Genitourinary and Renal Systems

13


Genitourinary and Renal Systems


Dysuria and Urinary Retention


General Recommendations


Anticholinergic drugs or α2-adrenergic blocking agents, as well as SNRIs and psychostimulants, may in rare cases cause urinary hesitancy or retention. Risk factors apart from preexisting benign prostatic hypertrophy have not been identified. Drugs suspected of causing urinary hesitancy or retention generally should be discontinued. Dysuria is an uncommon consequence of psychotropic agents that if not secondary to urinary hesitancy or retention, likely warrants independent urological evaluation. Symptomatic relief from urinary hesitancy or retention may occur from the temporary use of bethanechol (10–50 mg tid to qid), and dysuria may respond to the urinary tract analgesic phenazopyridine (200 mg tid with meals).



Anticholinergic agents can be associated with dysuria or urinary hesitancy, as well as urinary retention. Acute urinary retention also has been reported with SSRIs, SNRIs, and their combination (e.g., fluoxetine plus venlafaxine). Randomized controlled trials of duloxetine for major depression have collectively identified an incidence of 1% (20 of 2,097 subjects) encountering obstructive voiding symptoms, usually occurring (>80% of cases) within the first 2 weeks of treatment initiation; no subjects developed urinary retention requiring catheterization (Viktrup et al. 2004). SNRI-associated urinary retention presumably arises due to α2-adrenergic receptor antagonism, leading to contraction of the striated urethral sphincter. Amphetamine use has infrequently been associated with both urinary retention and incontinence. The risk for urinary hesitancy or urinary retention would presumably be higher in individuals with existing risk factors, such as benign prostatic hypertrophy, or in patients taking additional medications that may constrict bladder outflow. Urinary retention also has been reported as a rare adverse effect (~1% incidence) with the novel stimulant modafinil according to the manufacturer’s product information.


The parasympathomimetic agent bethanechol is sometimes used to counteract urinary hesitancy. Typical adult dosing is 10–50 mg tid to qid. Pyridium is a urinary tract analgesic that is frequently used for the symptomatic relief of pain caused by irritation of the urinary tract mucosa. Adult dosing is typically 200 mg tid with meals.


Symptoms of burning when urinating, increased urinary frequency and urgency, hematuria, or pelvic discomfort leads most health care professionals to think of urinary tract infections, although it should be kept in mind that patients who have repeated exposures to ketamine incur a risk for ulcerative cystitis, thought to occur from damage to interstitial cells lining the bladder, as well as endothelial microvascular damage to the bladder and kidneys.


Enuresis and Urinary Incontinence


General Recommendations


Urinary incontinence may be a rare adverse effect with a number of antipsychotic, antidepressant, or anticonvulsant drugs. Enuresis is not clearly dose related, although it may be influenced in part if heavy sedation occurs. Reasonable pharmacological remedies for enuresis and urinary incontinence include adjunctive anticholinergic drugs (e.g., benztropine), ephedrine, intranasal desmopressin acetate (DDAVP; 10 μg in each nostril at bedtime), oxybutynin (5 mg bid to tid), or substitution of alternative pharmacotherapies for the presumptive offending agent.



Enuresis is a relatively infrequent adverse effect associated with clozapine and may respond to the anticholinergic drugs trihexyphenidyl (5 mg nightly) or benztropine (0.5–2 mg nightly). Urinary incontinence has been reported with risperidone (especially during co-therapy with SSRIs such as fluoxetine, which may increase serum risperidone levels), olanzapine, clozapine, gabapentin, SSRIs (including paroxetine and sertraline), and some SNRIs (e.g., venlafaxine). Diagnostic evaluation of enuresis with SGAs may require determining the absence of diabetes mellitus and nocturnal seizures or the presence of neurogenic bladder dysfunction. Ephedrine, up to 150 mg/day, has been reported as a potentially useful strategy to counteract olanzapine- or clozapine-induced urinary incontinence.


Drugs that may cause urinary retention (e.g., modafinil, anticholinergic drugs, and SNRIs such as duloxetine) may potentially counterbalance urinary incontinence if co-therapy is otherwise appropriate within an overall pharmacotherapy regimen. With respect to more traditional strategies for managing urinary incontinence, lack of efficacy was reported with the bladder-specific antimuscarinic agent tolterodine 2 mg bid in an adolescent female whose clozapine-induced enuresis was ultimately ameliorated by intranasal desmopressin (English et al. 2001). When used to counteract clozapine-induced enuresis, desmopressin nasal spray (typically dosed as 10 μg in each nostril at bedtime) may be associated with significant hyponatremia (Sarma et al. 2005). Oxybutynin, dosed at 5 mg bid or tid, also may be of value in the general management of iatrogenic enuresis. Persistent enuresis that is unresponsive to the pharmacological interventions recommended in this section and that does not eventually remit spontaneously may ultimately require replacement of the suspected causal agent with an alternative psychotropic medication.


Nephrotic Syndrome


General Recommendations


Symptoms of nephrotic syndrome (proteinuria, hypoalbuminemia, and peripheral edema) can have multiple etiologies and require careful evaluation. In rare cases, lithium may cause nephrotic syndrome, which is remediable by cessation of the drug.



Nephrotic syndrome arises from damage to the glomerular basement membrane (causing leakage of protein from filtered blood to urine), therefore manifesting with proteinuria (i.e., without hematuria [cf. nephritic syndrome]), as well as hypoalbuminemia, edema, and hyperlipidemia. Nephrotic syndrome can be a primary disorder or may be secondary to other medical conditions, such as diabetes mellitus, viral infections, amyloidosis, preeclampsia, or systemic lupus erythematosus. A handful of published cases have linked its occurrence with lithium therapy, although no risk factors for its development have been identified. Drug cessation, sometimes followed by corticosteroids, generally leads to resolution of symptoms.


Nephrotoxicity and Nephrogenic Diabetes Insipidus


General Recommendations


Lithium-associated polyuria or nephrogenic diabetes insipidus (NDI) can usually be effectively managed by the addition of amiloride 5 mg qd or bid, sometimes in combination with hydrochlorothiazide; periodic monitoring of serum potassium levels would be appropriate in cases of ongoing or long-term amiloride use. Once-daily lithium dosing may diminish the potential for developing long-term lithium-induced glomerulosclerosis.



During the course of lithium therapy, urinary frequency or quantity (i.e., polyuria) is common (evident in up to 70% of otherwise healthy individuals) and potentially seen more often in women and individuals with increased body weight (Kinahan et al. 2015). NDI is the most common adverse renal effect of lithium, occurring with an incidence of up to 40% (Grünfeld and Rossier 2009), and is a clinical diagnosis defined by the presence of polyuria, polydipsia, and a dilute urine with low urine electrolytes and osmolality, caused by impaired urinary concentrating ability. In contrast to diabetes mellitus, NDI involves an absence of glycosuria or hyperglycemia. A first step in identification involves obtaining a urinalysis to determine whether urine specific gravity is low, as well as measurements of urine electrolytes and osmolality. Serum sodium levels may be elevated due to hypovolemia caused by polyuria. Although some authorities believe that the development of NDI warrants cessation of lithium, others advise treating it with the potassium-sparing diuretic amiloride (typically dosed at 5 mg bid) (Finch et al. 2003), which has been shown to restore renal medullary osmolytes (i.e., concentrating ability). The thiazide diuretic hydrochlorothiazide can paradoxically improve NDI via decreasing distal tubular sodium reabsorption, leading to increased urinary sodium excretion, decreased extracellular fluid volume, and increased proximal tubular sodium and water reabsorption with resultant decreased urine volume. The combination of amiloride plus hydrochlorothiazide may together further increase urine osmolality and reduce urine volume. In addition, NSAIDs such as indomethacin also can reduce urinary free water loss and are sometimes used to help manage NDI. One must keep in mind that NSAIDs (especially indomethacin) can increase serum lithium levels with great variability across agents and across individuals, leading some experts to advise monitoring of serum lithium levels as often as every 4–5 days during long-term NSAID use until a new steady state is determined.


