Antidepressant Withdrawal Syndrome and DUI Evaluation

Antidepressant Withdrawal Syndrome and DUI Evaluation

By Henry Spiller, MS, DABAT, FACFEI, DABFE, and Tama S. Sawyer, PharmD, CSPI

Key Words: withdrawal syndrome, DUI, selective serotonin reuptake inhibitor

Abstract

Millions of Americans annually receive selective serotonin reuptake inhibitor antidepressants and dual-action antidepressants for their symptoms of depression. These patients are at risk for a well-documented withdrawal syndrome if they abruptly stop their medication. This withdrawal syndrome may produce significant effects that may impair a person’s ability to drive, putting at risk both the driver and others on the road. In a situation of the antidepressant withdrawal syndrome, the impairment is due to the absence of drugs in the patient, producing the paradox of a potentially impaired driver because of an absence of the influence of a drug. This article reviews the antidepressant withdrawal syndrome and describes the effects on cognition, memory, vision, and motor performance and reviews how these clinical effects might be misinterpreted using standardized field sobriety tests suggesting the patient is intoxicated in the absence of other drugs or alcohol.

THE FORENSIC EXAMINER Fall 2007

This article is approved by the following for continuing education credit:

(ACFEI) The American College of Forensic Examiners International provides this continuing education credit for Diplomates.

(CFC) The American College of Forensic Examiners International provides this continuing education credit for Certified Forensic Consultants.

The American College of Forensic Examiners International is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). The American College of Forensic Examiners International designates this educational activity for a maximum of 1 hour AMA PRA Category 1 Credits™.. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Introduction

Worldwide use of antidepressants has increased dramatically in the past decade (Berndt, Bhattacharjya, Mishol, Arcelus, & Lasky, 2002; Ciuna et al., 2004; Helgason, Tomasson, & Zoega, 2004; Hemels, Koren, & Einarson, 2002). Use of antidepressants may range from 26 to 72 defined daily doses per 1000 people, depending on the country (Ciuna et al.; Helgason et al.; Hemels et al.). The estimated range of Americans using antidepressants is from 7 to 18 million patients annually. Of the various classes of antidepressants available, the Selective Serotonin Reuptake Inhibitors (SSRI) and Dual Action Antidepressants (DAA), involving serotonin and norepinephrine reuptake inhibition, make up more than 75% of the prescriptions filled for antidepressants (Berndt et al.; Hemels et al.). Additionally, use of SSRIs and DAAs has increased more than 600% in the last 10 years (Ciuna et al.). While the drugs in these two classes have proven to be generally safe and effective, studies have documented a problem with the effects of withdrawal (Stahl et al., 1997).

Though symptoms from withdrawal are diverse, all include effects on cognition (impaired concentration and/or confusion) and motor performance (impaired coordination, loss of balance). (See Table 2 for a complete list of the clinical effects reported with withdrawal syndrome associated with the SSRI and DAA drugs.) These withdrawal effects may put patients at risk of impaired driving in the absence of other drugs or alcohol. While this is a potentially serious problem for both the patient/driver and others on the road, it has not been previously explored in the literature. This article describes the withdrawal syndrome associated with the SSRI and DAA drugs including clinical effects, with a focus on the potential effects these drugs may have on driving. Additionally, this article includes a discussion on the impact antidepressant withdrawal syndrome might have on field evaluation of a driver with tests such as the standard field sobriety test.
Antidepressant Withdrawal syndrome

