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ODs must watch for ocular complications of psychotropic drugs
Careful attention to medication history can alert the optometrist to potential adverse effects of these systemic agents.
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Psychotropic (psycho = mind and tropic = change) agents are a group of compounds that cross the blood-brain barrier and act on the central nervous system to alter perception, mood and behavior. Archeological evidence suggests human use of psychoactive substances such as chewing coca leaves 8,000 years ago in Northern Peru. Coca leaves are known to contain various alkaloids, including cocaine, that alter the neurochemistry, reducing hunger and the effects of high-altitude, low-oxygen environments.
Nowadays, recreational use and abuse of psychoactive substances are the leading causes of addictions, crimes and deaths, secondary to drug overdose or drug-induced incidents.
Furthermore, in the current war on drugs, the authorities are struggling to fight illegal trade of psychoactive agents. A subset of psychoactive agents, psychotropic drugs, are approved by the U.S. Food and Drug Administration for medical use in psychiatry in addition to being used illegally and recreationally. Some of the most commonly prescribed classes of psychotropic drugs are antidepressants, antipsychotics, anticonvulsants, anti-anxiety medications and mood stabilizers.
For example, Abilify (aripiprazole, Bristol-Myers Squibb), an antipsychotic medication, and Cymbalta (duloxetine HCl, Lilly), a selective serotonin and norepinephrine reuptake inhibitor antidepressant, were among the top 10 drugs prescribed in 2012. A recent large-scale National Comorbidity Survey estimated the lifetime prevalence of behavioral disorders meeting the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria was at a staggering 46.4%, almost half of all lifetime cases began at age 14 and 75% began by the age of 24. Therefore, millions of patients, including adolescents, are taking one or more psychotropic drugs at any given time, and that does not include those individuals who use psychoactive substances recreationally or illegally.
Len V. Hua
Optometrists know well from their pharmacology training days that the liver is the primary organ that tackles and metabolizes xenobiotics, or foreign substances, to rid potentially toxic compounds from the body. The liver is designed with specialized cells packed with drug metabolizing enzymes to perform its duty.
On the contrary, the eye is designed for a different purpose – to maintain clarity for optimal vision – thus, it has minimal capacity to cope with foreign chemicals. Furthermore, a number of factors inherent to the eye make it vulnerable to drug exposure.
First, the eyes are made up of tissues derived from various embryological origins; for instance, the retina is a direct extension of the brain. Second, the eye has a relatively small surface area, but it is rich with blood supply. Third, the eye is one of the most metabolically active organs in the body because of its continual and ongoing phototransduction and visual perception.
A large proportion of psychiatric patients are required to take their medications on a long-term basis, and some of these psychoactive agents, for example, Mellaril (thioridazine, Novartis), exert ocular toxicity in a dose-dependent and cumulative way similar to Plaquenil (hydroxychloroquine, Sanofi-Aventis). As a consequence, the eyes are susceptible to drug-induced toxicity and second only to the liver in manifesting drug toxicity. Fortunately, many drug-induced ocular complications are asymptomatic or mild and reversible. However, some mild symptoms can significantly affect activities of daily living, whereas other drug-induced ocular complications can cause irreversible vision loss or blindness.
The main purposes of this article are to provide primary eye care providers or optometrists the knowledge of potential ocular adverse effects of commonly prescribed psychotropic medications and share practical in-office methods for evaluating suspicious ocular signs and symptoms that might be caused by psychotropic medications. It is by no means a comprehensive account of all potential ocular side effects of psychotropic drugs, but strives to focus on those most relevant to optometrists. Dozens of psychotropic drugs are currently in use for patients with numerous mental (behavioral) disorders, so the simplest way to approach this topic is to discuss the types of ocular complications that may arise from each class of psychotropic drugs. Moreover, recommendations for testing and management are presented, as relevant.
Ocular surface
Although ocular surface diseases are among the most commonly diagnosed conditions in eye clinics, only a few psychotropic drugs have been reported to cause more ocular signs than symptoms on the ocular surface.
The phenothiazine family, which includes Thorazine (chlorpromazine, no longer on the market) and Mellaril, is the earliest and most studied class of typical antipsychotics. Chlorpromazine and thioridazine were the first drugs marketed in the 1950s specifically for treating schizophrenia. When used in high doses (>2g/d), chlorpromazine can cause abnormal pigmentation of the eyelids, conjunctiva and cornea due to drug deposition, without affecting visual acuity. On the contrary, in rare cases, phenothiazines can induce phototoxic lysis of corneal endothelial cells, leading to corneal edema and severe, potentially irreversible visual impairment if the drug is not discontinued.