Lithium-associated nephrotoxicity has long been debated as a possible consequence of acute overdose, but whether it occurs at therapeutic dosages during long-term maintenance treatment has been more controversial. Before 2000, an extensive literature altogether challenged the nephrotoxicity of lithium, or the assertion that long-term lithium use caused changes in glomerular filtration rate (GFR) (Gitlin 1999; Schou 1988, 1997). Histopathological evidence from autopsy studies demonstrated unequivocal evidence of lithium-induced chronic tubulointerstitial nephrotoxicity (primarily affecting distal and collecting tubules) and segmental or global glomerulosclerosis (Markowitz et al. 2000), which challenged prior assumptions about the rarity (or even nonexistence) of structural kidney changes caused by lithium.


Reports in the literature have traditionally estimated the incidence of renal insufficiency as ranging from 4% (Gitlin 1993) to 20% (Lepkifiker et al. 2004), with variability based on the duration of exposure and the definition of renal insufficiency (e.g., loosely defined in some retrospective studies based on serum creatinine levels ≥1.5 mg/dL). Using a decision-analytic model based on 20 years of lithium exposure, Werneke and colleagues (2012) estimated an approximate 14% risk of developing end-stage renal disease once chronic kidney disease (CKD), defined as a serum creatinine level ≥ 1.7 mg/dL, has developed. A cross-sectional report found that about half of bipolar patients taking lithium >20 years had at least some degree of reduced renal function (Bocchetta et al. 2015). On the other hand, other prospective long-term data dispute any increased risk for lithium to reduce GFR after age, baseline GFR, co-prescription of nephrotoxic drugs, and past episodes of lithium toxicity were controlled for (Clos et al. 2015). Thus, while some experts identify the duration of lithium exposure as a key factor in the risk for eventual chronic renal disease, it is important to recognize the potential impact of confounding factors on this relationship (Presne et al. 2003).


Although existing proprietary formulations of lithium carbonate advise administration in divided doses two or three times daily, it can be dosed all at once, given its 24-hour elimination half-life; moreover, once-daily lithium dosing has been suggested to pose a lesser risk than multiple daily doses for developing glomerulosclerosis or chronic kidney disease (Hetmar et al. 1991; Plenge et al. 1982). In fact, a large joint database study from the Massachusetts General Hospital and Brigham and Women’s Hospital found that the most robust predictors of developing renal insufficiency while taking lithium were dosing more than once daily and having a maintenance serum lithium level that exceeds 0.6 mEq/L (Castro et al. 2016).


It is customary practice to monitor serum creatinine levels every 6 months for patients receiving long-term lithium therapy. Generally, if serum creatinine levels rise >25% from a patient’s own previous level, or exceed 1.6 ng/mL, further investigation is warranted (Gitlin 1993). Creatinine clearance (CrCl), which is an approximation of the GFR, is a more specific measurement of renal function than serum creatinine. It reflects the flow rate of fluid undergoing filtration through the renal tubular system. Moreover, serum creatinine alone may be insensitive to milder degrees of renal insufficiency and can be normal even in the setting of substantially reduced GFR (Jefferson 2010). As noted in the section “Older Adults” in Chapter 3 (“Vulnerable Populations”), GFR typically diminishes by 10 mL/min for every decade after age 40 and is also dependent on weight. A normal GFR is approximately 97–137 mL/min for men and 88–128 mL/min for women.


CrCl can be estimated by the Cockcroft-Gault equation:


image


Use of estimating equations such as this one are considered the best overall indicator of kidney function (National Kidney Foundation 2002) but can be imprecise in early stages of chronic kidney disease and may sometimes underestimate true GFR (Jefferson 2010). Some authorities point out that the Cockcroft-Gault equation is inadequate because of its standardization to CrCl rather than true GFR. Newer, alternative methods of calculating GFR include the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). There also has been increasing interest in the measurement of serum cystatin C, a low-molecular-weight renally filtered protein that has a stronger and more linear relationship to true GFR than does creatinine. Patients who exercise heavily or lift weights also may have elevated levels of muscle creatine kinase, favoring the measurement of serum cystatin C over serum creatinine. When measured alone or in conjunction with creatinine, cystatin C–based eGFRs may provide more accurate estimates of true GFR and the potential for underlying kidney disease (Shlipak et al. 2013). Degrees of chronic kidney disease are classified by the National Kidney Foundation’s (2002) Kidney Disease Outcomes Quality Initiative, as summarized in Table 13–1.


Clinicians also should consider other possible causes of age-related inappropriately diminished CrCl, such as medications (e.g., cimetidine, ACE inhibitors, and certain nephrotoxic antibiotics such as trimethoprim and cephalosporins).


Priapism


General Recommendations


Iatrogenic priapism is a rare phenomenon that may occur during treatment with trazodone, as well as several SGAs, SSRIs, psychostimulants, or bupropion. Priapism constitutes a medical and possible surgical emergency and requires urgent evaluation in an appropriate medical setting such as an emergency department.



Priapism is defined by the American Urological Association as an erection that occurs without sexual stimulation and lasts longer than 4 hours. As a type of compartment syndrome, it poses a medical (if not surgical) urological emergency and involves a specific management strategy as outlined in clinical guidelines published by the American Urological Association (Montague et al. 2003). Urologists differentiate between priapism that is ischemic (low-flow, painful) and nonischemic (high-flow, less common, and generally nonemergent, usually resulting from arterial steal or shunting of blood). Psychotropically induced priapism involves ischemic priapism. Nonischemic priapism may result from several primary medical conditions, including sickle cell anemia, hematological malignancies, thalassemia, and genital trauma.


By definition, ischemic priapism is not ameliorated by sexual intercourse or masturbation. Its proper evaluation and treatment should occur in an emergency department or similar medical setting. The American Urological Association advises urgent intracavernous injection of an α-adrenergic sympathomimetic agent, such as phenylephrine, with or without evacuation of blood in the corpus cavernosum, performed with local or regional anesthesia. If this treatment fails to alleviate priapism, a surgical shunting procedure may be necessary. Oral medications such as β2-adrenergic agonists (e.g., terbutaline) or the oral α-adrenergic agonist pseudoephedrine, although sometimes used in nonischemic priapism, are not recommended for the treatment of ischemic priapism.






































TABLE 13–1.Classification of chronic kidney disease


Stage


Description


Glomerular filtration rate (GFR)


1


Kidney damage with no GFR increase


≥90 mL/min/1.73 m2


2


Kidney damage with mild GFR decrease


60–89 mL/min/1.73 m2


3


Moderately decreased GFR


30–59 mL/min/1.73 m2


4


Severely decreased GFR


15–29 mL/min/1.73 m2


5


Kidney failure


<15 mL/min/1.73 m2 (or dialysis)


Source.National Kidney Foundation 2002.


