Ear, Nose, and Throat
Benzodiazepines such as clonazepam probably offer the most reliable and immediate relief for iatrogenic bruxism. Other potential pharmacological remedies may include buspirone, gabapentin, low-dose aripiprazole, propranolol, cyclobenzaprine, trazodone, divalproex, topiramate, metoclopramine, and hydroxyzine. Acrylic dental guards are considered the optimal strategy for long-term management. In severe or persistent cases, injection of botulinum toxin into the masseter muscle may provide symptomatic relief.
Bruxism is an involuntary grinding and gnashing of the teeth that may occur during sleep and in some instances may be considered a form of akathisia. Nocturnal bruxism is considered a type of non–rapid eye movement parasomnia and may be caused by a number of psychotropic agents, including SSRIs, SNRIs, buspirone, antipsychotics, atomoxetine, and dopaminergic compounds such as amphetamine or dopamine agonists used to treat Parkinson’s disease. Among serotonergic antidepressants, reported incidence rates range from 14% to 24% and may be associated with older age and female sex (Uca et al. 2015). Several authors have suggested that at least in the case of SSRIs, iatrogenic bruxism may arise via inhibition of dopaminergic pathways controlling masticatory muscle activity. The persistence of bruxism over time may lead to erosion of dental enamel and potential tooth fractures or receding gums. Patient-specific risk factors include female sex, older age, smoking, stress (pertinent more for bruxing when the patient is awake than when he or she is asleep), and genetic vulnerabilities.
The clinical trial literature on pharmacotherapies for bruxism addresses bruxism in its primary (idiopathic) occurrence much more extensively than bruxism as a phenomenon secondary to medications or other etiologies, and therefore it is often necessary to extrapolate from idiopathic cases when treating its iatrogenic occurrence. No standard pharmacological treatment exists for bruxism, although acrylic dental guards (“appliance therapy”) worn at night are usually considered the optimal intervention for persistent bruxism. Dosage reductions have been anecdotally reported as having potential benefit in SSRI-induced bruxism. Data from preliminary controlled trials suggest that in unmedicated, psychiatrically healthy sleep bruxers, benzodiazepines (notably, clonazepam 1 mg) may reduce bruxism and improve associated measures of sleep quality (Saletu et al. 2010). Anecdotal observations also support the possible value of cyclobenzaprine dosed from 2.5 to 10 mg at bedtime, trazodone 150–200 mg/night, divalproex 500 mg/night, hydroxyzine 10–25 mg/night, topiramate 25–100 mg/day, or metoclopramide 10–15 mg/night, all yielding improvement within 2–10 days following initiation. In a small double-blind crossover study, L-dopa 100 mg (dosed 1 hour before bedtime and again 4 hours later) has been shown to be better than placebo to reduce the frequency of noniatrogenic bruxing (Lobbezoo et al. 1997). Aripiprazole has been reported both to cause bruxism and to treat it when the bruxism is induced by SSRIs. Botulinum toxin injections into the masseter muscles also have been described as a novel periodontal procedure that can significantly reduce the number of bruxism events and consequent myofacial pain over time in individuals with persistent bruxism. There have also been anecdotal observations of preexisting bruxism improving after the initiation of SSRIs.
Case reports identify potential improvement in medication-induced bruxism with several other described agents, all yielding benefit within 2–7 days (Table 9–1).
Slow, slurred speech may be a consequence of psychotropic drugs, usually reflecting toxicity. Clinicians should be alert to the possible neurotoxic effects and the dosages of all medications and illicit substances being taken by a patient with dysarthric speech, as well as consider and evaluate other pertinent noniatrogenic (e.g., neurological) etiologies. Nondevelopmental stuttering may rarely occur as a possible dose-related consequence of antipsychotic pharmacotherapy. Lack of improvement from dosage reductions may require discontinuation of a suspected causal agent.