Lithium, a mood stabilizer used in the treatment of bipolar disorder, has been reported to cause eye irritation in the first few weeks of treatment because it might interfere with sodium-chloride transport and increase sodium content of the tear. Artificial tear supplements can be used to address the initial ocular symptoms.
The integrity of the ocular surface can be examined by gross observation of the lids and lashes with a penlight, followed by slit lamp examination of the conjunctiva and cornea for potential pigmentation or drug deposits. If the lid margins are inflamed and the meibomian glands are clogged, the tear film is most likely unstable; this can be confirmed via tear break-up time or Schirmer’s test. Lately, the TearLab Osmolarity System (TearLab Corp.) has been used to measure tear osmolarity (>308 mOsms/L) as a quantitative indicator of dry eye.
Uvea: Iris, ciliary body, choroid
The iris, ciliary body and choroid make up the uvea, a middle layer of the eye with rich vascular networks. The iris consists of two different types of muscles: a radial or dilator muscle innervated via the sympathetic nervous system and a sphincter muscle innervated by the parasympathetic nervous system.
The dilator muscle has adrenergic receptors and can be stimulated by adrenergic agonists such as noradrenaline or phenylephrine, whereas the sphincter muscle has cholinergic receptors and responds to cholinergic agonists such as acetylcholine or pilocarpine. Similar to the sphincter muscle, the ciliary body consists of ciliary processes and smooth muscle that is under cholinergic innervation. Therefore, cholinergic antagonists such as cyclopentolate, homatropine and atropine can induce mydriasis and cycloplegia by blocking the muscarinic receptors in the iris sphincter and ciliary body.
A number of psychotropic drugs affect the iris and ciliary body via identical mechanisms secondary to cross-reactive anticholinergic properties. The choroid is the vascular layer lying between the retina and sclera. It receives blood from the ophthalmic artery to supply oxygen and nutrients to the outer retina.
Tricyclic antidepressants (TCAs) such as Tofranil (imipramine, Mallinckrodt) and nortriptyline (Pamelor) were marketed in the 1960s for treatment of depression. TCAs are no longer first-line drugs for depression, having been replaced by selective serotonin reuptake inhibitors (SSRIs); however, they are still being used for depression that is not relieved by other treatments. In addition, TCAs are used off label for chronic pain, neuropathic pain, fibromyalgia and migraine prophylaxis.
Mydriasis and cycloplegia are the two most common ocular side effects of TCAs because of their anticholinergic actions on the pupil and ciliary body. Additionally, TCAs may block noradrenaline uptake, leading to stimulation of the dilator muscle of the iris. These effects usually subside with time; therefore, temporary treatment with 0.5% pilocarpine may counteract the effects, and tinted glasses or photochromic lenses may mitigate the symptoms.
Celexa (citalopram hydrobromide, Forest), Lexapro (escitalopram oxilate, Forest), Prozac (fluoxetine, Lilly), Paxil (paroxetine HCl, GlaxoSmithKline) and Zoloft (sertraline, Roerig) are amongst the most commonly prescribed SSRIs.
Another group of related drugs, Cymbalta (duloxetine HCl, Lilly), Effexor XR (venlafaxine extended release, Wyeth) and Pristiq (desvenlafaxine, Wyeth) are able to inhibit not only serotonin, but also norepinephrine reuptake; thus, they are known as serotonin and norepinephrine reuptake inhibitors (SNRIs). Most antidepressants work by modulating the levels of serotonin and/or norepinephrine neurotransmitters. Millions of patients are taking these drugs daily for depression; for example, the sales of Cymbalta were approximately $4.72 billion in 2012 in the U.S., according to IMS Health.
Potential ocular adverse effects for this popular group of drugs include mydriasis, increased intraocular pressure and oculogyric crisis (rotating of eyeballs). Seven families of serotonin receptors (5HT1 to 5HT7) have been classified and characterized, with various subtypes within each family.
In the eye, 5HT1A, 2A, 2C and 5HT7 have roles in the regulation of aqueous humor production and IOP. 5HT7 in the iris may relax the sphincter and result in mydriasis. Additionally, cross-adrenergic action can also stimulate the dilator muscle.
In 2002, Schmitt and colleagues reported Zoloft and Celexa induced maximal increase in pupil diameter 5 hours after administration, and the effect lingered over 2 weeks of treatment. Additionally, these drugs also cause a critical flicker fusion threshold, suggesting some sedative effects on the central nervous system.
