Current Psychiatry

Discuss this article

Benzodiazepines are the mainstay of alcohol detoxification treatment, with extensive evidence supporting their efficacy and relative safety.¹ The risk of benzodiazepine-alcohol interaction, however, and psychomotor and cognitive impairments associated with benzodiazepine use may limit early rehabilitation efforts in hospitalized patients.² Cross-tolerance with alcohol also limits benzodiazepines’ potential benefit in outpatients with substance use disorders.

Adding anticonvulsants to acute benzodiazepine therapy has been shown to decrease alcohol withdrawal symptom severity, reduce seizure risk, and support recovery, particularly in patients with multiple alcohol withdrawal episodes. After detoxification, long-term anticonvulsant use may reduce relapse risk by decreasing post-cessation craving, without abuse liability.³

Although not all studies endorse adding anticonvulsants to benzodiazepines for managing alcohol withdrawal syndrome (AWS),⁴ we present 3 cases in which anticonvulsants were used successfully as adjuncts to lorazepam. Valproic acid, levetiracetam, and gabapentin offer advantages in acute and long-term therapy of alcohol dependence with efficacy in AWS, low abuse potential, benign safety profile, and mood-stabilizing properties.

Neurobiologic rationale

AWS manifests as a cluster of clinical symptoms including delirium tremens (DTs) and seizures (Table 1). Its pathophysiology can be explained by alcohol’s agonist effect on the gamma-aminobutyric acid (GABA) system and antagonist effect on the glutamatergic system (Table 2).⁵

Chronic alcohol intake leads to neuroadaptation in the brain in the form of down-regulation of GABA_A receptors and upregulation of N-methyl-D-aspartate receptors. During alcohol withdrawal, this neuroadaptation leads to a decrease in central GABA activity and an increase in glutamate activity, resulting in hyperexcitation, anxiety, and seizures.⁶

Little data exist regarding time to relapse after detoxification in alcohol-dependent patients. One theory—called “protracted withdrawal syndrome” (Table 1)—suggests that abstinent alcoholics return to drinking because of the same, but attenuated, neuroadaptations that trigger acute AWS.⁷

Advantages of adjunct therapy. Ntais et al⁸ evaluated benzodiazepines’ effectiveness and safety in treating AWS in a clinical review of 57 randomized, controlled trials totaling 4,051 patients. Benzodiazepines showed similar success rates as other drugs (relative risk [RR] 1.00) or anticonvulsants in particular (RR 0.88), as measured by changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment. Benzodiazepines also offered significant benefit for seizure control compared with nonanticonvulsants (RR 0.23), but less when compared with anti convulsants (RR 1.99).

Although the literature does not support anticonvulsant use for monotherapy in AWS, anticonvulsants show potential as adjunctive therapy. Valproic acid, levetiracetam, and gabapentin offer unique mechanisms of action (Table 3) and demonstrate advantages over benzodiazepine monotherapy for AWS. Adjunctive use of valproic acid,^8,9 levetiracetam,¹⁰ and gabapentin^11,12 in detoxification also has demonstrated efficacy in reducing risk of relapse and delaying relapse.

The neurobiologic rationale for using anticonvulsants in acute AWS is speculative, but these agents appear to:

• inhibit “kindling” (neuronal changes that may be associated with repeated intoxications)
• facilitate GABAergic mechanisms.⁹

Table 1

Alcohol withdrawal: Acute vs long-term symptoms

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

CASE REPORT 1: Valproic acid for alcohol overdose

After attempting suicide with an alcohol overdose, Ms. J, age 45, is transferred from the emergency room (ER) to our psychiatry consult service 10 hours after admission. Her symptoms include nausea, tremor, headaches, agitation, disorientation, and auditory hallucinations.

Medical history reveals 25 years of alcohol dependence, multiple hospitalizations for withdrawal, and many failed attempts to quit. Ms. J reports consuming an average of 16 drink equivalents (eg, 12 oz beers) daily but denies illicit drug use.