Several groups of antidepressants, including the tricyclic antidepressants, the tetracyclic antidepressants, the SSRIs, the DAAs, and newer antidepressants such as mirtazapine (Remeron), may produce a withdrawal syndrome (Benazzi, 1998a; Coupland, Bell, & Potokar, 1996; Dilsaver, Kronfol, Sackellares, & Greden, 1983; Hindmarch, Kimber, & Cockle, 2000; Rosenbaum, Fava, Hoog, Ascroft, & Krebs, 1998). However, the withdrawal syndrome produced by the SSRIs and the DAAs is clinically different from that produced by the classic tricyclic antidepressants (Lejoyeux, Ades, Mourad, Solomon, & Dilsaver, 1996; Stahl et al., 1997). The withdrawal syndrome from the tricyclic and tetracyclic antidepressants is primarily a cholinergic syndrome with symptoms such as nausea, vomiting, anorexia, diarrhea, rhinorrhea (runny nose), diaphoresis (excessive sweating), myalgias (muscle pain), increased anxiety, agitation, and sleep disturbances (Dilsaver, 1994; Dilsaver et al.). In contrast, the withdrawal syndrome from the SSRIs and DAAs is primarily a serotonergic syndrome, with symptoms such as dizziness, lethargy, impaired concentration, electric-like shock sensations, impaired coordination, blurred vision, and sleep disturbances (see Table 2). This article discusses the impact of the serotonin-related antidepressants. The SSRI and DAA drugs that may produce a withdrawal syndrome are listed in Table 1. The syndrome may be seen in a substantial minority of patients taking these drugs—up to 25% (Coupland et al.; Michelson et al., 2000; Rosenbaum et al., 1998).

A brief understanding of the mechanism(s) of action of these drugs will improve the understanding of the withdrawal syndrome. The selective serotonin reuptake inhibitor class includes 6 drugs that are widely available. (See Table 1 for a list of drugs in this class with associated pharmacokinetic information.) These drugs inhibit the human serotonin transporter, inhibiting re-uptake of serotonin into presynaptic neurons (Schmidt, Fuller, & Wond, 1988). This allows for persistence of serotonin in the neuronal synapse and increased serotonergic neuron transmission. In effect, it increases activity on the pathways of the brain that use serotonin as the neurotransmitter. Chronic use has been shown to cause reduced serotonin transporter density, maintenance of normal cell-firing rates, and increased activation of post-synaptic firing.

The SSRIs produce little or no clinically significant activity on dopamine, norepinephrine, histamine, or acetylcholine receptors, or re-uptake transporters. The DAAs inhibit both the human serotonin transporter and the human norepinephrine transporter, inhibiting re-uptake of both serotonin and norepinephrine. The end result of the actions of both these classes of drugs is increased nerve transmission in select areas of the brain because of prolonged duration of neurotransmitters in the synapse. The sudden withdrawal of these drugs produces a sudden decrease in serotonin transmission due to reduced persistence of the neurotransmitter in the synaptic cleft (Zajecka, Tracey, & Mitchell, 1997). In effect, it produces a reduction of activity in some areas of the brain controlled by serotonin in the case of SSRIs and by serotonin and norepinephrine in the case of the DAAs.

It is this sudden decrease in activity that is responsible for the effects seen in these patients. If the decrease is of sufficient magnitude, an antidepressant withdrawal syndrome will occur. The dosage range of these drugs varies, with as much as a five-fold difference in some of the drugs between the lower and upper range of the therapeutic dose. (See table 1.) Any decrease that significantly effects serotonin transmission may produce a withdrawal syndrome. The withdrawal syndrome is transitory but may persist for days to weeks as the brain adjusts to new levels of activity on these neuronal pathways. Additionally, the syndrome may be reversed by restarting the antidepressant therapy. The true incidence of the withdrawal syndrome is unclear, with reports suggesting that 3%–30% of patients experience some form of the syndrome (Coupland et al., 1996; Oehrberg et al., 1995; Stahl et al., 1997).

The most frequently reported symptoms from the serotonin antidepressant withdrawal syndrome are dizziness, altered balance, lethargy, parathesias (numbness, tingling feeling, electric shock-like sensations), nausea, behavioral changes, and sleep disturbances. The clinical effects that can occur with the antidepressant withdrawal syndrome are diverse, and a broader list is provided in Table 2. It should be noted that the syndrome is varied from patient to patient—from mild to severe—and not all symptoms will be seen in every patient.

