What evidence is there for the use of demeclocycline in the treatment of SIADH?

What evidence is there for the use of demeclocycline in the treatment of SIADH?

Comment by InpharmD Researcher

Published literature and multisocietal clinical guidelines recommend against demeclocycline fort treatment of SIADH due to the risk of renal injury, although small studies and case reports suggest efficacy in hyponatremia management with demeclocycline doses of 600-1,200 mg/day (dosed 300-600 BID).

Background

The European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE), and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 2014 clinical practice guideline on the diagnosis and treatment of hyponatremia notes evidence suggesting potential harm, including acute kidney injury, with demeclocycline use. As a result, the guidelines recommend against demeclocycline use for any degree of chronic hyponatremia in patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) or for moderate or profound hyponatremia (Grade 1D). [1]

A 2015 systematic review evaluated the safety and efficacy of demeclocycline for the treatment of hyponatremia secondary to SIADH using data from 18 studies, including two randomized controlled trials (RCTs), six cohort studies, and ten case reports. Notably, all the included papers were published prior to the year 2000 except for two case reports. The findings across studies reported modest efficacy of demeclocycline in increasing serum sodium levels, but the onset of action was variable, typically ranging from 2-5 days. Doses often ranged from 600-1,200 mg/day, with safety concerns (i.e., renal impairment and gastrointestinal intolerance) commonly reported. A RCT conducted in 1991 evaluated nine psychiatric patients with polydipsia-associated chronic hyponatremia, reporting no significant difference in serum sodium normalization between demeclocycline and placebo groups (Table 1). Another trial involving 30 patients undergoing coronary artery bypass grafting noted that demeclocycline maintained serum sodium levels within normal ranges compared to placebo but was associated with adverse events such as gastrointestinal upset and hypersensitivity (Table 2). Observational studies and case reports further highlighted risks such as nephrotoxicity, hypernatremia, and phosphate diabetes, particularly in patients with comorbid conditions or concurrent nephrotoxic medications. The findings suggest that while demeclocycline may stabilize serum sodium levels, its safety profile necessitates close monitoring, limiting its utility as a first-line option for SIADH management. [2]

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What evidence is there for the use of demeclocycline in the treatment of SIADH?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-6 for your response.

A Double Blind, Placebo-Controlled Trial of Demeclocycline Treatment of Polydipsia- Hyponatremia in Chronically Psychotic Patients
Design	Randomized, double-blind, placebo-controlled, crossover trial N= 9
Objective	To evaluate the effect of demeclocycline in psychiatric patients with polydipsia-hyponatremia
Study Groups	Study subjects (n= 9)
Inclusion Criteria	Patients with histories of chronic psychiatric illness and documented episodic or chronic hyponatremia (serum sodium < 135 mEq/L) associated with polydipsia
Exclusion Criteria	Not explicitly stated
Methods	The subjects were maintained on a stable daily dose of neuroleptics (mean chlorpromazine equivalents: 1932 mg; range: 630-3360 mg) and a standard hospital diet with unrestricted fluid access. Treatment order was randomly assigned. During the active phase, subjects received demeclocycline 300 mg BID for 7 days, then TID for 7 days, and finally QID for 7 days. A similar procedure was followed using placebo during the control phase, with no mention of washout between the periods. Body weight (after voiding) was measured 3-4 times daily, and serum sodium levels were checked twice weekly in the morning and after episodes of acute weight gain. A maximum permissible body weight and weight gain threshold was set for each patient, typically aligning with serum sodium levels of 120-125 mEq/L. Patients exceeding this threshold underwent fluid restriction until weight and/or sodium levels returned to acceptable levels.
Duration	Observation: 2 weeks Active and placebo treatment: 3 weeks
Outcome Measures	Sodium levels
Baseline Characteristics		All subjects (n= 9)
	Age, years (range)	38.3 (31 to 47)
	Female	3 (33.3%)
	History of seizures	2 (22.2%)
	Psychiatric illnesses Chronic schizophrenia Schizoaffective disorder	8 (8.89%) 1 (11.1%)
	Duration of illness, years (range) Psychiatric Polydipsia	18.7 (11-31) 5.4 (2-19)
Results	All subjects (N = 9)	Placebo (N= 9)	Demeclocycline (N= 9)
	Mean sodium (all 3 weeks), mEq/L	132.7	133.8
	Mean sodium (3rd week only), mEq/L	131.4	134.1
	Mean diurnal weight gain, lbs	4.7	4.6
	No significant difference was observed in episodes of serum sodium <125 mEq/L between the drug (10/103 determinations) and placebo periods (13/110; p= 0.78) or in episodes <135 mEq/L (49/101 vs. 67/110; p = 0.10).
Adverse Events	All of the subjects experienced episodes of hyponatremia during the study and none experienced any adverse events related to demeclocycline.
Study Author Conclusions	We were unable to demonstrate a significant effect of demeclocycline on serum sodium in chronic psychotic patients with polydipsia-hyponatremia, although there was a trend toward a slight increase in mean serum sodium level, a decrease in episodes of serum sodium less than 135 mEq/L, and a decrease in the number of sporadic sodium levels obtained during the drug period.
InpharmD Researcher Critique	This study is limited by its small sample size and short treatment duration, which may have been insufficient to demonstrate significant effects. Additionally, the randomization order and prolonged drug effects may have influenced outcomes. Challenges in measuring serum levels, and limited applicability of the fluid restriction regimen to outpatient settings further restrict the generalizability and practicality of the findings. Notably, the included patients were not explicitly diagnosed with SIADH.