Priapism is an exceedingly rare but often-mentioned adverse effect associated with trazodone (incidence of approximately 1 in 6,000; reports include its occurrence after only a single dose; most reported cases occur within the first 28 days of its initiation). Less well recognized are rare cases of priapism associated with both FGAs and SGAs, possibly mediated by α1-adrenergic blockade (Andersohn et al. 2010), including reports involving quetiapine, risperidone, ziprasidone, clozapine, and olanzapine. Rare cases of priapism also have been reported with atomoxetine, fluoxetine, fluvoxamine, citalopram, and bupropion. In 2013 the FDA issued a warning that methylphenidate products may cause priapism, based on reports of 15 such cases to the FDA Adverse Event Reporting System (FAERS) from 1997 through 2012; no such warning was applied to amphetamine products (www.fda.gov/Drugs/DrugSafety/ucm375796.htm). Case reports (and product manufacturers’ warnings) also identify priapism as a risk associated with the use of PDE type 5 inhibitors such as sildenafil or vardenafil.


When using medications that may increase the risk for priapism, clinicians should recognize the presence of pretreatment baseline risk factors, such as the presence of blood dyscrasias (e.g., sickle cell disease, multiple myeloma, leukemia). Paradoxically, PDE type 5 inhibitors can also sometimes effectively treat recurrent ischemic priapism (also termed “stuttering priapism”).


Cases of clitoral priapism that manifest with vulvar pain lasting from 24 to 60 hours have been described in connection with the use of trazodone, olanzapine, nefazodone, citalopram, and bupropion; this effect is managed with drug cessation and the administration of α-adrenergic agonists in analogous fashion to that of male priapism. Clinicians should consider a broad differential diagnosis for priapism, particularly in women with respect to vascular obstruction due to pelvic floor and bladder malignancies.


Renal Calculi


General Recommendations


A history of renal calculi is a relative contraindication to treatment with topiramate. Adequate hydration is imperative in all patients taking topiramate to minimize the risk of stone formation.



Calcium phosphate renal calculi are a known risk (approximately 1% incidence) in individuals taking topiramate, attributable to topiramate’s inhibition of carbonic anhydrase in the kidney, which in turn can cause hypocitraturia, hypercalciuria, and acidified urine. Accordingly, a history of nephrolithiasis is a relative contraindication to the use of topiramate. Some practitioners advise increased oral water intake in patients taking topiramate, although it is not clear whether this precaution meaningfully counters the risk for developing renal calculi. Notably, individuals who follow a ketogenic diet (i.e., high-protein diet with avoidance of carbohydrates) may be independently predisposed to the development of renal calculi due to hypercalciuria, decreased urinary citrate excretion, and acidified urine; hence, the use of topiramate in conjunction with a ketogenic diet may warrant particular caution with respect to monitoring for nephrolithiasis (Paul et al. 2010).


Renal calculi (composed of calcium or urate salts) appear to be a rare phenomenon with zonisamide (15 cases reported from 1,296 clinical trial subjects [1.2% incidence] over an 8.7-year period; Wroe 2007). However, the manufacturer’s product information identifies a 4% incidence rate during drug development for adult epilepsy, arising most often from 6 to 12 months after drug initiation but with new cases still occurring >1 year after beginning therapy. The manufacturer advises that patients drink 6–8 glasses of water daily to help prevent kidney stone formation.


Renal Insufficiency


General Recommendations


Random creatinine measurements are advisable semiannually with lithium; serum creatinine rises of >25% from a prior baseline may warrant collection of 24-hour urine for direct measurement of CrCl. No absolute value has been established for GFRs below which lithium or other renally cleared drugs should be discontinued, but progressive declines in renal function or the emergence of moderate to severe renal impairment signals the need for closer, more frequent renal monitoring, as well as renal dosing of many medications and their probable eventual discontinuation.



Most psychotropic drugs either are directly excreted renally or have active metabolites that are renally excreted. Hence, the presence of impaired renal clearance often requires reduced dosing depending on the magnitude of renal insufficiency, as described in Table 13–1. A 2012 review alongside recommendations by the European Renal Best Practice (ERBP) observed that in patients with CKD stages 3–5, marked reductions in drug clearance were observed for oral selegiline, venlafaxine, desvenlafaxine, milnacipran, bupropion, reboxetine, and tianeptine.


Table 13–2 summarizes manufacturers’ recommendations for dosing adjustments of psychotropic medications in the setting of renal insufficiency.


Sexual Dysfunction


Impaired Arousal, Erectile Dysfunction, and Anorgasmia


General Recommendations


Lowest incident rates of antidepressant-associated sexual dysfunction have been reported in FDA registration trials with bupropion, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline transdermal system, vilazodone, and vortioxetine. SNRIs may be somewhat less likely than SSRIs to cause this phenomenon, although such differences have not been affirmed in comparative trials. Bupropion added to SSRIs has shown modest benefit to overcome existing iatrogenic sexual dysfunction. Adjunctive sildenafil 50–100 mg/day, up to 200 mg/day, appears to be the most effective pharmacological intervention to remedy sexual arousal that is diminished by serotonergic antidepressants in men or women. Other evidence-based antidotes to iatrogenic sexual dysfunction include adjunctive buspirone, testosterone, mirtazapine, and dehydroepiandrosterone (DHEA).



























































































































































TABLE 13–2.Renal considerations for psychotropic agents


Agent


Recommendations


Atomoxetine


No dosing adjustment is necessary in the setting of renal insufficiency.


Buspirone


Patients with CrCl of 10–70 mL/min demonstrate an approximate 4-fold increase in serum drug levels. Dosages should be reduced accordingly.


Anticonvulsants and lithium


Carbamazepine


No dosing adjustment is necessary in the setting of renal insufficiency.


Divalproex


Renal failure is associated with an increased unbound fraction (and slightly reduced clearance) of free valproic acid. No dosage adjustment is necessary in the setting of renal failure.


Gabapentin


For CrCl of 30–60 mL/min, maximum dosage=300 mg bid; for CrCl of 15–30 mL/min, maximum dosage=300 mg/day; for CrCl <15 mL/min, maximum dosage=300 mg every other day.


Lamotrigine


Manufacturer’s product information states that “reduced maintenance doses may be effective for patients with significant renal impairment” and that “Lamictal should be used with caution in these patients” because “there is inadequate experience in this population.”


Lithium


In chronic kidney disease patients for whom alternatives to lithium may not be feasible, some authors advise the following: for GFR >50 mL/min, no dosing modification is necessary; for GFR=10–50 mL/min, administer 50%–75% of usual dose; for GFR <10 mL/min, administer 20%–50% of usual dose (Aronoff et al. 1999). In end-stage renal disease patients undergoing hemodialysis, administer a single dose of 200–600 mg after each hemodialysis session, guided by levels checked immediately before hemodialysis (Cohen et al. 2004).


Oxcarbazepine


Dosing is halved when CrCl is <30 mL/min (in which case, dosing should be started at 150 mg bid).


Pregabalin


Dosing must be reduced in the presence of renal failure (for CrCl of 30–60 mL/min, maximum dosage=75–300 mg/day in 2–3 divided doses; for CrCl of 15–30 mL/min, maximum dosage=25–150 mg/day given once or in 2 divided doses daily; for CrCl of <15 mL/min, maximum dosage=25–75 mg/day).


Topiramate


For CrCl of <70 mL/min, the usual dosage is halved and upward titration is done slowly.