Criteria for diagnosis of antidepressant withdrawal syndrome vary, but generally include sudden discontinuance or reduction of dosage of an SSRI or DAA after a period of at least 1 month of use, two or more symptoms from Table 2, and symptoms not triggered by a general medical condition or other recognized cause (Black, Shea, Dursun, & Kutcher, 2000; Ditto, 2003). The onset of symptoms may be interpreted as a return of psychiatric symptoms (Benazzi, 1998b). Additionally, it may be interpreted by the patient as the onset of a flu-like syndrome (nausea, fatigue/lethargy, dizziness) along with return of depression (behavioral changes and sleep disturbances). The symptoms may be sufficiently severe to interrupt activities of daily living, such as going to work or driving a car, and patients should be warned about the dangers of operating a motor vehicle if they begin experiencing moderate to severe withdrawal symptoms. In some cases, the symptoms may be severe enough for the patients to recognize they should not drive (Campagne, 2005). However, in other cases, the patients may not recognize the degree of impairment and attempt to continue with their daily lives including commitments to work, school, or other outside commitments.

Patients may have an interruption in their medication for a number of reasons. They might miss one or several days of therapy due to non-compliance (“drug holiday”) (Hylan, Dunn, Tepner, & Meurgey, 1998) or there may be an interruption in the patients’ medication supply due to travel, lack of access to a pharmacy, or inability to pay (Campagne, 2005). In some cases, the patient will suddenly stop taking the medication due to perceived problems with the side effects of the medication itself (Leiter, Nierenberg, Sanders, & Stern, 1995).

Symptoms of the SSRI and DDA withdrawal syndrome may occur from as early as 12 hours after a missed dose and up to 3 weeks after discontinuance, although the average time of onset of symptoms is 1 to 3 days (Campagne, 2005; Zajecka et al., 1997). One factor impacting the onset of symptoms is the half-life of the drug involved, which can vary significantly depending on the drug involved (Michelson et al., 2000) (See Table 1).

Withdrawal Syndrome and Driving

Generally speaking, impaired driving (driving while intoxicated) is considered secondary to the effects of drugs or alcohol while these substances are in the patient and producing a direct effect on cognition, attention, motor control, and reaction time. However, in the situation of the antidepressant withdrawal syndrome, the impairment is due to the absence of drugs in the patient. This produces the paradox of a potentially impaired driver that is not under the influence of any drugs or alcohol. While there may be significant impairment, the term driving under the influence may be an inappropriate term for these cases.

There are a number of symptoms of the withdrawal syndrome that could potentially cause a patient to operate a motor vehicle in a manner that might be interpreted as operating under the influence of alcohol or drugs. These symptoms include visual disturbances, dizziness/vertigo, impaired coordination, tremors, confusion, impaired concentration, and jerking eye movements that cause difficulty with tracking and memory impairment. These clinical effects might produce an altered driving pattern, including weaving, erratic speed and erratic lane changes, which might be interpreted as driving while intoxicated. Additionally, if the vehicle were stopped for possible impaired driving and the patient evaluated, there are a number of symptoms that might be interpreted as the patient being under the influence of drugs or alcohol. These symptoms include confusion, agitated behavior, distracted affect if the patient is experiencing repeated sensations of electric shocks, an unsteady gait, and inattention to questions because of inability to hear on account of tinnitus.

Withdrawal Syndrome and the Standard Field Sobriety Test

When a police officer stops a driver for suspicion of impaired driving, the most common procedure is to have the driver perform a field sobriety test. The National Highway Traffic and Safety Administration (NHTSA) has validated three tests that have become generally recognized as the Standardized Field Sobriety Test (Tharp, Burns, & Moskowitz, 1981). These three tests are the Walk and Turn (WAT), Horizontal Gaze Nystagmus (HGN), and One Leg Stand (OLS). However, other tests may be performed at the discretion of the police officer or local jurisdiction such as asking the driver to count backwards from a certain number and to stop at a certain number (e.g. count down from 55 to 18) or to recite the alphabet beginning at a particular letter and ending at a particular letter (e.g., beginning at F and ending at R). These latter tests have not been validated by NHTSA.