Lab values on admission include blood alcohol concentration (BAC) 290 mg/dL (0.29%), mean corpuscular volume (MCV) 96 fL, gamma-glutamyltransferase (GGT) 164 U/L, aspartate aminotransferase (AST) 43 U/L, alanine aminotransferase (ALT) 31 U/L, and alkaline phosphatase (ALP) 151 U/L. Urine drug screen, acetaminophen, salicylate, vitamin B1 (thiamine), B12 (cyanocobalamin), B9 (folate), and electrolytes (including magnesium) are normal.

We assess alcohol withdrawal severity using the CIWA-Ar (Click here to view/download a copy of this scale). Ms. J’s initial score is 17, indicating a risk of moderate alcohol withdrawal if untreated.

In the ER, Ms. J is placed on a symptom-triggered benzodiazepine detoxification protocol with lorazepam. We add IV valproic acid, 1,250 mg (based on 20 mg/kg body weight)¹³ divided into 2 doses over the first 24 hours, then maintain IV valproic acid at 500 mg twice daily (Table 4). Within 12 hours of starting combination therapy, Ms. J scores 7 on the CIWA-Ar—indicating mild withdrawal—with subsequent scores <5. She scores 0 with no residual withdrawal symptoms within 36 hours.

Ms. J requires lorazepam, 7 mg, during the 10 hours before valproic acid is added. She requires only 2 mg lorazepam over the next 3 days and reports no side effects related to IV valproic acid. At discharge, Ms. J begins extended-release oral valproic acid, 1,250 mg (based on 25 mg/kg body weight)¹³ once daily for 2 weeks, until she can obtain outpatient follow-up.

Table 4

Benzodiazepines and anticonvulsants for alcohol detoxification

Less lorazepam needed

Adjunctive anticonvulsants can reduce the amount of lorazepam required during detoxification.^14,15 Compared with benzodiazepine monotherapy, the advantages of combination therapy—particularly in outpatient alcohol withdrawal treatment and relapse prevention—include:

• minimal interaction with alcohol (avoiding increased psychomotor deficits, cognitive impairment, and intoxication)¹⁵
• lower abuse potential
• possible efficacy in mood stabilization before, during, and after withdrawal (Table 5).¹⁶

Given the risk of seizures during AWS, anticonvulsants seem to make empirical sense. One study reported a 1% incidence of withdrawal-related seizures in 545 alcohol-dependent inpatients treated with valproic acid.¹⁷ Another case series of 37 patients found no acute sequelae when valproic acid was used for AWS.¹⁸

Anticonvulsants such as valproic acid may reduce the frequency and severity of alcohol relapse, whereas benzodiazepines may increase relapse risk.¹⁹ During a 6-week trial, patients receiving valproic acid maintenance therapy had greater abstinence rates and improved drinking outcomes compared with detoxification-only groups.⁹

One disadvantage of valproic acid is potential hepatotoxicity, an important consideration in patients with liver damage. Fortunately, Ms. J’s AST and ALT values remained within normal limits during valproic acid treatment.

Table 5

Pharmacologic profiles of benzodiazepines vs 3 anticonvulsants

CASE REPORT 2: Levetiracetam for withdrawal seizures

Mr. H, age 42, presents to the ER after suffering a seizure. His medical history includes hypertension, alcohol dependence, and seizures during alcohol withdrawal. He denies a history of psychiatric illness, and his family history is unknown. He is noncompliant with hypertension treatment, which includes clonidine. Mr. H reports his usual alcohol consumption as a 6-pack of beer nightly during the week and a 12-pack nightly on weekends. He says his last drink was 4 days before admission.

Mr. H scores 19 on the CIWA-Ar, placing him at risk for moderate withdrawal. Head CT shows diffuse atrophy, without evidence of an acute intracranial process. BAC is zero on admission, and urine drug screen is negative. Amylase, lipase, and lactate dehydrogenase (LDH) levels suggest acute pancreatitis. AST is elevated to 131 U/L, ALT is elevated to 42 U/L, but MCV is within normal limits.