Topamax (topiramate, Janssen), a sulfa-based drug, was originally approved in 1996 as an anticonvulsant. Since then it has been used to prevent migraine, treat bipolar disorders and reduce binge eating. In late 2012, Qsymia (phenteramine and topiramate, Catalent), was approved as a combination drug with Adipex-P (phenteramine HCl, Gate Pharmaceuticals) for weight loss. This is a notorious drug that most eye care professionals probably have heard of at least once either during optometric training or continuing education. Topiramate is unique in that it can cause acute angle closure bilaterally. Additionally it can induce acute myopia of up to 8.75 D. The mechanism for these drastic ocular effects is unclear, but a few postulations have been made including idiosyncratic swelling of the ciliary body, forward rotation of the lens and intense spasm of accommodation. Fortunately, these effects are transient and reversible if the drug is discontinued early.
Antipsychotics, such as chlorpromazine and Prolixin (fluphenazine HCl, Bristol-Myers Squibb), have strong anticholinergic actions and also lead to mydriasis and cycloplegia.
The best way to examine the pupil is via penlight to measure its response and size in bright and dim settings. Near visual acuity and accommodative amplitude can be used to evaluate the status of accommodation. Moreover, mydriatic effects of these drugs can induce night vision complaints that could adversely affect driving ability, so a diluted or low dose of pilocarpine may be applied to see if it solves the night vision complaint. Alternatively, tinted and polarized glasses such as Drivewear (Transitions) may be useful for driving.
Tonometry and gonioscopy can be used, respectively, to measure the eye pressure and evaluate the openness of the angle to assure that the angles are not blocked. Furthermore, acute and dramatic myopia shift can be confirmed with refraction, but prompt changes in spectacle prescription are not necessary because the effects are transient, similar to myopic shift in patients with diabetes and fluctuating blood sugar levels.
Fundus photo of the left eye of a 38-year-old male who has been treated for schizophrenia with multiple psychotropic medications for more than a decade. His visual acuity was correctable
to 20/20 at the initial visit, but fundus exam revealed pigmentary maculopathy. Comanagement
was established with his psychiatrist, and his eyes have been examined yearly for the past few
years without progression.
Image: Hua LV
Intraocular pressure
IOP is determined by two main processes, inflow or production by the ciliary body and outflow through trabecular or uveoscleral outflow. As discussed so far, numerous psychotropic drugs affect the pupils and ciliary body so they can modulate both aqueous inflow and outflow of the eye. Although daily fluctuations of IOP per se may not lead to optic nerve damage, drug-induced significant increase in IOP could put persistent stress on the nerve fibers, leading to optic neuropathy.
The drug that is well known for inducing a drastic change in IOP, not just unilaterally, is topiramate. As mentioned previously, it is a sulfa-based antiepileptic drug with multiple indications including migraine, bipolar disorder and weight loss. More than 100 cases of topiramate-induced angle closures have been reported to date, the majority of them occurring bilaterally and within the first 2 weeks of drug administration, with blurry vision as the most common initial symptom secondary to myopia and/or angle closure.
Because topiramate is a sulfa-based drug, allergic reaction has been proposed as a possible mechanism leading to swelling of the lens and the ciliary body. Whenever this drug is suspected as the cause of increased IOP, the patient must be treated with maximum medical therapy such as Combigan (brimonidine tartrate and timolol maleate, Allergan) or Simbrinza (brinzolamide and brimonidine tartrate, Alcon); a prostaglandin analog, such as Lumigan (bimatoprost, Allergan), Travatan Z (travoprost, Alcon) or Xalatan (latanoprost, Pfizer); and possibly oral Diamox (acetazolamide, Duramed). Pilocarpine is not recommended because it may cause pupillary block. Additionally, immediate consultation with the prescriber is necessary to identify an effective substitute. Fortunately, the ocular adverse effect of Topamax is so transient that the ocular anatomy and physiology return to normal within hours to days of discontinuation.
SSRIs and SNRIs are amongst the most commonly prescribed drugs in the U.S. market for treatment of depression. They may increase IOP because of their effects on serotonin neurotransmitters because serotonin can stimulate 5HT2A and 5HT2C receptors in the ciliary body to increase aqueous humor production. Additionally, they can increase norepinephrine neurotransmitter in the synapse to stimulate pupil dilation.
A recent review of the literature identified multiple reports of SSRI-induced IOP changes; for examples, six were caused by Paxil and two were caused by Celexa. Although SSRIs have been implicated as potential IOP-inducing drugs, the effect is usually mild and asymptomatic and most likely under-reported. Therefore, it is important for eye care providers to be alert about this potential adverse ocular side effect, especially when patients with risk factors for angle closure are taking this popular antidepressant.