In the course of administering the WAT, the subject is given oral instructions to take nine steps heel-to-toe along a straight line. After taking nine steps the subject must execute a one-foot turn and return in the same manner in the opposite direction. There are 7 indicators of impairment for which the police officer is instructed to watch to indicate successful completion or failure of the test: 1) subject cannot maintain balance while listening to instructions, 2) subject begins test before instructions are complete, 3) subject stops to regain balance while walking, 4) subject does not touch heel-to-toe, 5) subject uses arms to maintain balance, 6) subject loses balance during turn, and 7) subject takes incorrect number of steps. In a patient experiencing antidepressant withdrawal syndrome, there are a number of symptoms that would cause them to fail the WAT test, even in the absence of intoxicants. The most important of these are gait instability, dizziness/vertigo, lack of coordination, and loss of balance. Additionally, such symptoms as confusion, impaired concentration, and short-term memory impairment might cause the patient to fail by beginning too soon, failing to take the correct number of steps, or failing to walk heel-to-toe on the return walk.

In the course of administering the HGN, the subject is instructed to focus on an object 12 to 15 inches in front of his or her face as the object is moved horizontally to the left and right. The police officer is instructed to watch for smooth pursuit, nystagmus before onset of 45 degrees, distinct nystagmus at maximal deviation, and head movements and/or jerks. A patient experiencing antidepressant withdrawal syndrome might fail the HGN because of misinterpretation of already existing jerking eye movements and blurred vision.

In the course of administering the OLS, the subject is instructed to stand with one foot held approximately 6 inches off the ground and to count by thousands (e.g. one thousand one, one thousand two, etc.) until told to put the foot down. The subject is timed for 30 seconds. There are 4 indicators of impairment that the police officer is instructed to watch for to indicate successful completion or failure of the test: 1) swaying while balancing; 2) using arms to balance; 3) hopping to maintain balance; and 4) putting the raised foot down. There are numerous symptoms that could cause a patient experiencing antidepressant withdrawal syndrome to fail the OLS test, even in the absence of intoxicants. The most important of these are dizziness/vertigo, lack of coordination, and loss of balance.

Finally, the patient may be agitated and experiencing significant anxiety. The patient’s behavior may initially be interpreted by the police officer as a refusal to obey commands during the initial evaluation or during one of the SFSTs. In either case, refusal may be interpreted as reason to suspect intoxication.

It should be noted that the primary role of field sobriety tests is to give the police officer a reasonably accurate tool to determine if intoxication might be suspected and if further verifiable documentation such as an alcohol breathalyzer test or blood alcohol test should be administered. The tests themselves should not be sufficient evidence of intoxication without clinical evidence such as a breathalyzer test or blood alcohol test. In the case of drug intoxication, field sobriety tests again are not sufficient evidence of intoxication without supporting evidence of a blood concentration of the suspected drug. Because of situations such as the antidepressant withdrawal syndrome, the field sobriety tests may provide misleading indications of intoxication when no intoxication has occurred.

Conclusion

Millions of Americans annually receive SSRIs and DAAs for their symptoms of depression. These patients are at risk for a well-documented withdrawal syndrome if they abruptly stop their medication. The antidepressant withdrawal syndrome may produce significant effects on cognition and motor performance. Further, these effects might be misinterpreted in the use of standardized field sobriety tests to suggest the patient is intoxicated in the absence of other drugs or alcohol.

References

Benazzi, F. (1998a). Mirtazapine withdrawal symptoms. Canadian Journal of Psychiatry, 43(5), 525.