Bruxism induced by
Improvement shown with
Propranolol, 60–160 mg/day in three divided doses (Amir et al. 1997)
SSRI (sertraline) or venlafaxine
Gabapentin, 300 mg/day (Brown and Hong 1999)
Note. bid=twice daily; tid=three times daily; SSRI=selective serotonin reuptake inhibitor.
Dysarthria involves impaired pronunciation of speech. When dysarthria is thought to result from psychotropic drugs, it usually reflects excessive dosing or toxicity, particularly during the use of benzodiazepines or other sedative-hypnotics and opiate analgesics, as well as lithium, divalproex, buspirone, antipsychotics, TCAs, and rarely, SSRIs. Dysarthria accompanied by difficulty clearing oral secretions may suggest possible laryngeal dystonia during antipsychotic therapy. The evaluation of dysarthria should include pertinent history taking; an assessment of the motor branch of the trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X), and hypoglossal nerve (XII) (see Table 9–2); and assessment of overall motor strength and deep tendon reflexes, in order to rule out upper motor neuron disease (e.g., strokes, basal ganglia deficits).
Nondevelopmental stuttering is a rare, possibly dose-dependent adverse drug event that has been identified in a handful of case reports with risperidone, olanzapine, clozapine, and FGAs. An equal number of cases have been reported that describe treatment of developmental (i.e., noniatrogenic) stuttering with SGAs, including risperidone, olanzapine, and aripiprazole. The mechanisms by which antipsychotics could either cause or treat stuttering are not well understood, although preliminary functional imaging studies suggest that developmental stuttering may be related to increased hyperdopaminergic tone in the striatum. However, early suspicions that antipsychotic-induced stuttering could represent an extrapyramidal symptom were unsustained when adjunctive benztropine failed to demonstrate efficacy in its treatment. From a practical clinical standpoint, if new-onset stuttering does not improve via reducing the dosage of the suspected causal agent, drug discontinuation is likely warranted. Further neurological or otolaryngological evaluation is advisable if problems persist despite drug cessation.
Trigeminal nerve, motor branch
Assess jaw strength by palpating the temporal and masseter muscles as the patient clenches and moves the jaw.
Ask the patient to raise the eyebrows, frown, resist opening the eyes while shut, smile (showing teeth), and puff out both cheeks.
Observe the symmetry of palatal rise and fall; assess gag reflex (afferent limb).
Assess gag reflex (efferent limb).
As the patient protrudes and moves the tongue in various directions, inspect it for asymmetries, fasciculations, and deviation from the midline.
Abnormal taste sensation in the absence of other neurological adverse effects likely represents a benign phenomenon for which no intervention is medically necessary. A suspected causal medication may be eliminated if the problem persists, jeopardizes adherence, or otherwise remains objectionable to the patient. Drug cessation may be necessary.
Dysgeusia refers to an impaired sense of taste. It has rarely been identified as a manifestation of clinical depression. Iatrogenic dysgeusia can result from a number of psychotropic agents, including topiramate, carbamazepine, and lithium. In addition to being a side effect of nonpsychotropic medications (e.g., anti-inflammatory drugs, antineoplastic agents, allopurinol), dysgeusia can occur with numerous primary medical conditions, including oropharyngeal infections, vitamin or mineral (e.g., zinc) deficiencies, malignancies, Sjögren’s syndrome, and smoking. Although no systematic studies have examined pharmacological antidotes for iatrogenic dysgeusia, the case report literature suggests possible value for sertraline to improve idiopathic primary dysgeusia (Mizoguchi et al. 2012).
New oral lesions that arise within the first few days or weeks after starting any new medication should be evaluated for their possible association with a drug, as well as alternative (noniatrogenic) explanations. Particular attention should be paid to blistering lesions on oral mucosal tissue and any associated systemic features (e.g., fever, lymphadenopathy) that could be suggestive of serious dermatological reactions; the expected time course for such drug hypersensitivity reactions to occur is usually within the first 2 months of treatment initiation.