References:

Alexander RC, Karp BI, Thompson S, Khot V, Kirch DG. A double blind, placebo-controlled trial of demeclocycline treatment of polydipsia-hyponatremia in chronically psychotic patients. Biol Psychiatry. 1991;30(4):417-420. doi:10.1016/0006-3223(91)90300-b

Perioperative vasopressin secretion treated by demeclocycline
Design	Randomized, double-blind, placebo-controlled, clinical trial N= 30
Objective	To evaluate the perioperative effects of demeclocycline on vasopressin (VP) in patients undergoing coronary artery bypass grafting (CABG)
Study Groups	Demeclocycline (n= 13) Placebo (n= 15)
Inclusion Criteria	Undergoing CABG, willing to participate, normal electrolytes and renal function
Exclusion Criteria	Renal or hepatic dysfunction, endocrine abnormalities, pregnancy, recent antibiotic use, hypersensitivity to tetracycline
Methods	Participants were randomized to receive demeclocycline 600 mg BID or placebo starting 5 days preoperatively through postoperative day 2. Serum and urine osmolality, electrolytes, and VP levels were measured daily.
Duration	5 days preoperatively through postoperative day 2.
Outcome Measures	Primary: Serum sodium and osmolality levels Secondary: Urine sodium and osmolality, VP levels
Baseline Characteristics		All patients (N= 30)
	Age, years (range)	61.4 (40-70)
	Male	20 (67%)
	Two patients additionally received carotid endarterectomy, and one received an automatic implantable cardiovascular defibrillator pacemaker intraoperatively.
Results	No patients died in either group. The only significant postoperative morbidity reported was epicardial bleeding in one patient (study group not mentioned). Serum sodium levels were similar preoperatively (138.9 vs 138.1 mEq/L); however, the demeclocycline group significantly maintained closer to normal levels on the day of surgery and postoperative days 1 and 2 (p= 0.05, p= 0.02, and p< 0.01, respectively). Urine sodium levels were generally lower in the demeclocycline group, though only significantly different on postoperative day 1 for urine osmolality. Overall, urinary output was higher in the demeclocycline group. Vasopressin levels were significantly higher in the demeclocycline group preoperatively and on the operative and first postoperative days.
	No significant difference in postoperative length of stay (PLOS) was observed between the two groups when excluding outliers; the mean PLOS was 7 days for the demeclocycline group and 6.9 days for the placebo group. Including the outliers, the means were 9.1 days for the demeclocycline group and 11.9 days for the placebo group, indicating a significant difference.
Adverse Events	Two patients in the demeclocycline group withdrew due to adverse events: GI distress and hypersensitivity (severe rash). In both cases, the adverse event resolved after stopping demeclocycline.
Study Author Conclusions	This study shows that perioperative administration of demeclocycline can reliably inhibit the effects of increased VP secretion. Although serum VP levels are higher, the demeclocycline group had serum sodium and osmolality values closer to normal with appropriate urine concentrating ability. The placebo group had a significantly lower serum sodium and osmolality with an inappropriately high urine osmolality.
InpharmD Researcher Critique	While this was a double-blind, placebo-controlled trial, limited information was given regarding the baseline characteristics, procedure details (e.g., fluid use, fluid type, etc.), and results. Other limitations include the small sample size and lack of long-term follow-up.

References:

Horattas MC, Evasovich MR, Muakkassa FF, Hopkins S, Kamienski P. Perioperative vasopressin secretion treated by demeclocycline. Am Surg. 1998;64(3):281-286.