Benazzi, F. (1998b). Sertraline discontinuation syndrome presenting with severe depression and compulsions. Biological Psychiatry, 43(12), 929–930.

Berndt, E. R., Bhattacharjya, A., Mishol, D. N., Arcelus, A., & Lasky, T. (2002). An analysis of the diffusion of new antidepressants: Variety, quality, and marketing efforts. Journal of Mental Health Policy and Economics, 5(1), 3–19.

Black, K., Shea, C., Dursun, S., & Kutcher, S. (2000). Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. Journal of Psychiatry and Neuroscience, 25(3), 255–261.

Campagne, D. M. (2005). Venlafaxine and serious withdrawal symptoms: Warning to drivers. Medscape General Medicine, 7(3), 22.

Ciuna, A., Andretta, M., Corbari, L., Levi, D., Mirandola, M., Sorio, A., et al. (2004). Are we going to increase the use of antidepressants up to that of benzodiazepines? European Journal of Clinical Pharmacology, 60(9), 629–634.

Coupland, N. J., Bell, C. J., & Potokar, J. P. (1996). Serotonin reuptake inhibitor withdrawal. Journal of Clinical Psychopharmacology, 16(5), 356–62.

Dilsaver, S. C. (1994). Withdrawal phenomena associated with antidepressant and antipsychotic agents. Drug Safety, 10(2), 103–114.

Dilsaver, S. C., Kronfol, Z., Sackellares, J. C., & Greden, J. F. (1983). Antidepressant withdrawal syndromes: Evidence supporting the cholinergic overdrive hypothesis. Journal of Clinical Psychopharmacology, 3(3), 157–164.

Ditto, K .E. (2003). SSRI discontinuance syndrome: Awareness as an approach to prevention. Postgrad Medicine, 114(2), 79–84.

Helgason, T., Tomasson, H., & Zoega, T. (2004). Antidepressants and public health in Iceland. Time series analysis of national data. British Journal of Psychiatry, 184(2), 157–162.

Hemels, M. E., Koren, G., & Einarson, T. R. (2002). Increased use of antidepressants in Canada 1991–2000. Annals of Pharmacotherapy, 36(9), 1375–1379.

Hindmarch, I., Kimber, S., & Cockle, S. M. (2000). Abrupt and brief discontinuation of antidepressant treatment: Effects on cognitive function and psychomotor performance. International Clinical Psychopharmacology, 15(6), 305–318.

Hylan, T. R., Dunn, R. L., Tepner, R. G., & Meurgey, F. (1998). Gaps in antidepressant prescribing in primary care in the United Kingdom. International Clinical Psychopharmacology, 13(6), 235–243.

Leiter, F. L., Nierenberg, A. A., Sanders, K. M., & Stern, T. A. (1995). Discontinuation reactions following sertraline. Biological Psychiatry, 38(10), 694–695.

Lejoyeux, M., Ades, J., Mourad, I., Solomon, J., & Dilsaver, S. (1996). Antidepressant withdrawal syndrome. Recognition, prevention and management. CNS Drugs, 5(4), 278–292.

Michelson, D., Fava, M., Amsterdam, J., Apter, J., Londborg, P., Tamura, R., et al. (2000). Interruption of selective serotonin reuptake inhibitor treatment: Double-blind placebo-controlled trial. British Journal of Psychiatry, 176(4), 363–368.

Oehrberg, S., Christiansen, P. E., Behnke, K., Borup, A. L., Severin, B., Soegaard, J., et al. (1995). Paroxetine in the treatment of panic disorder. British Journal of Psychiatry, 167(3), 374–397.

Rosenbaum, J. F., Fava, M., Hoog, S. L., Ascroft, R. C., & Krebs, W. B. (1998). Selective serotonin reuptake inhibitor discontinuation syndrome: A randomized clinical trial. Biological Psychiatry, 44(2), 77–87.

Schmidt, M. J., Fuller, R. W., & Wond, D. T. (1988). Fluoxetine, a highly selective serotonin reuptake inhibitor: A review of preclinical studies. British Journal of Psychiatry, 153(3), 40–46.