Oral ulcers can have many etiologies. They may be aphthous ulcers (canker sores), typically 3–10 mm in diameter, arising from a variety of causes, including physical trauma, stress, and immune deficiencies, among others. Aphthous lesions seldom persist beyond 1–2 weeks, typically remit spontaneously, and likely do not represent iatrogenic phenomena. Ulcerative tongue lesions can sometimes arise as part of a viral syndrome or reflect a chronic inflammatory process, the presence of autoimmune disease, or other immunocompromised states. They may be common phenomena in individuals with HIV. Persistent lesions sometimes warrant brush biopsies by an otolaryngologist or oral surgeon to evaluate the possibility of an oropharyngeal malignancy. Visually, malignancies usually do not appear synchronously as multiple lesions.
Inspection of the oral cavity should include assessment for the presence of thrush. Among patients taking psychotropic agents, rare cases of nonspecific oral ulcerations or mucositis have been reported in connection with carbamazepine, lithium, fluoxetine, and meprobamate. Among patients taking common nonpsychotropic drugs, oral lesions may rarely occur from the use of NSAIDs, β-blockers, thiazide diuretics, spironolactone, ACE inhibitors, and certain antibiotics. Of primary concern when evaluating oral lesions in the aftermath of starting a psychotropic drug is the recognition of blistering oropharyngeal lesions that may occur as part of the clinical presentation of a systemic rash, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (see the section “Serious Rashes” in Chapter 8, “Dermatological System”).
Symptomatic management of benign but painful oral ulcerative lesions can often be achieved by rinsing with oral solutions of viscous lidocaine with diphenhydramine and elixir antacids.
If dosage reductions prove unhelpful for sialorrhea, the most compelling data support the use of glycopyrrolate 1 mg bid, biperiden 2 mg qd or bid, or metoclopramide 10–30 mg/day. Alternative strategies include atropine sulfate 1% ophthalmic solution 1–2 drops administered sublingually qhs or 2–3 times/day, or ipratropium bromide 0.03% nasal spray, 2 sprays administered sublingually qhs, potentially increased up to 3 times/day as needed.
Excessive drooling (sialorrhea) is a medically benign but often distressing side effect associated with several psychotropic agents, most notably clozapine (arising in about 30%–80% of clozapine-treated patients with schizophrenia), as well as risperidone, olanzapine, and quetiapine. Hypersalivation from clozapine appears to be a paradoxical phenomenon, in light of clozapine’s antimuscarinic-anticholinergic and α2-adrenergic antagonistic effects. Hypersalivation has been described in the absence of extrapyramidal symptoms and thus is unlikely a manifestation of parkinsonism. It also does not appear to be dose dependent in the case of clozapine, although a dose relationship may exist in cases associated with risperidone or quetiapine. Several mechanisms have been proposed to account for antipsychotic-induced hypersalivation, including postsynaptic α-adrenergic blockade at salivary glands; increased saliva production via M4-muscarinic cholinergic receptor stimulation; decreased nocturnal pharyngeal peristalsis; and blockade of receptors at pharyngeal muscles that regulate swallowing. In addition, as noted in Chapter 2 (“Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics”), preliminary pharmacogenetic studies suggest that a genetic variant of the dopamine D4 receptor may contribute to the development of clozapine-induced sialorrhea.
Antimuscarinic anticholinergic agents represent the most extensively studied pharmacological class to counteract clozapine- or risperidone-induced sialorrhea, with varying efficacy. Significant improvement has been demonstrated from randomized data examining both oral glycopyrrolate (1 mg bid) and biperiden (2 mg qd or bid), with more robust effects seen with glycopyrrolate for clozapine-induced sialorrhea (Liang et al. 2010). Glycopyrrolate, as a peripherally acting agent, is significantly less likely than biperiden to impair cognitive function. Case reports also suggest possible value with oxybutinin 5 mg once or twice daily. Inasmuch as anticholinergic agents as a class carry the risk of cognitive dulling and sedation, their use becomes a further consideration that must be balanced against the potential for relief from hypersalivation.