Antidepressants


Bupropion


ERBP advises against dosing >150 mg/day in CKD stages 3–5 (Nagler et al. 2012).


Citalopram


No dosing adjustment is necessary for individuals with mild to moderate renal impairment. Caution is advised for use in severe renal disease, although ERBP advises that no dosing adjustments are necessary in CKD stages 3–5 (Nagler et al. 2012).


Desvenlafaxine


Recommended dosage in the setting of moderate renal impairment is 50 mg/day; 50 mg every other day is advised in severe renal impairment; ERBP advises dosing of 25 mg/day with “careful increases” in CKD stage 3 and dosing no higher than 25 mg/day in CKD stages 4–5 (Nagler et al. 2012).


Duloxetine


Administration is not recommended for patients with end-stage renal disease or severe renal impairment (i.e., CrCl of <30 mL/min). ERBP recommends no dosing adjustment in CKD stage 3 but careful increases >40 mg/day in CKD stages 4–5 (Nagler et al. 2012).


Escitalopram


No dosing adjustment is necessary for individuals with mild to moderate renal impairment. Dosages >10 mg/day should be done with caution in CKD stages 4–5 (Nagler et al. 2012).


Fluoxetine


No dosing adjustment is necessary in the setting of renal insufficiency.


Fluvoxamine


Low initial dosing is advised in the setting of mild to moderate renal impairment, although ERBP advises no dosing adjustments as being necessary in CKD stages 3–5 (Nagler et al. 2012).


Levomilnacipran


Maximum dosage is 40 mg/day in setting of moderate renal impairment (CKD stages 3–4) and 80 mg/day in severe renal impairment (CKD stage 5); not recommended in patients with ESRD.


MAOIs


Isocarboxazid, phenelzine, and tranylcypromine are not recommended in patients with clinically significant renal disease; however, the ERBP advises that in CKD stages 3–5, no dosing adjustment is necessary with isocarboxazid or phenelzine, but in CKD stages 4–5, tranylcypromine should be started at 30 mg/day and “increased carefully.” Transdermal selegiline requires no dosing modification in the setting of renal insufficiency, although the ERBP advises oral selegiline dosing no greater than 5 mg/day in CKD stages 4–5.


Mirtazapine


Clearance of mirtazapine is reduced by ~30% in moderate renal insufficiency (CrCl of 11–39 mL/min) and by ~50% for CrCl ≤10 mL/min. The manufacturer advises caution when administering to patients with renal impairment. ERBP advises no dosing adjustment in CKD stage 3 but “careful increases” above 15 mg/day in CKD stages 4–5 (Nagler et al. 2012).


Nefazodone


No dosing adjustment is necessary in the setting of renal insufficiency, although the ERBP advises caution if dosing >100 mg/day in CKD stages 3–5 (Nagler et al. 2012).


Paroxetine


Mean plasma concentrations increase approximately 4-fold in the setting of severe renal impairment (i.e., CrCl of <30 mL/min), and about 2-fold when CrCl is 30–60 mL/min. Dosage reductions and slowed titration schedules are therefore advised if dosing >10 mg/day occurs in CKD stages 3–5 (Nagler et al. 2012).


Sertraline


No dosing adjustment is necessary in the setting of renal insufficiency; however, the ERBP advises “careful increases” if dosing above 50 mg/day in CKD stage 4 and if dosing above 25 mg/day in CKD stage 5, with a reduced maximum dose (Nagler et al. 2012).


TCAs


In CKD stages 3–5, the ERBP advises no necessary dosing adjustments with doxepin, nortriptyline, and amitriptyline; for desipramine, no dosing adjustments are advised for CKD stages 3–4, while dosing initiation at 25 mg/day should be “increased carefully” in CKD stage 5; for clomipramine or imipramine, no dosing adjustment is recommended for CKD stage 3, but dose initiation should be 10 mg/day and the doasge “increased carefully” in CKD stages 4–5 (Nagler et al. 2012).


Venlafaxine


For CrCl of 10–70 mL/min, total daily dosing should be decreased by 25%–50%. ERBP advises no dosing adjustment in CKD stage 3 but dosing only from 37.5–112.5 mg/day in CKD stages 4–5 (Nagler et al. 2012).


Vilazodone


No dosing adjustment is necessary in the setting of renal insufficiency.


Vortioxetine


No dosing adjustment is necessary in the setting of renal insufficiency.


Benzodiazepines


Short-acting agents, and those with fewer active metabolites, such as oxazepam or lorazepam, are preferred over longer-acting agents (e.g., clonazepam or chlordiazepoxide) and those with many active metabolites (e.g., diazepam).


SGAs


Aripiprazole


No significant pharmacokinetic differences in patients with significant renal failure (Mallikaarjun et al. 2008); renal dosing adjustments are likely unnecessary.


Asenapine


No dosing adjustment is necessary in the setting of renal impairment.


Brexpiprazole


For patients with CKD stages 3–5, the maximum recommended dosage is 2 mg/day in major depressive disorder and 3 mg/day in schizophrenia.


Cariprazine


No dosing adjustment is necessary in mild to moderate renal impairment (CrCl≥30 mL/min). Use is not recommended when CrCl<30 mL/min.


Lurasidone


For CrCl of 10–50 mL/min (i.e., moderate to severe renal impairment), the manufacturer recommends that daily dosage should not exceed 40 mg/day.


Olanzapine


No dosing adjustment is necessary in the setting of renal impairment.


Paliperidone


In mild impairment (CrCl of 50–80 mL/min), recommended dosage is 3–6 mg/day. In moderate to severe impairment (CrCl of 10–50 mL/min), recommended initial dosage is 1.5 mg/day and maximum dosage is 3 mg/day.


Quetiapine


Plasma concentrations of quetiapine appear no different in the setting of renal insufficiency. Dosing adjustment is therefore not necessary in the setting of renal impairment.


Risperidone


The manufacturer advises an initial dosage not exceeding 0.5 mg bid in patients with renal impairment, with subsequent increases of no more than 0.5 mg bid; dosage increases above 1.5 mg bid should occur at least 1 week apart.


Ziprasidone


Dosing adjustment is not necessary in the setting of renal impairment.


Sedative-hypnotics


Eszopiclone


Dosing adjustment is not necessary in the setting of renal impairment.


Suvorexant


Dosing adjustment is not necessary in the setting of renal impairment.


Zolpidem


Dosing adjustment is not necessary in the setting of renal impairment.


Other CNS agents


Deutetrabenazine


No data, but because deutetrabenazine is renally excreted, usage in CKD stages 4–5 should likely be done with caution pending further studies.


Valbenazine


Dosing adjustment is not necessary in mild to moderate renal impairment (CrCl ≥ 30 mL/min); not recommended in CKD stages 4–5.


Note. bid=twice daily; CKD=chronic kidney disease; CNS=central nervous system; CrCl=creatinine clearance; ERBP=European Renal Best Practice; ESRD=end-stage renal disease; GFR=glomerular filtration rate; MAOI=monoamine oxidase inhibitor; SGA=second-generation antipsychotic; TCA=tricyclic antidepressant.