The psychiatric service is consulted on day 2 of admission, and we prescribe levetiracetam, 500 mg IV every 8 hours.²⁰ IV lorazepam also is available as needed: 1 mg every 8 hours for the first 2 days, then 1 mg every 12 hours for 2 days, then 1 mg every 24 hours. The patient’s CIWA-Ar score is 9 on days 2 and 3 of admission, followed by scores consistently between 2 and 3 after scheduled levetiracetam administration. Mr. H requires 3 mg of lorazepam the remainder of his hospitalization. He is discharged on day 7 with a CIWA-Ar score of 2, and reports no adverse effects related to levetiracetam. He leaves the hospital with a 2-week prescription for oral levetiracetam, 500 mg tid.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.

Discuss this article

Benzodiazepines are the mainstay of alcohol detoxification treatment, with extensive evidence supporting their efficacy and relative safety.¹ The risk of benzodiazepine-alcohol interaction, however, and psychomotor and cognitive impairments associated with benzodiazepine use may limit early rehabilitation efforts in hospitalized patients.² Cross-tolerance with alcohol also limits benzodiazepines’ potential benefit in outpatients with substance use disorders.

Adding anticonvulsants to acute benzodiazepine therapy has been shown to decrease alcohol withdrawal symptom severity, reduce seizure risk, and support recovery, particularly in patients with multiple alcohol withdrawal episodes. After detoxification, long-term anticonvulsant use may reduce relapse risk by decreasing post-cessation craving, without abuse liability.³

Although not all studies endorse adding anticonvulsants to benzodiazepines for managing alcohol withdrawal syndrome (AWS),⁴ we present 3 cases in which anticonvulsants were used successfully as adjuncts to lorazepam. Valproic acid, levetiracetam, and gabapentin offer advantages in acute and long-term therapy of alcohol dependence with efficacy in AWS, low abuse potential, benign safety profile, and mood-stabilizing properties.

Neurobiologic rationale

AWS manifests as a cluster of clinical symptoms including delirium tremens (DTs) and seizures (Table 1). Its pathophysiology can be explained by alcohol’s agonist effect on the gamma-aminobutyric acid (GABA) system and antagonist effect on the glutamatergic system (Table 2).⁵

Chronic alcohol intake leads to neuroadaptation in the brain in the form of down-regulation of GABA_A receptors and upregulation of N-methyl-D-aspartate receptors. During alcohol withdrawal, this neuroadaptation leads to a decrease in central GABA activity and an increase in glutamate activity, resulting in hyperexcitation, anxiety, and seizures.⁶

Little data exist regarding time to relapse after detoxification in alcohol-dependent patients. One theory—called “protracted withdrawal syndrome” (Table 1)—suggests that abstinent alcoholics return to drinking because of the same, but attenuated, neuroadaptations that trigger acute AWS.⁷

Advantages of adjunct therapy. Ntais et al⁸ evaluated benzodiazepines’ effectiveness and safety in treating AWS in a clinical review of 57 randomized, controlled trials totaling 4,051 patients. Benzodiazepines showed similar success rates as other drugs (relative risk [RR] 1.00) or anticonvulsants in particular (RR 0.88), as measured by changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment. Benzodiazepines also offered significant benefit for seizure control compared with nonanticonvulsants (RR 0.23), but less when compared with anti convulsants (RR 1.99).

Although the literature does not support anticonvulsant use for monotherapy in AWS, anticonvulsants show potential as adjunctive therapy. Valproic acid, levetiracetam, and gabapentin offer unique mechanisms of action (Table 3) and demonstrate advantages over benzodiazepine monotherapy for AWS. Adjunctive use of valproic acid,^8,9 levetiracetam,¹⁰ and gabapentin^11,12 in detoxification also has demonstrated efficacy in reducing risk of relapse and delaying relapse.

The neurobiologic rationale for using anticonvulsants in acute AWS is speculative, but these agents appear to:

• inhibit “kindling” (neuronal changes that may be associated with repeated intoxications)
• facilitate GABAergic mechanisms.⁹

Table 1

Alcohol withdrawal: Acute vs long-term symptoms

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

CASE REPORT 1: Valproic acid for alcohol overdose

After attempting suicide with an alcohol overdose, Ms. J, age 45, is transferred from the emergency room (ER) to our psychiatry consult service 10 hours after admission. Her symptoms include nausea, tremor, headaches, agitation, disorientation, and auditory hallucinations.

