Bone Demineralization and Osteoporosis

Certain anticonvulsant drugs, particularly those that induce liver enzymes (e.g., carbamazepine), are known to decrease bone mineral density. In nongeriatric adults with epilepsy, long-term use of divalproex has been linked with an increased risk for osteoporosis or osteopenia in some studies but not others. Some investigators have suggested that drugs that inhibit histone deacetylase (e.g., divalproex) may have value in promoting osteoblast maturation, thereby mitigating a risk for bone demineralization. To date, no published reports have linked osteoporosis or osteopenia with gabapentin, lamotrigine, oxcarbazepine, topiramate, levetiracetam, or tiagabine.

Separately, SSRIs have been shown to reduce bone mineral density in hip and lumbar spinal joints by approximately 4%–6% in older adult men and women, presumably due to inhibition of serotonin sites in osteoblasts and osteoclasts. One prospective population-based study of 7,983 individuals found a 2.35-fold increased risk for nonvertebral fractures among SSRI recipients among individuals ≥age 55 (Ziere et al. 2008). Whether these observations pose a broad, clinically meaningful risk for fractures in older adults remains the subject of controversy, and at present no formal recommendation has been made either to perform bone densitometry studies on patients before and during treatment with SSRIs or to refrain from using SSRIs in osteoporotic patients for whom no other safety concerns exist regarding their use. Furthermore, depression itself has been suggested to induce bone loss via hypothalamic-pituitary-adrenocortical axis hyperactivity (Schweiger et al. 2000).

Of note, the use of hypermetabolic thyroid hormone as a psychotropic intervention (e.g., as may occur in rapid-cycling bipolar disorder) poses a potential risk for hastening bone demineralization. Some authorities advise periodic bone mineral densitometry testing in patients who continue high-dose thyroid hormone as a long-term therapy.

Hyperprolactinemia, Galactorrhea, and Gynecomastia

Antipsychotic-induced blockade of dopamine D₂ receptors on mammotropic cells of the anterior pituitary can cause release of prolactin. Hyperprolactinemia is a well-known consequence of virtually all FGAs and several SGAs (notably, risperidone and paliperidone), as described in Table 11–1. The clinician must bear in mind that hyperprolactinemia can result from other medications, including calcium channel blockers, TCAs, the sleep aid ramelteon, opiates, and histamine H₂ antagonists. Psychotropic agents other than antipsychotics have also been reported, although more rarely, to cause hyperprolactinemia and consequent gynecomastia with galactorrhea; these include venlafaxine, fluoxetine, paroxetine, diazepam (in the case of diazepam, possibly secondary to estrogen elevation), and methamphetamine. Hyperprolactinemia from some serotonergic antidepressants may arise via indirect GABAergic modulation of tuberoinfundibular dopaminergic projections (Emiliano and Fudge 2004). Among the SSRIs, the risk for hyperprolactinemia may be especially low with sertraline (Sagud et al. 2002). Rarely, carbamazepine and divalproex also have been implicated as causes of hyperprolactinemia.

Menstrual Disturbances and Polycystic Ovary Syndrome

A number of psychotropic agents can cause menstrual irregularities through a variety of mechanisms. Irregular menstruation caused by hyperprolactinemia (e.g., secondary to antipsychotic medications) is readily diagnosed by measurement of serum prolactin levels.

PCOS was defined by the National Institutes of Health as the presence of hyperandrogenism with oligomenorrhea (Zawadzki and Dunaif 1992). Documented anatomical evidence of subcapsular ovarian cysts (known as polycystic ovaries) is not considered necessary for the diagnosis of PCOS, although it is often present.

Concerns that divalproex might contribute to PCOS arose following a large observational study of 238 women with epilepsy, in whom the use of divalproex was associated with a higher prevalence of irregular menses (45%) or anatomical evidence of polycystic ovaries (43%) than occurred during treatment with carbamazepine or other anticonvulsants (Isojärvi et al. 1993). Extensive subsequent debate ensued about parsing the effects of divalproex on the menstrual cycle relative to the potential unique contributions of epilepsy, obesity, and other factors. A later study specifically in women with bipolar disorder found a 7.5-fold increased relative risk for developing PCOS during divalproex treatment than during therapy with other anticonvulsants (Joffe et al. 2006). Collectively, these reproductive findings and the drug’s teratogenic risks have prompted some authorities to advise against the use of divalproex among women of childbearing potential. Less extreme perspectives would favor monitoring the menstrual cycle of any woman of reproductive potential who receives divalproex, and further evaluation (i.e., measurement of serum androgen levels) would likely be warranted in the presence of clinical signs of a change in menstrual patterns. The treatment of PCOS involves the discontinuation of agents that may be causing it or the administration of oral contraceptives.