Patient concerns about impaired sexual functioning resulting from psychotropic medications rank among the highest reasons for poor adherence to continued treatment with antidepressants and other (usually serotonergic or antidopaminergic) agents (Kennedy and Rizvi 2009; Serretti and Chiesa 2011). However, because patients tend not to spontaneously discuss sexual functioning, either as a possible drug side effect or illness symptom, clinicians need to proactively assess sexual function with an awareness of the relative adverse sexual effects of different psychotropic agents, as well as the distinct areas of human sexual responsivity affected by common medications. Indeed, although premarketing studies of many antidepressants identify relatively low rates of spontaneously reported sexual dysfunction, adverse sexual effects are often not proactively assessed in pivotal trials, and hence are underreported. Findings from studies in which patients were specifically asked about sexual dysfunction with SSRIs or other antidepressants suggest that incidence rates may be as high as 80% (Hu et al. 2014). Formal assessment ratings, such as the Arizona Sexual Experiences Scale (ASEX; McGahuey et al. 2000), the Changes in Sexual Functioning Questionnaire (CSFQ; Clayton et al. 1997), or the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ; Montejo and Rico-Villademoros 2008) (see “Rating Scales for Measuring Adverse Drug Effects” in Appendix 3) may aid clinicians in detecting and monitoring sexual dysfunction during longitudinal treatment.


The human sexual response cycle is divided into three components, including interest (libido), excitation and arousal (i.e., erections in men and vaginal lubrication in women), and orgasm. Diminished interest in sex is a common adverse effect of serotonergic antidepressants, although even nonserotonergic antidepressants have been associated with an increased risk for delayed ejaculation in some studies. Men taking antidepressants appear significantly more likely than women to encounter impaired sexual desire and orgasm, whereas women may be more prone to impaired arousal (Clayton et al. 2006). SSRI treatment may be more likely to lead to remission of impaired sexual desire and arousal in depressed women, but not orgasmic dysfunction in depressed men.


Antidepressants


Serotonergic antidepressants may adversely affect all components of sexual functioning, as well as sexual satisfaction. Although it is often difficult to distinguish whether depression itself or antidepressants are the proximal cause of decreased libido and sexual dysfunction, antidepressants are often thought to be more prone to impair excitation and arousal (i.e., erectile dysfunction and delayed ejaculation in men, or impaired lubrication in women) and orgasm, whereas depression may more often impair libido than other phases of the sexual response cycle.


Agonism of serotonin type 2A (5-HT2A) postsynaptic receptors is believed to contribute to impaired sexual functioning and, consequently, may be an unintended effect of serotonergic agents that fail to block or antagonize 5-HT2A receptors. Correspondingly, serotonergic agents that block postsynaptic 5-HT2A receptors may incur minimal sexual dysfunction, as has been demonstrated in preliminary open-label fashion with mirtazapine (Saiz-Ruiz et al. 2005) or adjunctive trazodone for SSRI-induced sexual dysfunction (Stryjer et al. 2009). Preliminary data suggest that adjunctive mirtazapine is superior to placebo for improving FGA-associated orgasmic dysfunction in schizophrenia (Terevnikov et al. 2017), but data are lacking on the use of adjunctive mirtazapine for SSRI- or SNRI-associated sexual dysfunction.


A prospective multicenter study comparing various SSRIs found that paroxetine caused significantly more orgasmic delay, ejaculation, or impotence than did fluoxetine, sertraline, or fluvoxamine (Montejo-González et al. 1997). These authors also found SSRI-induced sexual dysfunction to be a dose-related phenomenon. Similarly, paroxetine 20 mg/day was significantly more likely than citalopram 20 mg/day (Waldinger et al. 2001) or mirtazapine 30 mg/day (Waldinger et al. 2003) to delay orgasm and ejaculation in affectively healthy men with premature ejaculation. Another study of men with premature ejaculation, comparing paroxetine 20 mg/day, fluoxetine 20 mg/day, sertraline 50 mg/day, fluvoxamine 100 mg/day, and placebo, found that paroxetine caused the greatest delay in ejaculation and that fluvoxamine caused the least (Waldinger et al. 1998).


The novel serotonergic antidepressants vortioxetine and vilazodone appear to have relatively modest incident rates of prospectively measured sexual dysfunction in clinical trials of major depression. For ex-ample, a randomized 8-week comparison of vortioxetine (10–20 mg/day) or escitalopram (10–20 mg/day) among treated major depression patients who had developed sexual dysfunction while taking sertraline, paroxetine, or citalopram found a significantly greater improvement in overall sexual functioning, as well as in component domains (e.g., desire, arousal, orgasm), among those switched to vortioxetine than among those switched to escitalopram (Jacobson et al. 2015). Pooled analyses of seven randomized trials of vortioxetine for major depressive disorder or generalized anxiety disorder found no differences from placebo in ASEX scores at doses of 5 mg/day or 10 mg/day, but treatment-emergent sexual dysfunction was higher than with placebo at doses of 15 mg/day or 20 mg/day (Jacobson et al. 2016). Across dosages, ASEX scores were lower with vortioxetine than with duloxetine (which was studied as an active comparator).


Another prospective trial comparing paroxetine, sertraline, venlafaxine, and moclobemide found that men were more likely than women to encounter diminished sexual desire but that no gender differences emerged in arousal and orgasm (Kennedy et al. 2000). Overall rates of sexual dysfunction were lower with moclobemide or venlafaxine than with SSRIs. Other trials similarly suggest a lower incidence of sexual dysfunction with SNRIs (e.g., duloxetine, dosed at 40–120 mg/day) than with pure serotonergic reuptake inhibitors (e.g., paroxetine, dosed at 20 mg/day) (Delgado et al. 2005).


Antipsychotics


SGAs might be expected to incur relatively low rates of sexual dysfunction by virtue of their postsynaptic 5-HT2A blockade, although agents that increase prolactin release can in turn induce sexual adverse effects. In patients with chronic schizophrenia, findings from the CATIE study found relatively similar rates of sexual dysfunction (19%–27%) across the FGAs and SGAs studied, without clear links to differences in reported changes in serum prolactin (Lieberman et al. 2005). In fact, even agents that showed reductions from baseline serum prolactin levels in CATIE (i.e., quetiapine and ziprasidone) had approximate 20% incidence rates of sexual dysfunction. Because of interindividual variability between changes in serum prolactin and the potential for sexual dysfunction, other endocrinological or physiological factors likely contribute to (or mediate) iatrogenic sexual dysfunction from SGAs.


A meta-analysis of reported incidence rates of sexual dysfunction with FGAs and SGAs (N=7,975 subjects) identified the following rank ordering of global sexual dysfunction (most dysfunction to least dysfunction): thioridazine > clozapine > haloperidol > risperidone > olanzapine > aripiprazole > perphenazine > ziprasidone > quetiapine. In addition, aripiprazole and ziprasidone caused the least degree of impaired sexual desire, whereas aripiprazole and quetiapine both caused the least degree of arousal dysfunction and orgasmic dysfunction (Serretti and Chiesa 2011).


Other Agents


Tables 13–3 through 13–6 summarize information regarding iatrogenic sexual dysfunction from randomized controlled trials with commonly used psychotropic medications: SGAs (Table 13–3), sedative-hypnotics (Table 13–4), lithium and anticonvulsants (Table 13–5), and antidepressant and related noradrenergic or serotonergic agents (Table 13–6).