Medical history reveals 25 years of alcohol dependence, multiple hospitalizations for withdrawal, and many failed attempts to quit. Ms. J reports consuming an average of 16 drink equivalents (eg, 12 oz beers) daily but denies illicit drug use.

Lab values on admission include blood alcohol concentration (BAC) 290 mg/dL (0.29%), mean corpuscular volume (MCV) 96 fL, gamma-glutamyltransferase (GGT) 164 U/L, aspartate aminotransferase (AST) 43 U/L, alanine aminotransferase (ALT) 31 U/L, and alkaline phosphatase (ALP) 151 U/L. Urine drug screen, acetaminophen, salicylate, vitamin B1 (thiamine), B12 (cyanocobalamin), B9 (folate), and electrolytes (including magnesium) are normal.

We assess alcohol withdrawal severity using the CIWA-Ar (Click here to view/download a copy of this scale). Ms. J’s initial score is 17, indicating a risk of moderate alcohol withdrawal if untreated.

In the ER, Ms. J is placed on a symptom-triggered benzodiazepine detoxification protocol with lorazepam. We add IV valproic acid, 1,250 mg (based on 20 mg/kg body weight)¹³ divided into 2 doses over the first 24 hours, then maintain IV valproic acid at 500 mg twice daily (Table 4). Within 12 hours of starting combination therapy, Ms. J scores 7 on the CIWA-Ar—indicating mild withdrawal—with subsequent scores <5. She scores 0 with no residual withdrawal symptoms within 36 hours.

Ms. J requires lorazepam, 7 mg, during the 10 hours before valproic acid is added. She requires only 2 mg lorazepam over the next 3 days and reports no side effects related to IV valproic acid. At discharge, Ms. J begins extended-release oral valproic acid, 1,250 mg (based on 25 mg/kg body weight)¹³ once daily for 2 weeks, until she can obtain outpatient follow-up.

Table 4

Benzodiazepines and anticonvulsants for alcohol detoxification

Less lorazepam needed

Adjunctive anticonvulsants can reduce the amount of lorazepam required during detoxification.^14,15 Compared with benzodiazepine monotherapy, the advantages of combination therapy—particularly in outpatient alcohol withdrawal treatment and relapse prevention—include:

• minimal interaction with alcohol (avoiding increased psychomotor deficits, cognitive impairment, and intoxication)¹⁵
• lower abuse potential
• possible efficacy in mood stabilization before, during, and after withdrawal (Table 5).¹⁶

Given the risk of seizures during AWS, anticonvulsants seem to make empirical sense. One study reported a 1% incidence of withdrawal-related seizures in 545 alcohol-dependent inpatients treated with valproic acid.¹⁷ Another case series of 37 patients found no acute sequelae when valproic acid was used for AWS.¹⁸

Anticonvulsants such as valproic acid may reduce the frequency and severity of alcohol relapse, whereas benzodiazepines may increase relapse risk.¹⁹ During a 6-week trial, patients receiving valproic acid maintenance therapy had greater abstinence rates and improved drinking outcomes compared with detoxification-only groups.⁹

One disadvantage of valproic acid is potential hepatotoxicity, an important consideration in patients with liver damage. Fortunately, Ms. J’s AST and ALT values remained within normal limits during valproic acid treatment.

Table 5

Pharmacologic profiles of benzodiazepines vs 3 anticonvulsants

CASE REPORT 2: Levetiracetam for withdrawal seizures

Mr. H, age 42, presents to the ER after suffering a seizure. His medical history includes hypertension, alcohol dependence, and seizures during alcohol withdrawal. He denies a history of psychiatric illness, and his family history is unknown. He is noncompliant with hypertension treatment, which includes clonidine. Mr. H reports his usual alcohol consumption as a 6-pack of beer nightly during the week and a 12-pack nightly on weekends. He says his last drink was 4 days before admission.

Mr. H scores 19 on the CIWA-Ar, placing him at risk for moderate withdrawal. Head CT shows diffuse atrophy, without evidence of an acute intracranial process. BAC is zero on admission, and urine drug screen is negative. Amylase, lipase, and lactate dehydrogenase (LDH) levels suggest acute pancreatitis. AST is elevated to 131 U/L, ALT is elevated to 42 U/L, but MCV is within normal limits.

