Can Zonisamide, Sertraline, or Trazodone Elevate SHBG?
Among these three medications, only zonisamide—as an anticonvulsant—has documented potential to elevate sex hormone-binding globulin (SHBG), while sertraline and trazodone are not recognized causes of elevated SHBG.
Anticonvulsants and SHBG Elevation
Certain anticonvulsant medications are well-established causes of elevated SHBG through hepatic enzyme induction 1, 2, 3.
The older enzyme-inducing antiepileptic drugs—including carbamazepine, phenobarbital, and phenytoin—induce hepatic cytochrome P450-dependent steroid hormone breakdown and increase production of SHBG, thereby reducing biologically active sex hormone serum concentrations 1.
Zonisamide, as an anticonvulsant agent, falls into the category of medications that can raise SHBG levels, consistent with the mechanism observed with other antiepileptic drugs 2, 3.
Antidepressants and SHBG
Neither sertraline (an SSRI) nor trazodone (a serotonin antagonist and reuptake inhibitor) appear in the established list of medications that elevate SHBG 4, 2, 3.
The recognized medication classes that increase SHBG include oral estrogens, thyroid hormone replacement, and anticonvulsants—but not selective serotonin reuptake inhibitors or serotonin modulators 4, 2.
Clinical Implications in Female Patients
When SHBG is markedly elevated in a woman taking zonisamide, the increased binding protein will reduce free (bioavailable) testosterone and estradiol, potentially causing symptoms despite normal total hormone levels 4, 2.
In women with epilepsy, enzyme-inducing antiepileptic drugs cause menstrual disturbances characterized by low estradiol and a low estradiol/SHBG ratio in approximately 25% of cases 1.
The free androgen index (total testosterone ÷ SHBG) provides a practical assessment of bioavailable androgens; a ratio < 0.3 indicates functional hypogonadism even when total testosterone appears normal 4, 2.
Diagnostic Approach
Measure both total sex hormones AND SHBG simultaneously to accurately interpret androgen and estrogen status in any patient on anticonvulsants 4, 2.
Consider checking thyroid function (TSH, free T4), liver function tests (AST, ALT, bilirubin, albumin), and reviewing all medications, as hyperthyroidism and chronic liver disease are the other major causes of markedly elevated SHBG 4, 2, 3.
In women with epilepsy on anticonvulsants who develop menstrual irregularity, oligomenorrhea, or amenorrhea, obtain LH, FSH, prolactin, progesterone (mid-luteal), testosterone, and pelvic ultrasound to differentiate between polycystic ovary syndrome, hypothalamic amenorrhea, and hyperprolactinemia 1.
Common Pitfalls to Avoid
Relying solely on total testosterone or estradiol measurements when a patient is taking an anticonvulsant will miss functional hormone deficiency caused by elevated SHBG 4, 2.
Do not attribute all menstrual dysfunction in women with epilepsy to the seizure disorder itself; anticonvulsant-induced SHBG elevation is a reversible medication effect 1.
If zonisamide is suspected of causing symptomatic SHBG elevation with reproductive dysfunction, discuss with the prescribing neurologist whether switching to a non-enzyme-inducing antiepileptic drug (such as levetiracetam or lamotrigine) is feasible 1.