Case reports exist of divalproex-associated anorgasmia and decreased libido in men and women with bipolar disorder, migraine, or epilepsy; these effects are possibly dose related and are generally in the context of cotherapy with other medications. Dosage reductions have not reliably eliminated sexual side effects in reported cases, although drug cessation has. With respect to lithium, one study of 104 outpatients with bipolar disorder revealed an incidence of sexual dysfunction among 14% of those undergoing monotherapy but among 49% of those taking lithium plus a benzodiazepine (Ghadirian et al. 1992). A subsequent review identified only 13 publications examining lithium-associated sexual dysfunction, noting from preclinical studies that lithium can reduce testosterone levels and impair nitric oxide–mediated relaxation of corpus cavernosum musculature (Elnazer et al. 2015).


Controlled trials conducted outside of industry, for purposes other than label indications, often reveal higher rates of sexual dysfunction with antidepressants than identified in FDA registration trials. These include incidence rates for overall sexual dysfunction of 22% and 25% with bupropion IR and SR, respectively, over a variable duration from less than 1 week to more than 3 years (Clayton et al. 2002); 33% with duloxetine over 8 months (Clayton et al. 2007); and 49% with escitalopram over 8 months (Clayton et al. 2007).


Management


Strategies to manage anorgasmia or other sexual side effects of SSRIs—apart from switching altogether to alternative primary agents—focus mainly on the use of adjunctive pharmacotherapies, although the concept of “weekend holidays” from an SSRI (specifically, sertraline or paroxetine, but not fluoxetine) has been suggested to significantly improve sexual functioning (Rothschild 1995). The potential benefit of such a break must be weighed against the potential for SSRI-discontinuation withdrawal symptoms.


A wide range of pharmacotherapy strategies have been proposed on mechanistic grounds and studied empirically as intended remedies to counteract antidepressant-induced sexual dysfunction. Some capitalize on putative mechanisms of action (e.g., introducing blockade of 5-HT2 receptors) or efforts to reverse antidepressant-induced increases in peripheral/genitourinary serotonergic tone (e.g., cyproheptadine) or to “override” serotonergic effects by introducing catecholaminergic agents (e.g., bupropion, stimulants). Others focus on the role of nitric oxide and PDE inhibitors, such as sildenafil, vardenafil, or tadalafil. Inhibition of PDE prevents the catabolism of cyclic guanosine monophosphate, which in turn facilitates the relaxation of smooth muscle lining the corpus cavernosum. A related strategy involves using L-arginine, a precursor of nitric oxide, for a similar purpose.




















































TABLE 13–3.Incidence of sexual dysfunction in clinical trials of second-generation antipsychotics


Agent


Rates reported in FDA registration trials or randomized controlled studies


Aripiprazole


Libido either increased or decreased in <1% across FDA registration trials. Greater improvement from baseline in overall sexual functioning was seen with aripiprazole compared with olanzapine, risperidone, or quetiapine in a 26-week multisite open randomized industry-supported study (Schizophrenia Trial of Aripiprazole; Hanssens et al. 2008).


Asenapine


In all registration trials for bipolar mania or schizophrenia, both short- and long-term, incidence of sexual dysfunction was ≤1% (per manufacturer).


Brexpiprazole


NR


Cariprazine


NR


Iloperidone


In schizophrenia FDA registration trials, decreased libido and anorgasmia were reported in ≥1%; ejaculation failure occurred in 2% across dosages.


Lurasidone


NR


Olanzapine


Across indications, FDA registration trials reported decreased libido in ≤1%. In CATIE, sexual dysfunction was reported in 27% (Lieberman et al. 2005).


Paliperidone


NR


Pimavanserin


NR


Quetiapine


Across all indications, FDA registration trials reported decreased libido in 1%–2% and abnormal ejaculation in ≤1%. In CATIE, sexual dysfunction was reported in 20% (Lieberman et al. 2005).


Risperidone


Across indications, FDA registration trials and postmarketing reports identified impaired ejaculation in ≤1%, and decreased libido and anorgasmia in <1%. In CATIE, sexual dysfunction was reported in 27% (Lieberman et al. 2005).


Ziprasidone


In FDA registration trials for schizophrenia, impotence, anorgasmia, or abnormal ejaculation occurred in ≤1%. In CATIE, sexual dysfunction was reported in 19% (Lieberman et al. 2005). Incidence rates of sexual dysfunction in trials for bipolar disorder were not reported.


Note. CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; FDA=U.S. Food and Drug Administration; NR=not reported.


PDE inhibitors were initially studied and adapted for the treatment of sexual dysfunction in men, although more recent studies have also demonstrated their value in SSRI-associated sexual dysfunction in women (see Table 13–7). Notably, however, adjunctive sildenafil in women appears better than placebo in helping to improve anorgasmia but not desire, arousal-sensation, arousal-lubrication, or orgasmic satisfaction (Nurnberg et al. 2008). By contrast, in men, all measured components of sexual functioning, including sexual desire, arousal, erectile function, ability to orgasm, and orgasmic satisfaction, have shown significant improvement with adjunctive sildenafil (Fava et al. 2006; Nurnberg et al. 2003).


PDE inhibitors represent the best studied and most robust strategy to counteract sexual dysfunction caused by serotonergic antidepressants. A 2013 Cochrane Review reported an overall 11.5-fold improvement in erectile function among men taking tadalafil (vs. placebo) caused by serotonergic antidepressants, while potential benefits in women appear more uncertain (Taylor et al. 2013). Prescribers must be aware of the potential of PDE inhibitors to cause modest decreases in blood pressure (e.g., sildenafil has been shown to lower blood pressure in healthy volunteers by about 9/6 mm Hg). The vasodilatory effects of sildenafil pose at least a theoretical risk for exacerbating underlying cardiovascular disease, although adverse hemodynamic effects in men with coronary artery disease have not been demonstrated, and use of sildenafil is not necessarily contraindicated in this population.






























TABLE 13–4.Incidence of sexual dysfunction in sedative-hypnotic clinical trials


Agent


Rates reported in FDA registration trials or randomized controlled studies


Benzodiazepines


In general, ≤1%–3% incidence of sexual dysfunction across agents


Eszopiclone


Decreased libido in <3% of patients taking 3 mg/day; no reports of erectile dysfunction or anorgasmia


Suvorexant


NR


Zaleplon


Decreased libido or impotence in <1%


Zolpidem


Decreased libido or impotence in <0.1%


Note. FDA=U.S. Food and Drug Administration; NR=not reported.


There have been rare reports of vision loss from sildenafil or vardenafil due to nonarteritic anterior ischemic optic neuropathy. The manufacturers of these drugs point out that most people who take them have underlying predispositions to visual problems (e.g., diabetic retinopathy), although risk factors for developing loss of vision with PDE inhibitors have not been described. Patients who begin a PDE inhibitor should be counseled to inform the prescriber if they notice any visual changes, and treatment should be discontinued unless alternative explanations are identified.


A number of other pharmacological approaches have been described and studied with more variable results, as summarized in Table 13–7. Also, with few exceptions, there has been little study of combination therapy approaches that use complementary and possible synergistic mechanisms to overcome impaired sexual functioning caused by psychotropic agents.
































































TABLE 13–5.Incidence of sexual dysfunction in FDA registration trials of lithium and anticonvulsants


Agent


Impotence


Decreased libido


Delayed ejaculation


Anorgasmia


Carbamazepine


<5%


NR


NR


NR


Divalproex


NR


NR


NR


NR


Gabapentin


NR


≥1%


<1%


<1%


Lamotrigine


<1%


<1%


<1%


NR


Lithium


NR


NR


NR


NR


Oxcarbazepine


NR


NR


NR


NR


Topiramate


NR


1%–3%


NR


NR


Note. FDA=U.S. Food and Drug Administration; NR=not reported.