The psychiatric service is consulted on day 2 of admission, and we prescribe levetiracetam, 500 mg IV every 8 hours.²⁰ IV lorazepam also is available as needed: 1 mg every 8 hours for the first 2 days, then 1 mg every 12 hours for 2 days, then 1 mg every 24 hours. The patient’s CIWA-Ar score is 9 on days 2 and 3 of admission, followed by scores consistently between 2 and 3 after scheduled levetiracetam administration. Mr. H requires 3 mg of lorazepam the remainder of his hospitalization. He is discharged on day 7 with a CIWA-Ar score of 2, and reports no adverse effects related to levetiracetam. He leaves the hospital with a 2-week prescription for oral levetiracetam, 500 mg tid.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.

Discuss this article

Benzodiazepines are the mainstay of alcohol detoxification treatment, with extensive evidence supporting their efficacy and relative safety.¹ The risk of benzodiazepine-alcohol interaction, however, and psychomotor and cognitive impairments associated with benzodiazepine use may limit early rehabilitation efforts in hospitalized patients.² Cross-tolerance with alcohol also limits benzodiazepines’ potential benefit in outpatients with substance use disorders.

Adding anticonvulsants to acute benzodiazepine therapy has been shown to decrease alcohol withdrawal symptom severity, reduce seizure risk, and support recovery, particularly in patients with multiple alcohol withdrawal episodes. After detoxification, long-term anticonvulsant use may reduce relapse risk by decreasing post-cessation craving, without abuse liability.³

Although not all studies endorse adding anticonvulsants to benzodiazepines for managing alcohol withdrawal syndrome (AWS),⁴ we present 3 cases in which anticonvulsants were used successfully as adjuncts to lorazepam. Valproic acid, levetiracetam, and gabapentin offer advantages in acute and long-term therapy of alcohol dependence with efficacy in AWS, low abuse potential, benign safety profile, and mood-stabilizing properties.

Neurobiologic rationale

AWS manifests as a cluster of clinical symptoms including delirium tremens (DTs) and seizures (Table 1). Its pathophysiology can be explained by alcohol’s agonist effect on the gamma-aminobutyric acid (GABA) system and antagonist effect on the glutamatergic system (Table 2).⁵

Chronic alcohol intake leads to neuroadaptation in the brain in the form of down-regulation of GABA_A receptors and upregulation of N-methyl-D-aspartate receptors. During alcohol withdrawal, this neuroadaptation leads to a decrease in central GABA activity and an increase in glutamate activity, resulting in hyperexcitation, anxiety, and seizures.⁶

Little data exist regarding time to relapse after detoxification in alcohol-dependent patients. One theory—called “protracted withdrawal syndrome” (Table 1)—suggests that abstinent alcoholics return to drinking because of the same, but attenuated, neuroadaptations that trigger acute AWS.⁷

Advantages of adjunct therapy. Ntais et al⁸ evaluated benzodiazepines’ effectiveness and safety in treating AWS in a clinical review of 57 randomized, controlled trials totaling 4,051 patients. Benzodiazepines showed similar success rates as other drugs (relative risk [RR] 1.00) or anticonvulsants in particular (RR 0.88), as measured by changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment. Benzodiazepines also offered significant benefit for seizure control compared with nonanticonvulsants (RR 0.23), but less when compared with anti convulsants (RR 1.99).

Although the literature does not support anticonvulsant use for monotherapy in AWS, anticonvulsants show potential as adjunctive therapy. Valproic acid, levetiracetam, and gabapentin offer unique mechanisms of action (Table 3) and demonstrate advantages over benzodiazepine monotherapy for AWS. Adjunctive use of valproic acid,^8,9 levetiracetam,¹⁰ and gabapentin^11,12 in detoxification also has demonstrated efficacy in reducing risk of relapse and delaying relapse.