A variety of other anticholinergic compounds have been used, with most having shown potential value from small proof-of-concept studies, often followed by lack of separation from placebo in larger randomized trials. These agents include the antimuscarinic-anticholinergic spray ipratropium bromide (favorable data from case reports, but negative findings from placebo-controlled trials) and the selective M4-muscarinic receptor antagonist pirenzepine (significant reductions in hypersalivation from baseline in open-trial data reported at a dose of 50 mg/day or 25–100 mg/day, but negative data from an 8-week placebo-controlled trial begun at 25 mg/day and increased by 25 mg/week to a target dose of 100 mg/day [Bai et al. 2001]). Open data with trihexyphenidyl (mean dose=10.7 mg/day) have shown about a 50% reduction in hypersalivation, although no randomized controlled trials have as yet been reported for this use. The anticholinergic agent benztropine—popularly used to counteract parkinsonian adverse effects of antipsychotics, and known to cause dry mouth—has received little if any study for the intended purpose of counteracting hypersalivation.
A placebo-controlled trial using the D2 antagonist metoclopramide dosed 10–30 mg/day found that sialorrhea fully or near-fully resolved in two-thirds of afflicted patients taking clozapine (Kreinin et al. 2016).
A number of case reports over the past two decades have described the local application of 1–2 drops of sublingual ophthalmic atropine sulfate 1% solution (initially qhs and then qam or bid) as an apparently effective and well-tolerated novel strategy (provided it is properly administered). Similarly, ipratropium bromide 0.03% nasal spray can sometimes be used successfully to treat clozapine-associated sialorrhea, beginning with 2 sprays administered sublingually qhs and then increased as needed up to three times daily.
Open case reports have also described benefits from the α2-adrenergic agonist clonidine (orally dosed from 0.05 to 0.1 mg/day) or a clonidine patch (0.1 mg/week), although randomized controlled trials have not been reported.
Stomatodynia (Burning Mouth Syndrome)
Stomatodynia is rarely associated with psychotropic medicines. Topical clonazepam has been reported as being among the more successful interventions, although referral to an otolaryngologist may be necessary to clarify etiology and address therapeutic management.
Burning mouth syndrome involves a painful burning sensation of the tongue or oral mucous membranes that, in the absence of any visible physical or laboratory abnormalities, has been associated with the presence of major depressive disorder or generalized anxiety disorder. It is especially common in postmenopausal women and is rare in men, and it may be either constant or intermittent. It has no known pathophysiology or structural etiology, although conditions such as mucosal diseases, nutritional deficiencies (notably, deficiencies of vitamins B1, B2, B6, or B12; niacin; iron; folate; or zinc), oral thrush, non–insulin-dependent diabetes mellitus, xerostomia, or cranial nerve injuries should be ruled out when considering differential diagnosis. Some authors regard stomatodynia as a type of somatoform pain disorder. It may derive from depression or an anxiety disorder, rather than being a true pharmacodynamic consequence of treatment.
Psychotropic medications associated with burning mouth syndrome are quite rare and limited to case reports with some SSRIs (notably, fluoxetine or sertraline), venlafaxine, and clonazepam. A small number of nonpsychotropic medications, particularly ACE inhibitors such as lisinopril or enalapril, have been reported to cause burning mouth syndrome. The otolaryngological literature describes the use of TCAs and gabapentin as potentially beneficial for treating stomatodynia, as well as topical clonazepam (i.e., patients suck a 1-mg clonazepam tablet bid or tid near the pain site for several minutes, then spit).
Tinnitus is a rare, medically benign adverse effect without a clear antidote other than drug cessation if the symptom produces significant distress.