Noteworthy from the findings presented in Table 13–7 is the failure in two studies (DeBattista et al. 2005; Masand et al. 2001) of adjunctive bupropion to reverse SSRI-induced sexual dysfunction with dosages of 150 mg/day, but the apparent benefit in other studies with dosages of 75–150 mg/day (Ashton and Rosen 1998) or 150 mg twice daily (Safarinejad 2010). A further corollary to these observations is that replacement (rather than augmentation) of purely serotonergic agents with catecholaminergic, nonindoleaminergic antidepressants (such as bupropion) or with antidepressants that selectively block 5-HT2A postsynaptic receptors (e.g., mirtazapine) may produce substantially less sexual dysfunction than seen with an SSRI. The incidence of sexual dysfunction with SNRIs (i.e., duloxetine, venlafaxine, desvenlafaxine) appears less than that seen with purely serotonergic agents.


In unmedicated men with erectile dysfunction (Lebret et al. 2002) or women with sexual arousal disorder (Meston and Worcel 2002), the combination of yohimbine (6 mg/day) with the nitric oxide precursor L-arginine glutamate (6 g/day) has shown benefits over placebo that may reflect synergistic effects (presynaptic α2 blockade may both enhance genital nitric oxide release and reduce risk of hypotension from nitric oxide–related vasodilation, while nitric oxide donation may increase genital effects of yohimbine). However, this combination has not been studied specifically as a strategy to counteract sexual dysfunction induced by antidepressants or other psychotropics. Other possible viable strategies for noniatrogenic hypoactive sexual arousal in postmenopausal women include DHEA 300 mg/day.





























































































































































TABLE 13–6.Incidence of sexual dysfunction in U.S. Food and Drug Administration registration trials of antidepressant and related noradrenergic or serotonergic agentsa


Agent


Impotence


Decreased libido


Erectile dysfunction


Delayed ejaculation


Anorgasmia


Atomoxetine


NR


4%


9%


3%


≥2%


Bupropion


<1%


<1%


NR


<1%


NR


Buspirone


<0.1%


<1%


NR


<0.1%


NR


Citalopram


3%


3.8% (men), 1.3% (women)


NR


6.1%


1.1% (women)


Desvenlafaxineb


NR


4%–5%


3%–6%


1%–5%


0–3%


Duloxetinec


NR


NR


NR


NR


NR


Escitalopram


2%


6% (men), 3% (women)


NR


12%


3% (women)


Fluoxetine


NR


4%


NR


NR


NR


Fluvoxamine


2%


4%–8%


3%


11%


4%–5%


Levomilnacipran


NR


NR


6%


5%


NR


MAOIs other than transdermal selegiline: isocarboxazid, phenelzine, tranylcypromine


NR


NR


NR


NR


NR


Mirtazapine


<1%


≥1%


NR


≥1%


NR


Paroxetine


10%


7%–9%


NR


26%–27%


NR


Sertraline


NR


6%


NR


14%


NR


TCAs


NR


NR


NR


NR


NR


Transdermal selegiline


≤1%


≤1%


NR


≤1%


≤1%


Venlafaxine


NR


3%–8%


NR


8%–19%


NR


Vilazodone


NR


3%–5%


2%


2%


2%–4%


Vortioxetined


NR


1.6% (men), 0.8% (women)


0.2%


0.5%


0.4% (men), 0.3% (women)


Note. FDA=U.S. Food and Drug Administration; MAOI=monoamine oxidase inhibitor; NR=not reported; TCA=tricyclic antidepressant.


aReported incidence rates are based on spontaneous reports rather than on systematic assessments, unless otherwise noted.


bAdverse effects as reported with desvenlafaxine dosages of 50–100 mg/day for major depression.


cAdverse sexual effects with duloxetine were assessed in FDA trials using the Arizona Sexual Experiences Scale (McGahuey et al. 2000), which revealed significantly poorer scores versus placebo for global sexual function among men but not women and significantly greater difficulty reaching orgasm with duloxetine than placebo in men but not women. No significant drug-placebo differences were observed in sex drive; arousal; ability to achieve erections (men) or lubrication (women); orgasmic satisfaction; or ease of reaching orgasm (women).


dAs reported from spontaneous reports of pooled trials of vortioxetine in major depressive disorder and generalized anxiety disorder (N=3,377) (Jacobson et al. 2016).






























































































TABLE 13–7.Pharmacological strategies used to counteract drug-induced sexual dysfunction


Agent


Rationale


Positive data


Equivocal or negative data


Phosphodiesterase type 5 inhibitors (e.g., sildenafil, vardenafil, tadalafil)


Nitric oxide–mediated vasodilator


Case reports describe improvement or resolution of SSRI-associated ejaculatory delay with sildenafil 50–100 mg/day prn or higher (up to 200 mg/day; Seidman et al. 2003), including improvement of anorgasmia in women (Nurnberg et al. 2008). Significant improvement also identified from placebo-controlled data (Fava et al. 2006; Nurnberg et al. 2003), and in placebo-controlled trials of sildenafil (25–50 mg/day) to counteract antipsychotic-associated sexual dysfunction (Gopalakrishnan et al. 2006). Vardenafil (10 mg 30 minutes before sexual activity; Berigan 2004) and tadalafil (20 mg/day; Segraves et al. 2007) have been described in case reports and open trials as a strategy to counteract sexual dysfunction secondary to antidepressants.


None.


Amantadine


Dopamine agonism


Case reports indicate favorable results when used to treat anorgasmia related to fluoxetine (Balogh et al. 1992; Balon 1996) or paroxetine (Shrivastava et al. 1995).


In women with sexual dysfunction secondary to fluoxetine, adjunctive amantadine (50–100 mg/day) was no different from placebo (Michelson et al. 2000).


Aripiprazole


Relatively prolactin sparing


Over 12–26 weeks, open-label add-on or substitution from another SGA significantly improved libido and overall sexual satisfaction in men and women (N=27), ejaculatory or erectile dysfunction in men, and menstrual dysfunction in women (Mir et al. 2008).


None.


Bethanechol


Procholinergic, may help counteract sexual dysfunction caused by anticholinergic drugs (e.g., TCAs or MAOIs)


Case reports used 10–50 mg/day (Gross 1982).


None.


Bupropion


Prodopaminergic and noradrenergic agent without known serotonergic effects


Outpatients (N=47) taking SSRIs received open-label bupropion 75–150 mg 1–2 hours before sexual activity, yielding improvement in 38%; a standing adjunctive dose of bupropion 75 mg tid for 2 weeks reversed sexual dysfunction in 66% of patients (Ashton and Rosen 1998).


In a 12-week randomized comparison of bupropion SR 150 mg bid or placebo added to SSRIs in 234 remitted male depressed patients with SSRI-induced sexual dysfunction, significantly greater improvement occurred in overall sexual functioning (by ASEX) with bupropion than placebo (Safarinejad 2010).


In 12-week randomized comparison of bupropion SR 150 mg bid or placebo added to SSRIs in 218 remitted female depressed patients with SSRI-induced sexual dysfunction, significantly greater improvement in desire and lubrication occurred with bupropion than placebo (Safarinejad 2011).


In 6-week randomized comparison of bupropion SR 150 mg/day or placebo (N=41) added to SSRIs in remitted depressed patients with SSRI-induced sexual dysfunction, no differences were found between drug and placebo on any measures of sexual functioning (DeBattista et al. 2005); identical findings in a similarly designed 3-week study with the same dosing (N=30) were reported by Masand et al. (2001).