The neurobiologic rationale for using anticonvulsants in acute AWS is speculative, but these agents appear to:

• inhibit “kindling” (neuronal changes that may be associated with repeated intoxications)
• facilitate GABAergic mechanisms.⁹

Table 1

Alcohol withdrawal: Acute vs long-term symptoms

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

CASE REPORT 1: Valproic acid for alcohol overdose

After attempting suicide with an alcohol overdose, Ms. J, age 45, is transferred from the emergency room (ER) to our psychiatry consult service 10 hours after admission. Her symptoms include nausea, tremor, headaches, agitation, disorientation, and auditory hallucinations.

Medical history reveals 25 years of alcohol dependence, multiple hospitalizations for withdrawal, and many failed attempts to quit. Ms. J reports consuming an average of 16 drink equivalents (eg, 12 oz beers) daily but denies illicit drug use.

Lab values on admission include blood alcohol concentration (BAC) 290 mg/dL (0.29%), mean corpuscular volume (MCV) 96 fL, gamma-glutamyltransferase (GGT) 164 U/L, aspartate aminotransferase (AST) 43 U/L, alanine aminotransferase (ALT) 31 U/L, and alkaline phosphatase (ALP) 151 U/L. Urine drug screen, acetaminophen, salicylate, vitamin B1 (thiamine), B12 (cyanocobalamin), B9 (folate), and electrolytes (including magnesium) are normal.

We assess alcohol withdrawal severity using the CIWA-Ar (Click here to view/download a copy of this scale). Ms. J’s initial score is 17, indicating a risk of moderate alcohol withdrawal if untreated.

In the ER, Ms. J is placed on a symptom-triggered benzodiazepine detoxification protocol with lorazepam. We add IV valproic acid, 1,250 mg (based on 20 mg/kg body weight)¹³ divided into 2 doses over the first 24 hours, then maintain IV valproic acid at 500 mg twice daily (Table 4). Within 12 hours of starting combination therapy, Ms. J scores 7 on the CIWA-Ar—indicating mild withdrawal—with subsequent scores <5. She scores 0 with no residual withdrawal symptoms within 36 hours.

Ms. J requires lorazepam, 7 mg, during the 10 hours before valproic acid is added. She requires only 2 mg lorazepam over the next 3 days and reports no side effects related to IV valproic acid. At discharge, Ms. J begins extended-release oral valproic acid, 1,250 mg (based on 25 mg/kg body weight)¹³ once daily for 2 weeks, until she can obtain outpatient follow-up.

Table 4

Benzodiazepines and anticonvulsants for alcohol detoxification

Less lorazepam needed

Adjunctive anticonvulsants can reduce the amount of lorazepam required during detoxification.^14,15 Compared with benzodiazepine monotherapy, the advantages of combination therapy—particularly in outpatient alcohol withdrawal treatment and relapse prevention—include:

• minimal interaction with alcohol (avoiding increased psychomotor deficits, cognitive impairment, and intoxication)¹⁵
• lower abuse potential
• possible efficacy in mood stabilization before, during, and after withdrawal (Table 5).¹⁶

Given the risk of seizures during AWS, anticonvulsants seem to make empirical sense. One study reported a 1% incidence of withdrawal-related seizures in 545 alcohol-dependent inpatients treated with valproic acid.¹⁷ Another case series of 37 patients found no acute sequelae when valproic acid was used for AWS.¹⁸

Anticonvulsants such as valproic acid may reduce the frequency and severity of alcohol relapse, whereas benzodiazepines may increase relapse risk.¹⁹ During a 6-week trial, patients receiving valproic acid maintenance therapy had greater abstinence rates and improved drinking outcomes compared with detoxification-only groups.⁹

One disadvantage of valproic acid is potential hepatotoxicity, an important consideration in patients with liver damage. Fortunately, Ms. J’s AST and ALT values remained within normal limits during valproic acid treatment.

Table 5

Pharmacologic profiles of benzodiazepines vs 3 anticonvulsants

CASE REPORT 2: Levetiracetam for withdrawal seizures

Mr. H, age 42, presents to the ER after suffering a seizure. His medical history includes hypertension, alcohol dependence, and seizures during alcohol withdrawal. He denies a history of psychiatric illness, and his family history is unknown. He is noncompliant with hypertension treatment, which includes clonidine. Mr. H reports his usual alcohol consumption as a 6-pack of beer nightly during the week and a 12-pack nightly on weekends. He says his last drink was 4 days before admission.