A small number of psychotropic drugs, including bupropion, buspirone, sertraline, and venlafaxine, have been suggested in case reports or premarketing studies to cause tinnitus. In addition, tinnitus can occur as part of withdrawal phenomena from SNRIs such as venlafaxine or short-half-life SSRIs such as sertraline. Divalproex has been reported both to cause tinnitus (Hori et al. 2003; Reeves et al. 2000) and to treat it (Menkes and Larson 1998). Tinnitus has not been observed to be dose related and often occurs in the first few weeks or months after drug initiation. Risk factors remain unidentified.
Primary (i.e., non-iatrogenic) tinnitus has been suggested in open trials to be responsive to carbamazepine, alprazolam, clonazepam, fluoxetine, duloxetine, ginkgo biloba, or melatonin, whereas randomized trials with paroxetine and with trazodone produced negative findings in treating idiopathic tinnitus in nondepressed subjects. A 4-week study of ondansetron 4–16 mg/day was superior to placebo in reducing the severity of idiopathic tinnitus (Taslimi et al. 2013). A 3-month randomized trial of intratympanic dexamethasone in combination with melatonin 3 mg nightly produced significant improvement for idiopathic tinnitus (Albu and Chirles 2014). Mirtazapine 7.5 mg/day has been reported to counteract tinnitus induced by sertraline, but there are no published open trials or systematic studies of any pharmacotherapies that specifically ameliorate tinnitus caused by psychotropic agents. Cessation of the likely causal agent typically eliminates the problem if tinnitus causes substantial distress.
Dry mouth is one of the most common side effects of numerous psychotropic drugs and is not necessarily dose related. It is usually of no medical consequence unless its chronic persistence leads to dental complications. Dry mouth that is of mild severity may attenuate with time or can sometimes be ameliorated by sugarless gum or glycerin-based oral lubrication solutions. Oral remedies may also include cevimeline 30 mg/day, pilocarpine 2.5–10 mg one to three times per day, and bethanechol 25 mg three times per day. Severe persistent dry mouth may necessitate drug discontinuation.
Xerostomia, or dry mouth, may result from a variety of psychotropic medications, most often from anticholinergic drugs and lithium, although dry mouth is identified as a more common adverse effect than seen with placebo in controlled trials of most classes of psychotropic compounds, regardless of an absence of known anticholinergic effects or other anticholinergic manifestations (e.g., constipation). It is often unrelated to drug dose (see Table 1–5 in Chapter 1, “The Psychiatrist as Physician”), although empirically, dosage reductions may sometimes lessen severity. Xerostomia differs from sheer thirst (as often occurs with lithium, which, as a salt, may stimulate the need for increased fluid intake).
Sugarless gums that contain aspartame, mannitol, sorbitol, or xylitol may help to stimulate saliva production. A number of nonprescription glycerin-based aerosolized sprays or gels may serve as oral moisturizers, including the glycerate polymer Biotene Oral Balance Gel, carboxymethyl cellulose or hydroxyethyl cellulose solutions (e.g., Oralube saliva substitute, Salivart Oral Moisturizer, Xero-Lube Artificial Saliva), and the water-glycerin solution Plax. Procholinergic or parasympathomimetic drugs are sometimes used to counteract the antimuscarinic effects of medications thought to cause xerostomia. These include bethanechol 25 mg three times per day, oral pilocarpine 2.5–10 mg one to three times per day (Masters 2005), and cevimeline 30 mg/day (typically used in Sjögren’s syndrome or xerostomia after head and neck antineoplastic radiation therapy). Notably, in our experience, a single 10-mg dose of pilocarpine can cause profuse sweating, rhinorrhea, and diarrhea; therefore, the prudent action may be to initiate dosing at 2.5 or 5 mg to assure tolerability. Salivary stimulants versus saliva substitutes appear similar with respect to patient preference for their effects on xerostomia.