Stahl, M. M. S., Lindquist, M., Pettersson, M., Edwards, I. R., Sanderson, J. H., Taylor, N. F. A., et al. (1997). Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system. European Journal of Clinical Pharmacology, 53(3–4), 163–169.

Tharp, V., Burns, M., & Moskowitz, H. (1981). Development and field test of psychophysical tests for DWI arrest. (DOT HS 805–864). Washington, DC: U.S. Department of Transportation, NHTSA.

Young, A., & Haddad, P. (2000). Discontinuation symptoms and psychotropic drugs. Lancet, 355(9210), 1184.

Zajecka, J., Tracey, K. A., & Mitchell, S. (1997). Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. Journal of Clinical Psychiatry, 58(7), 291–297.

Henry A. Spiller, MS, DABAT, DABFE, FACFEI, is board certified in Toxicology and the Director of a certified regional poison center, with more than 20 years clinical experience. He has authored more than 180 toxicology related publications, including peer-reviewed medical/scientific journals, comprehensive toxicology textbooks, and scientific abstracts. He has more than a decade of experience in training toxicologists and specialists in poison information and has directed, as principal investigator, more than 35 multi-center national studies in toxicology. He has made toxicology-related presentations at scientific meetings in North America, South America, and Europe and has presented evidence as an expert in numerous state and federal courts on toxicology related subjects.

Tama Sawyer, PharmD, is a Certified Specialist in Poison Information with more than 20 years clinical experience at a regional poison center.

Fall 2007 THE FORENSIC EXAMINER

THE FORENSIC EXAMINER Fall 2007

Table 1: SSRI and DAA Medications

Generic Drug Name Brand Name Drug Class Elimination Half-life Starting Dose Dosing Range

Escitalopram

Citalopram

Fluoxetine

Fluvoxamine

Paroxetine

Sertraline

Duloxetine

Venalfaxine

Lexapro

Celexa

Prozac

Luvox

Paxil

Zoloft

Cymbalta

Effexor

SSRI

SSRI

SSRI

SSRI

SSRI

SSRI

DAA

DAA

22–32 hours

33–37 hours

70 hours

17–23 hours

15–22 hours

24–27 hours

11–16 hours

5 hours

10mg

20mg

20mg

50mg

10mg

50mg

20mg

75mg

10–20mg

20–60mg

20–60mg

50–300mg

10–50mg

50–200mg

20–60mg

75–375mg

Cognitive Impairment Effects

• Agitation
• Anxiety
• Confusion
• Depersonalization/detachment
• Electric shock-like sensations
• Impaired concentration
• Irritability
• Short-term memory impairment

(Table complied from references: Black, Shea, Durson, & Kutcher, 2000; Campagne, 2005; Coupland, Bell, & Potokar, 1996; Leiter, Nierenberg, Sanders, & Stern, 1995; Michelson et al., 2000; Rosenbaum, Fava, Hoog, Ascroft, & Krebs, 1998; Stahl et al., 1997; Young & Haddad, 2000; Zajecka, Tracey, & Mitchell, 1997)

Table 2: Clinical Effects Reported with Antidepressant Withdrawal Syndrome

Motor Impairment Effects

• Blurred vision
• Dizziness/lightheaded/vertigo
• Gait instability
• Incoordination or impaired coordination
• Jerking eye movements
• Loss of balance
• Tremor
• Visual disturbances

Other Effects

• Diarrhea
• Chills
• Headache
• Insomnia
• Myalgia
• Nausea/vomiting
• Parathesias
• Sleep disturbances
• Suicide thoughts or behavior
• Sweating
• Tinnitus (ringing in the ears)
• Vivid dreams or nightmares

Fall 2007 THE FORENSIC EXAMINER

THE FORENSIC EXAMINER Fall 2007 - published by Dr. Robert OBlock