Mr. H scores 19 on the CIWA-Ar, placing him at risk for moderate withdrawal. Head CT shows diffuse atrophy, without evidence of an acute intracranial process. BAC is zero on admission, and urine drug screen is negative. Amylase, lipase, and lactate dehydrogenase (LDH) levels suggest acute pancreatitis. AST is elevated to 131 U/L, ALT is elevated to 42 U/L, but MCV is within normal limits.

The psychiatric service is consulted on day 2 of admission, and we prescribe levetiracetam, 500 mg IV every 8 hours.²⁰ IV lorazepam also is available as needed: 1 mg every 8 hours for the first 2 days, then 1 mg every 12 hours for 2 days, then 1 mg every 24 hours. The patient’s CIWA-Ar score is 9 on days 2 and 3 of admission, followed by scores consistently between 2 and 3 after scheduled levetiracetam administration. Mr. H requires 3 mg of lorazepam the remainder of his hospitalization. He is discharged on day 7 with a CIWA-Ar score of 2, and reports no adverse effects related to levetiracetam. He leaves the hospital with a 2-week prescription for oral levetiracetam, 500 mg tid.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.

Up to one-third of psychiatric out-patients in 2006 received ≥3 medications, compared with 17% a decade earlier.¹ Polypharmacy is expensive, increases the risk of adverse effects, and may contribute to nonadherence. Although we recognize that at times long medication lists are justified, we offer 4 principles to help you limit unnecessary polypharmacy.

Do not treat patients’ symptoms indefinitely

William Osler stressed the importance of treating diseases, not symptoms.² Symptoms without a diagnosis are experiences. Whether physicians should treat experiences is an ethical question; however, even if your answer is “yes,” such treatment should be transient. Symptoms occurring within a diagnosis should be treated conservatively, but humanely, only while waiting for syndromal relief.³

Do not use syndrome-oriented drugs to treat symptoms

Mood disorders are not just unpleasant emotions, and anxiety disorders are more than simply nervousness. Medications that are effective for psychopathologic syndromes might not help isolated patient complaints. For example, antidepressants do not simply lift sadness, nor do they usually relieve the nonsyndromal “anxiety” many patients report. Some clinicians might disagree with this recommendation based on flaws in DSM-IV-TR taxonomy; however, these shortcomings do not translate into pharmacologic efficacy.

Do not accumulate medications when faced with nonresponse

If the first 3 medications you prescribed were working, you wouldn’t need to add a fourth. Consider discontinuing one medication for every new one you start. This principle can help you set limits with patients who demand more medications to try to eradicate nonsyndromal distress or clinically significant symptoms that psychopharmacology cannot address. Nonresponse to aggressive treatment should trigger a reassessment of the original diagnosis.

Do not match ‘soft’ diagnoses with ‘soft’ treatments

“Soft” diagnoses come in 2 types:

• an equivocal or mild psychopathologic picture that may be called, for example, “soft bipolar illness”
• using imprecise terms as diagnostic proxies, such as “depression and anxiety.”

Patients with soft diagnoses often receive combinations of lower-than-standard dosages or drugs with milder side effects but substandard efficacy. For these patients, we recommend postponing pharmacotherapy or “firming up” the diagnosis and then initiating the standard of care.

Up to one-third of psychiatric out-patients in 2006 received ≥3 medications, compared with 17% a decade earlier.¹ Polypharmacy is expensive, increases the risk of adverse effects, and may contribute to nonadherence. Although we recognize that at times long medication lists are justified, we offer 4 principles to help you limit unnecessary polypharmacy.