Goldmann applannation tonometry (GAT) still remains the gold standard for measuring IOP, so it should be used to examine potential drug-induced changes. It is important to note that this tonometer needs to be calibrated monthly or at least quarterly to ensure its continual accuracy. A recent survey from the U.K. of 100 ophthalmology residents found that only 30% of the residents felt that the doctors were responsible for regular calibration prior to use. Here is a YouTube link on how to calibrate for GAT (http://www.youtube.com/watch?v=uQpnbZ_97uk). Furthermore, gonioscopy can be helpful to check the openness of the angle when narrow angle is suspected.
One caveat regarding drug-induced changes in pupil size and possibly IOP is that package inserts for many drugs have contraindications, warnings or precautions stating that the drug should not be used in patients with narrow angle or glaucoma. For example, one of the warnings on the package insert for Benadryl (diphenhydramine, McNeil), a common over-the-counter allergy medication, is to ask a doctor before use if you have glaucoma, so primary eye care providers must be ready to answer this common question.
A useful online resource for U.S. Food and Drug Administration drug labels or package inserts is DailyMed (http://dailymed.nlm.nih.gov/dailymed/about.cfm). It provides high-quality information about marketed drugs via user-friendly search features. These drugs are safe most of the time, even for patients with glaucoma, but a few of the drugs may increase IOP substantially in some patients, especially those with higher risk factors for acute angle closure. These risk factors include narrow angle, shallow anterior chamber depth, hyperopia and advanced age.
One practical approach to confirm whether the drug significantly increases IOP or risk of glaucoma is to have the patient come in for an IOP check a few hours after taking the medication. If the pupil size and IOP are increased significantly, gonioscopy can be performed to confirm the openness of the angle, and an IOP reducing drop may be given in-office to control the pressure. If the angle is chronically narrow, the patient may benefit from a prophylactic laser peripheral iridotomy.
Additionally, for patients with risk factors of angle closure, more frequent follow-ups for IOP check are warranted when they are taking medications that affect the pupils and ciliary body. Furthermore, these patients should be educated about the signs and symptoms of acute angle closure, including sudden onset of eye pain, brow pain, headache, photophobia, cloudy vision, nausea and red eye, and instructed to return to the clinic promptly.
Lens
The lens is divided into three layers, the capsule, the cortex and the nucleus, within which drugs can deposit or interact, leading to lens opacities or cataracts. Despite the advances in surgery, cataracts still remain the leading cause of treatable blindness in the world. Common photosensitizing medications such as statins, tetracyclines, fluoroquinolones, retinoids, nonsteroidal anti-inflammatory drugs and antipsychotic phenothiazines can render denaturation of lens protein, forming opacities.
The only class of psychotropic drugs that can cause lens opacities or cataracts is phenothiazine, particularly chlorpromazine and thioridazine. Studies performed in the 1960s when these drugs were used widely found that high doses (>800 mg/d) for long durations (>2 years) led to pigmentary deposits in not just the lens but also the cornea in more than 50% of the patients.
Fortunately, these drugs have been replaced by newer and safer atypical antipsychotics such as Risperdal (risperidone, Janssen) and Abilify. However, generic versions of phenothiazines are still being used for patients who do not respond to other therapy. Furthermore, thioridazine has received some recent attention for its ability to treat resistant tuberculosis and selectively kill cancer cells, so it may make a comeback and deserves close attention because ocular damages by phenothiazines are usually permanent. Preventive measures to mitigate ocular adverse effects of photosensitizing drugs include using the lowest effective dose, avoiding direct sun exposure and wearing sunglasses.
Evaluation of the cornea and especially the lens is best done via slit lamp examination after pupil dilation. Additionally, brightness acuity test can be used to assess the effect of glare on vision.
Retina
The retina is made up of multiple layers of non-neuronal cells such as astrocytes, microglia and Muller cells and neuronal cells such as photoreceptors, bipolar cells and ganglion cells. The retina lines the inner surface of the eye and is a true derivative of the brain with a unique ability to absorb and convert light into digital signals for visual perception. This thin 200 um to 250 um layer of transparent nervous tissue has a high metabolic rate and is vulnerable to systemic medications that often reach the eye first due to its high blood supply. Retinal pigmentation and degeneration are the most commonly seen adverse ocular effects of systemic medications.
Phenothiazines, particularly thioridazine and chlorpromazine, have been widely publicized since the 1960s as causing pigmentary retinopathy. The pigmentary deposits begin gradually in the peripheral retina before encroaching onto the central retina, leading to initial peripheral vision loss and night vision loss. If these drugs are not discontinued in time, irreversible central scotoma and eventual total blindness would ensue.