Demeclocycline Improves Hyponatremia in Chronic Schizophrenics
Design	Open-label, cohort study N= 8
Objective	To assess the efficacy of demeclocycline in improving hyponatremia in chronic schizophrenic patients
Study Groups	Study subjects (N= 8)
Inclusion Criteria	Chronic schizophrenic patients identified as compulsive water drinkers with hyponatremia (serum sodium 115-130 meq/L)
Exclusion Criteria	Patients who became normonatremic upon repeated testing or after switching medications, and those taking carbamazepine
Methods	Subjects received 600 mg demeclocycline PO BID. Serum sodium and urine osmolality were measured weekly before, during, and after treatment.
Duration	3 weeks for each period (before, during, and after treatment), with a 2-week washout period.
Outcome Measures	Change in serum sodium concentration
Baseline Characteristics	Subject	Study subjects (N= 8)
	Age, years	46 (43-54)
	Male	7 (87.5%)
	Duration of psychiatric illness, years (range)	23 (10-30)
	History of seizures	6 (75%)
	Unexplained syncopal episodes	2 (25%)
Results	Variable	Before	On Drug	After	p-value
	Serum sodium, mEq/L	128.1 ± 3.4	131.9 ± 4.3	128.2 ± 4.5	0.02
	Serum sodium <125 meq/L	6 (75%)	1 (12.5%)	6 (75%)	0.05
	Urine osmolality, mOsm/kg	74.0 ± 32.1	134.1 ± 76.1	115.4± 71.9	Not significant
	BUN, mg/dL	8.0 ± 1.2	9.0 ± 1.9	8.4 ± 3.2	Not significant
	Five of the eight subjects met the criteria for syndrome of inappropriate antidiuretic hormone (SIADH) based on urine osmolalities greater than 100 mosmol/kg in the absence of hemodynamic or hormonal disorders, cardiac, renal, or hepatic failure.
Adverse Events	No serious side effects reported; no hypernatremia or renal failure observed
Study Author Conclusions	Demeclocycline reduces the frequency and severity of hyponatremic episodes in chronic psychotic patients, suggesting its potential to prevent water intoxication.
Critique	Limitations include the small sample size, lack of a control group, and potential bias due to open-label design. Further studies with larger samples and controlled conditions are needed.

References:

Goldman MB, Luchins DJ. Demeclocycline improves hyponatremia in chronic schizophrenics. Biol Psychiatry. 1985;20(11):1149-1155. doi:10.1016/0006-3223(85)90172-6

Serious Hyponatremia in Patients with Cancer: Management with Demeclocycline
Design	Retrospective chart review N= 17
Objective	To evaluate the efficacy and risks of demeclocycline in treating hyponatremia in cancer patients
Study Groups	Study cohort (N= 17)
Inclusion Criteria	Patients with cancer or aplastic anemia experiencing serious hyponatremia (<125 mEq/L)
Exclusion Criteria	Patients with fluid overload, saline depletion, or other reversible causes of hyponatremia
Methods	Demeclocycline was administered at doses of 600 mg/day or 1200 mg/day; monitoring of serum sodium, urine osmolality, and renal function was conducted.
Duration	January 1977 to August 1979
Outcome Measures	Primary: Increase in serum sodium levels Secondary: Weight loss, changes in serum urea nitrogen and creatinine
Baseline Characteristics		Study cohort (N= 17)
	Serum Na concentration on demeclocycline initiation, mEq/L	119
	Mean serum osmolality, mOSM/kg	249
	Urine Na concentration, mEq/L	92
Results		Study cohort (N= 17)
	Peak serum Na attained, mEq/L	138.8
	Weight loss, kg	2.7
	Peak serum Na concentration obtained 9 days (range, 3-28 days) following demeclocycline initiation. After demeclocycline initiation, serum Na increased in all patients; serum Na was ≥130 mEq/L an 3 days (range 1,-7 days) after demeclocycline.
Adverse Events	Azotemia, increased serum creatinine, particularly with higher doses and concurrent nephrotoxic agents. Three patients died within ten days of receiving demeclocycline, with azotemia prominent at death and moderately increased serum creatinine concentrations for each patient (2 died from advanced systemic infections and uncontrolled malignancy, 1 died from widespread metastases; renal dysfunction from demeclocycline may have contributed to deaths).
Study Author Conclusions	Demeclocycline is effective in correcting hyponatremia in cancer patients but poses a risk of renal toxicity, especially at higher doses or with nephrotoxic agents.
Critique	Limitations of the study include its retrospective design, small sample size, lack of control group, and potential confounding by concurrent medications. The dated nature of the study means that findings may not be applicable to a patient population receiving modern clinical care.