There is no absolute contraindication to prescribing divalproex in women with preexisting PCOS. In other words, no evidence indicates clinical worsening of existing PCOS after superimposition of divalproex, although most practitioners would likely be reluctant to risk further disruption of the hypothalamic-pituitary-gonadal steroid axis by prescribing divalproex.

Table 11–2 provides recommendations for monitoring reproductive safety in women who take divalproex during reproductive years.

Parathyroid Abnormalities

Hypercalcemia in conjunction with both hyperplastic and multiglandular hyperparathyroidism has been reported to occur in about 10%–25% of patients taking lithium, more commonly (4:1 ratio) in women than in men (Albert et al. 2013; Meehan et al. 2015; Shapiro and Davis 2015). Lithium can cause a shift in the inhibitory set point for parathyroid hormone secretion to a higher serum calcium concentration, while antagonizing the calcium sensing receptor (CaSR) located on the surface of parathyroid cells, which results in an increase in the threshold levels of extracellular calcium required to suppress PTH release from the parathyroid gland, leading to increased serum PTH. Lithium also can inhibit renal excretion of calcium, causing hypercalcemia with inappropriately low-normal urinary calcium excretion, measurable by 24-hour urine collection. (By contrast, primary hyperparathyroidism typically causes both hypercalcemia and hypercalciuria.) Duration of lithium exposure may be a predisposing risk factor. We recommend periodic monitoring of serum calcium and PTH in patients taking lithium.

Thyroid Abnormalities

Subclinical hypothyroidism may manifest as a consequence of lithium use in 5%–35% of individuals receiving lithium, particularly women (Kraszewska et al. 2016), and usually within the first 6–18 months of treatment. The duration of exposure appears not to contribute to risk (Kraszewska et al. 2016). The condition is thought to result from several effects of lithium, including antagonism of TSH, reduced deiodination of peripheral T₄ to triiodothyronine (T₃), and interference with cyclic adenosine monophosphate–mediated production of thyroid hormone within the thyroid gland. More rarely, lithium may also cause hyperthyroidism due to thyroiditis or Graves’ disease (Lazarus 2009). Some studies suggest that lithium-associated hypothyroidism may be more common among individuals who have circulating thyroid antibodies. Typically, in patients with an elevated serum TSH level, the clinician measures antiperoxidase and antithyroglobulin to determine whether autoimmune thyroiditis is present. Note that in contrast to goiter, thyroid nodules are generally not thought to result from treatment with lithium.

No firm consensus exists on when supplemental thyroid hormone should be added to the regimen of patients with an elevated serum TSH level who are taking lithium. Some authorities advocate more frequent monitoring of serum TSH levels (e.g., every 3 months) in the setting of biochemical hypothyroidism, without adding exogenous thyroid hormone unless serum TSH levels exceed 10 mU/L or clinical manifestations emerge. Others advise a lower threshold for adding supplemental thyroid hormone whenever serum TSH levels rise above the upper limit of a laboratory’s reference range, particularly in the setting of affective symptoms. T₄ is usually preferred over T₃ to produce steadier hormone levels, even though T₃ may exert more potent psychotropic (e.g., antidepressant) effects.

Supplementation of thyroid hormone for lithium-induced hypothyroidism usually begins with the addition of 0.025 mg/day of T₄, followed by a reassessment of thyroid function tests after 6 weeks, and iterative increases of T₄ by 0.025 mg/day until TSH levels have normalized. High-dose exogenous thyroid hormone—as is sometimes used to achieve suprametabolic levels of free T₄ in rapid-cycling bipolar disorder—requires clinicians to recognize the potential for developing arrhythmias (notably, atrial fibrillation) and promoting bone demineralization and osteoporosis (sometimes prompting a need for obtaining periodic bone mineral densitometry assessments).

Carbamazepine also hastens the metabolism of T₄ and T₃ and may produce secondary hypothyroidism. In addition, a handful of case reports have described hypothyroidism induced by quetiapine, usually in patients with a history of past thyroid abnormalities (Kelly and Conley 2005), and potentially subject to spontaneous resolution (Kontaxakis et al. 2009). Proposed mechanisms include competitive metabolism of thyroid hormones and quetiapine by uridine diphosphate–glucuronosyltransferase (Kelly and Conley 2005) or possibly an autoimmune-mediated process, although the rarity of this phenomenon does not appear to warrant routine monitoring of thyroid function during quetiapine treatment.