Most of the cases in the literature attributed severe pigmentary retinopathy more to thioridazine (>800 mg/d) and less to chlorpromazine (>800 mg/d). The onset of pigmentary retinopathy could be evident within weeks of high-dose therapy, followed soon thereafter with retinal degeneration or atrophy. Therefore, it is important to detect the signs and symptoms of ocular toxicity early in these patients to save sight.
Sabril (vigabatrin, Pantheon), a structural analog of GABA, is an anticonvulsant drug used as an adjunctive treatment for resistant epilepsy and a monotherapy in infantile spasms. Viagabatrin is associated with concentric visual field loss in up to 40% of patients and retinal atrophy in children. Additionally, it has been reported to cause impairment in color discrimination based on Farnsworth-Munsell 100 (FM 100) Hue Test in up to 33% of patients. Therefore, visual field testing is recommended at the start of treatment and regularly thereafter.
The approach to monitor and manage potential pigmentary retinopathy secondary to psychotropic drugs is similar to the recommendations on screening for Aralen (chloroquine, Sanofi-Aventis) and Plaquenil retinopathy. The 2011 updates recommended a baseline examination prior to drug administration, a 10-2 automated visual field plus multifocal electroretinogram (mfERG), spectral domain optical coherence topography or fundus autofluorescence (FAF). Amsler grid testing was no longer recommended because it is relatively insensitive to early changes.
For phenothiazines and vigabatrin, a 30-2 visual field may be more informative to check for more peripheral field loss, while a 10-2 field can also be done when central defect is found. Color vision testing with FM 100 hue or Farnsworth D15 is useful for vigabatrin. Not many practicing clinicians have access to mfERG or FAF at the moment, so SD-OCT is the better option in conjunction with visual field and color vision testing and, of course, color fundus photography. Additionally, patients on phenothiazines may need to be monitored more closely, at least semi-annually for the first few years.
Ocular motility
Oculogyric crisis (rotating of eyeballs) has been seen with the use of SSRI antidepressants. Chlorpromazine has also been shown to induce oculogyric crisis in about 2% of patients taking it for more than 5 months. Palinopsia is a visual symptom of seeing the same image persistently. Desyrel (trazodone, Bristol-Myers Squibb), an antidepressant chemically unrelated to other known antidepressants, has been reported to induce palinopsia in a few cases. Downbeat nystagmus has been implicated in a few mood stabilizing medications such as Eskalith (lithium carbonate, GlaxoSmithKline), Tegretol (carbamazepine, Novartis) and Lamictal (lamotrigine, DSM). On the contrary, Klonopin (clonazepam, Genentech), a benzodiazepine, was effective in the treatment of idiopathic downbeat nystagmus.
These are only a few examples of possible ocular motility anomalies induced by psychotropic substances. A thorough medication history including questions on alternative medicine and recreational use followed by ocular motility examination can identify more drug-induced oculomotor anomalies, including diplopia.
Psychotropic drugs are among the most commonly prescribed medications in the U.S. market, and many of our patients are taking them for behavioral problems or recreation. Moreover, more and more of these medications are prescribed to younger and younger patient populations. Furthermore, psychiatrists usually may not have time to put a high priority on the potential adverse effects on the eye when it comes to prescribing these medications. Primary care providers also prescribe psychotropic drugs for many patients, and there is an ongoing movement to get clinical psychologists to have prescribing privilege. Currently, clinical psychologists in New Mexico and Louisiana and in the U.S. military have prescribing privileges. Therefore, many psychotropic drugs are being used, even excluding recreational use or abuse.
As primary eye care providers, optometrists are often the first health care entry point for many of these patients, so a little more attention to the medications they take may reveal a potential drug-induced sight-threatening problem to which optometrists can alert the prescriber. Optometrists may not need to know all the potential ocular adverse effects of systemic medications, but one should know when to suspect and where to look for more information and report any suspicion via MedWatch (http://www.fda.gov/Safety/MedWatch/default.htm). The National Registry of Drug-Induced Ocular Side Effects (http://www.eyedrugregistry.com/) would be a useful resource for all health care providers and patients, but the American Academy of Ophthalmology restricts access to its members.
More psychotropic drugs will be developed, approved and marketed in the future, and more patients, including younger ones, will take them. Further, some old psychotropic drugs will have new indications or off-label uses, so the best way to have a better handle on this topic is to note the medication history and always be on alert to include adverse effects of systemic medications as potential ocular differential diagnoses.
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Disclosures: Hua has no relevant financial disclosures.