References:

Trump DL. Serious hyponatremia in patients with cancer: management with demeclocycline. Cancer. 1981;47(12):2908-2912. doi:10.1002/1097-0142(19810615)47:12<2908::aid-cncr2820471228>3.0.co;2-r

Demeclocycline in the treatment of the syndrome of inappropriate secretion of antidiuretic hormone
Design	Open-label study N= 14
Objective	To evaluate the effectiveness of demeclocycline in treating syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and its effects on renal function
Study Groups	Study cohort (N= 14)
Inclusion Criteria	Patients diagnosed with SIADH
Exclusion Criteria	Not explicitly stated
Methods	Patients were treated with demeclocycline 1200 mg daily in divided doses. Serum electrolytes, urea, creatinine, osmolarity, and PCV were measured before and during treatment. 24-hour urine collections were obtained in seven patients.
Duration	Treatment duration varied; follow-up after discontinuation was a mean of 60 days (range 7-143 days)
Outcome Measures	Primary: Serum sodium levels Secondary: Blood urea, serum creatinine, urine sodium concentration, urine urea-serum urea ratio
Baseline Characteristics		Study cohort (N= 14)
	Age, years	61 ± 11
	Female	7 (50%)
	Serum sodium before treatment, mmol/L	118 ± 8
	Urine sodium before treatment, mmol/L	54 ± 24
	Urine urea serum urea ratio (uu/su) before treatment	59 ± 46
Results	Endpoint	Study cohort (N= 14)
	Serum sodium, mmol/L During treatment at 10 days	138 ± 7
	Serum sodium where demeclocycline discontinued, mmol/L During treatment at 10 days After treatment	138 ± 6 125 ± 7
	Urine sodium, mmol/L During treatment at 10 days	29 ± 21
	Urine urea-serum urea ratio During treatment at 10 days	22 ± 10
Adverse Events	Significant rise in blood urea and creatinine levels, indicating azotemia. In four patients, blood urea rose above 20 mmol/L, leading to discontinuation in two patients.
Study Author Conclusions	Demeclocycline is effective in normalizing serum sodium in SIADH, but it may cause reversible and dose-dependent azotemia. Fluid restriction may not be necessary during treatment.
InpharmD Researcher Critique	The study provides valuable insights into the effectiveness of demeclocycline for SIADH but lacks a control group and detailed exclusion criteria. The sample size is small, and the study is open-label, which may introduce bias. However, this study to date is one of the largest sample sizes utilizing demeclocycline in this patient population.

References:

Perks WH, Walters EH, Tams IP, Prowse K. Demeclocycline in the treatment of the syndrome of inappropriate secretion of antidiuretic hormone. Thorax. 1979;34(3):324-327. doi:10.1136/thx.34.3.324

Long-term Use of Demeclocycline for the Treatment of Chronic Hyponatremia
Design	Case report
Case presentation	A 76-year-old male presented with a complex medical history, including recurrent episodes of severe hyponatremia (serum sodium ranging from 109-115 mEq/L) requiring repeated hospitalizations. Initial management strategies, including fluid restrictions and administration of hypertonic saline, resulted only in transient improvements. The patient did not exhibit clinical evidence of hypervolemia, and his presentation met diagnostic criteria for syndrome of inappropriate antidiuretic hormone (SIADH) based on laboratory findings such as serum hypo-osmolality, elevated urine osmolality (>100 mOsmol/kg), and high urine sodium levels (>40 mEq/L). A workup for malignancy or other underlying etiologies of SIADH was unremarkable. Demeclocycline therapy was initiated at a dose of 300 mg BID after hypersonic saline failed to achieve sustained serum sodium normalization. Over a nine-month observation period after starting demeclocycline, his serum sodium levels stabilized between 125-130 mEq/L with no additional hospitalizations required. The patient demonstrated significant improvement in overall well-being and achieved notable reductions in weight secondary to water diuresis. Importantly, the prescribed dose of demeclocycline avoided common adverse effects such as nephrotoxicity or hepatic dysfunction, which are typically seen with higher doses.
Study Author Conclusions	We have demonstrated long-term successful management of hyponatremia associated with SIADH with demeclocycline. Our experience suggests that demeclocycline may be an alternate option in patients with difficult-to-manage hyponatremia associated with SIADH of unclear etiology. The exact mechanism of demeclocycline-related attenuation of hyponatremia is unknown; however, it has been shown to reduce aquaporin-2 (AQP-2) expression in the renal inner medulla.

References:

Singh A, Dass B, Ejaz A, Bali A. Long-term Use of Demeclocycline for the Treatment of Chronic Hyponatremia. Cureus. 2019;11(12):e6415. Published 2019 Dec 18. doi:10.7759/cureus.6415