Buspirone


5-HT1A partial agonist


In 4-week comparison of placebo vs. flexibly dosed buspirone (20–60 mg/day; mean dose=49 mg/day) added to citalopram or paroxetine, greater improvement in sexual function occurred with buspirone (58%) than placebo (20%); results more pronounced in women than men (Landén et al. 1999).


Among women with sexual dysfunction secondary to fluoxetine, adjunctive buspirone (20–30 mg/day) was no different from placebo (Michelson et al. 2000).


Cyproheptadine


Serotonin antagonist


Case series data show improvement of delayed male ejaculation from fluoxetine, fluvoxamine, or clomipramine using adjunctive cyproheptadine (4–12 mg) 1–2 hours before sexual activity (Aizenberg et al. 1995).


None.


Ginkgo biloba


Hypothesized effects on vasodilation and stimulation of prostaglandin synthesis


Favorable open-label data were reported in men and women (N=63) with dosages of 60–120 mg/day (Cohen and Bartlik 1998).


In 2-month comparison of Gingko biloba (N=19) or placebo (N=18), no significant differences were found (Kang et al. 2002).


In 12-week trial of Ginkgo biloba 240 mg/day or placebo in 24 antidepressant-treated subjects, no significant differences were found (Wheatley 2004).


Maca root (Lepidium meyenii; a Peruvian plant)


Unknown


In 12-week double-blind, randomized comparison of 1.5 vs. 3.0 mg/day of maca in 20 SSRI-treated outpatients with remitted major depression, improved libido and sexual functioning from baseline were seen with 3.0-mg/day dosage (Dording et al. 2008).


 


Methylphenidate


Dopamine agonism may increase sexual function


Case reports (Roeloffs et al. 1996).


No significant differences were found between methylphenidate extended release (OROS) and placebo with respect to change in ASEX scores for sexual functioning over 4 weeks in patients with treatment-resistant major depression (Pae et al. 2009).


Mirtazapine


Postsynaptic 5-HT2A blockade may counteract 5-HT2A serotonergic stimulation


In depressed outpatients in remission with SSRIs receiving open-label adjunctive mirtazapine 15–30 mg/day (N=49), significant improvement was seen usually after 4 weeks (Ozmenler et al. 2008).


Improvement from baseline found with mirtazapine (N=36) but similar to placebo (N=39) over 1 month in premenopausal women receiving fluoxetine (Michelson et al. 2002).


Saffron (Crocus savatis L.)


Reported to have aphrodisiac effects in animals and humans


Randomized 4-week comparison of 30 mg/day for fluoxetine-associated sexual dysfunction in women (N=34) demonstrated significant improvement in global sexual functioning, arousal, lubrication, and pain (Kashani et al. 2013).


 


Testosterone (gel or transdermal)


Improves libido and arousal


Improved ejaculatory function in men (randomized 6-week placebo-controlled trial; Amiaz et al. 2011) or sexual satisfaction in women (randomized 12-week placebo-controlled trial; Fooladi et al. 2014).


 


Trazodone


5-HT2A postsynaptic antagonism


Open-trial data using trazodone 50–100 mg/day added to SSRIs for 4 weeks led to improvement in desire, arousal, orgasm, and overall satisfaction in men and women (N=20) (Stryjer et al. 2009).


 


Yohimbine (+/– L-arginine glutamate)


Presynaptic α2-adrenergic antagonism increases noradrenergic tone


In 2-week crossover study of yohimbine 6 mg/day+L-arginine glutamate 6 g/day vs. yohimbine 6 mg/day or placebo (N=45), combination therapy was found superior to placebo (Lebret et al. 2002).


Five favorable outcomes were found in 6 open cases receiving yohimbine as needed for SSRI-induced sexual dysfunction (Hollander and McCarley 1992).


Improved sexual function was found in 8 of 9 fluoxetine-treated outpatients given open-label yohimbine 5.4 mg tid (Jacobson 1992).


Improvement from baseline found with yohimbine (N=35) but similar to placebo (N=39) after 1 month among women with SSRI-induced sexual dysfunction (Michelson et al. 2002).


May cause anxiety, tachycardia, and hypertension.


Note. 5-HT1A=serotonin type 1A ; 5-HT2A=serotonin type 2A ; ASEX=Arizona Sexual Experiences Scale; bid=twice daily; MAOI=monoamine oxidase inhibitor; OROS=osmotic-release oral system; prn=as needed; SGA=second-generation antipsychotic; SR=sustained release; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant; tid=three times daily.



In addition to the findings from randomized trials summarized in Table 13–7, a handful of case reports and proof-of-concept open trials describe novel strategies to counteract antidepressant-induced sexual dysfunction. One such example, focusing on patients who developed sexual dysfunction after successful treatment for generalized anxiety disorder with an SSRI or SNRI, involved substituting the novel GABAergic anticonvulsant tiagabine for the original agent; the change yielded significant overall improvement in sexual function with sustained improvement in anxiety symptoms (Schwartz et al. 2007).


Drug-induced sexual dysfunction typically remits after cessation of the suspected causal agent. However, some case reports describe sexual dysfunction that may persist indefinitely after the discontinuation of citalopram, fluoxetine, or sertraline and that remains unimproved with a variety of dopamine agonists.


Sexual dysfunction due to antipsychotic medications has been attributed to likely effects of hyperprolactinemia, although the postsynaptic 5-HT2A blockade exerted by SGAs should, at least in theory, minimize sexual adverse effects. As noted in Table 13–7, adjunctive sildenafil has demonstrated value in improving erectile dysfunction and orgasmic satisfaction in men taking antipsychotics (Gopalakrishnan et al. 2006). Also, according to a Cochrane Database analysis, sildenafil constitutes the sole known effective adjunctive therapy to counteract antipsychotic-associated sexual dysfunction (Berner et al. 2007) apart from the use of adjunctive dopamine agonists.


Remarkably, only a small literature exists describing the use of dopamine agonists such as bromocriptine (dosed at 5–7.5 mg/day) to overcome sexual dysfunction caused by antipsychotics. Perhaps this dearth of studies results from concerns that dopamine agonism could potentially reverse the antipsychotic effects of dopamine D2 antagonism or otherwise cause a direct psychotomimetic effect. Preliminary open-trial data suggest value for ropinirole (begun at 0.25 mg/day and increased to 2–4 mg/day, with a mean dose of about 2 mg/day to alleviate antidepressant-induced sexual dysfunction). Dopamine agonists such as bromocriptine, amantadine, pramipexole, or ropinirole could at least in theory diminish antipsychotic-associated sexual dysfunction via reduction of antipsychotic-induced hyperprolactinemia.



Retrograde Ejaculation


General Recommendations


Retrograde ejaculation may be caused by a select number of FGAs or SGAs. Dosage reductions, or if necessary, drug cessation typically ameliorates the complication.



The phenomenon of retrograde ejaculation has been reported with a limited number of antipsychotic agents, most notably thioridazine, risperidone, and clozapine. Some authors have suggested that retrograde ejaculation more likely occurs due to α1-adrenergic antagonism than to other mechanisms (e.g., hyperprolactinemia) because of the lack of interference with arousal or the ability to attain or sustain erections. Short of altogether discontinuing the causal agent, the prescriber can try dosage reductions to resolve the side effect.

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