and serum sodium levels. Epilepsia 1984;25:390-7.
Pae CU, Park GY, Im S, Ko SB, Lee SJ. Low-dose escitalopram-associated hyponatremia. Asia Pac Psychiatry 2013;5:E90.
Chuang YF, Chiu YL, Hwang TJ, Chu TS. Delirium and multiple electrolyte abnormalities associated with high dose paroxetine exposure. Psychiatry Clin Neurosci 2006;60:642-3.
Schmidt D, Sachdeo R. Oxcarbazepine for treatment of partial epilepsy: A review and recommendations for clinical use. Epilepsy Behav 2000;1:396-405.
Kim YS, Kim DW, Jung KH, Lee ST, Kang BS, Byun JI, et al.
Frequency of and risk factors for oxcarbazepine-induced severe and symptomatic hyponatremia. Seizure 2014;23:208-12.
Bagshaw SM, Townsend DR, McDermid RC. Disorders of sodium and water balance in hospitalized patients. Can J Anaesth 2009;56:151-67.
Patterson JH. The impact of hyponatremia. Pharmacotherapy 2011;31 5 Suppl: 5S-8S.
Usala RL, Fernandez SJ, Mete M, Cowen L, Shara NM, Barsony J, et al.
Hyponatremia is associated with increased osteoporosis and bone fractures in a large US health system population. J Clin Endocrinol Metab 2015;100:3021-31.
Ayus JC, Negri AL, Kalantar-Zadeh K, Moritz ML. Is chronic hyponatremia a novel risk factor for hip fracture in the elderly? Nephrol Dial Transplant 2012;27:3725-31.
Fujisawa H, Sugimura Y, Takagi H, Mizoguchi H, Takeuchi H, Izumida H, et al.
Chronic hyponatremia causes neurologic and psychologic impairments. J Am Soc Nephrol 2016;27:766-80.
Ghali JK. Mechanisms, risks, and new treatment options for hyponatremia. Cardiology 2008;111:147-57.
Stahl SM. Stahl′s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3 rd
ed. Cambridge: Cambridge University Press; 2008.
Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: A systematic approach to laboratory diagnosis. CMAJ 2002;166:1056-62.
Smellie WS, Heald A. Hyponatraemia and hypernatraemia: Pitfalls in testing. BMJ 2007;334:473-6.
Hoyle GE, Chua M, Soiza RL. Volaemic assessment of the elderly hyponatraemic patient: Reliability of clinical assessment and validation of bioelectrical impedance analysis. QJM 2011;104:35-9.
Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al.
Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. Am J Med 2013;126 10 Suppl 1:S1-42.
Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: Current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol 1996;46:149-69.
Shapiro DS, Sonnenblick M, Galperin I, Melkonyan L, Munter G. Severe hyponatraemia in elderly hospitalized patients: Prevalence, aetiology and outcome. Intern Med J 2010;40:574-80.
Aaseth JO, Tangen MK, Beitnes JO. Hyponatremic crisis - A serious side effect of diuretics in the elderly. Tidsskr Nor Laegeforen 2001;121:921-3.
Spigset O, Hedenmalm K. Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Drug Saf 1995;12:209-25.
Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J. Harrison′s Principles of Internal Medicine. 18 th
ed. New York: McGraw-Hill Professional; 2011.
Zietse R, van der Lubbe N, Hoorn EJ. Current and future treatment options in SIADH. NDT Plus 2009;2 Suppl 3:iii12-9.
Thompson CJ. Hyponatraemia: New associations and new treatments. Eur J Endocrinol 2010;162 Suppl 1:S1-3.
Decaux G. Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide. Am J Med 2001;110:582-4.
Staab JP, Yerkes SA, Cheney EM, Clayton AH. Transient SIADH associated with fluoxetine. Am J Psychiatry 1990;147:1569-70.
Thornton SL, Resch DS. SIADH associated with sertraline therapy. Am J Psychiatry 1995;152:809.
Flint AJ, Crosby J, Genik JL. Recurrent hyponatremia associated with fluoxetine and paroxetine. Am J Psychiatry 1996;153:134.
Jackson C, Carson W, Markowitz J, Mintzer J. SIADH associated with fluoxetine and sertraline therapy. Am J Psychiatry 1995;152:809-10.
Aminoff MJ, Simon RP, Wiedemann E. The hormonal responses to generalized tonic-clonic seizures. Brain 1984;107(Pt 2):569-78.
Finlayson AJ, Vieweg WV, Wilkey WD, Cooper AJ. Hyponatremic seizure following ECT. Can J Psychiatry 1989;34:463-4.
Greer RA, Stewart RB. Hyponatremia and ECT. Am J Psychiatry 1993;150:1272.
Grover S, Kattharaghatta Girigowda V, Aggarwal M, Malhotra N. Catatonia associated with hyponatremia treated with electroconvulsive therapy. J ECT 2012;28:e33-4.
Brent RH, Chodroff C. ECT as a possible treatment for SIADH: Case report. J Clin Psychiatry 1982;43:73-4.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]