Do not treat patients’ symptoms indefinitely

William Osler stressed the importance of treating diseases, not symptoms.² Symptoms without a diagnosis are experiences. Whether physicians should treat experiences is an ethical question; however, even if your answer is “yes,” such treatment should be transient. Symptoms occurring within a diagnosis should be treated conservatively, but humanely, only while waiting for syndromal relief.³

Do not use syndrome-oriented drugs to treat symptoms

Mood disorders are not just unpleasant emotions, and anxiety disorders are more than simply nervousness. Medications that are effective for psychopathologic syndromes might not help isolated patient complaints. For example, antidepressants do not simply lift sadness, nor do they usually relieve the nonsyndromal “anxiety” many patients report. Some clinicians might disagree with this recommendation based on flaws in DSM-IV-TR taxonomy; however, these shortcomings do not translate into pharmacologic efficacy.

Do not accumulate medications when faced with nonresponse

If the first 3 medications you prescribed were working, you wouldn’t need to add a fourth. Consider discontinuing one medication for every new one you start. This principle can help you set limits with patients who demand more medications to try to eradicate nonsyndromal distress or clinically significant symptoms that psychopharmacology cannot address. Nonresponse to aggressive treatment should trigger a reassessment of the original diagnosis.

Do not match ‘soft’ diagnoses with ‘soft’ treatments

“Soft” diagnoses come in 2 types:

• an equivocal or mild psychopathologic picture that may be called, for example, “soft bipolar illness”
• using imprecise terms as diagnostic proxies, such as “depression and anxiety.”

Patients with soft diagnoses often receive combinations of lower-than-standard dosages or drugs with milder side effects but substandard efficacy. For these patients, we recommend postponing pharmacotherapy or “firming up” the diagnosis and then initiating the standard of care.

Up to one-third of psychiatric out-patients in 2006 received ≥3 medications, compared with 17% a decade earlier.¹ Polypharmacy is expensive, increases the risk of adverse effects, and may contribute to nonadherence. Although we recognize that at times long medication lists are justified, we offer 4 principles to help you limit unnecessary polypharmacy.

Do not treat patients’ symptoms indefinitely

William Osler stressed the importance of treating diseases, not symptoms.² Symptoms without a diagnosis are experiences. Whether physicians should treat experiences is an ethical question; however, even if your answer is “yes,” such treatment should be transient. Symptoms occurring within a diagnosis should be treated conservatively, but humanely, only while waiting for syndromal relief.³

Do not use syndrome-oriented drugs to treat symptoms

Mood disorders are not just unpleasant emotions, and anxiety disorders are more than simply nervousness. Medications that are effective for psychopathologic syndromes might not help isolated patient complaints. For example, antidepressants do not simply lift sadness, nor do they usually relieve the nonsyndromal “anxiety” many patients report. Some clinicians might disagree with this recommendation based on flaws in DSM-IV-TR taxonomy; however, these shortcomings do not translate into pharmacologic efficacy.

Do not accumulate medications when faced with nonresponse

If the first 3 medications you prescribed were working, you wouldn’t need to add a fourth. Consider discontinuing one medication for every new one you start. This principle can help you set limits with patients who demand more medications to try to eradicate nonsyndromal distress or clinically significant symptoms that psychopharmacology cannot address. Nonresponse to aggressive treatment should trigger a reassessment of the original diagnosis.

Do not match ‘soft’ diagnoses with ‘soft’ treatments

“Soft” diagnoses come in 2 types:

• an equivocal or mild psychopathologic picture that may be called, for example, “soft bipolar illness”
• using imprecise terms as diagnostic proxies, such as “depression and anxiety.”

Patients with soft diagnoses often receive combinations of lower-than-standard dosages or drugs with milder side effects but substandard efficacy. For these patients, we recommend postponing pharmacotherapy or “firming up” the diagnosis and then initiating the standard of care.

CASE: Self-reported TBI

When charged with raping a 19-year-old woman, Mr. P, age 32, pleads not guilty by reason of insanity (NGRI). He has a self-reported history of traumatic brain injury (TBI) and claims that since suffering a blow to the head 8 years before the rape, he has experienced episodes of personality changes, psychosis, and violent behavior. Mr. P is adamant that any wrongdoing on his part was beyond his control, and he argues that consequences of the brain injury, such as hallucinations and aggressive behavior, had recently emerged. The court asks that a forensic psychiatrist evaluate Mr. P.

An only child, Mr. P was raised by his mother in an inner city area. His father was dependent on alcohol and cocaine and abandoned the family shortly after Mr. P’s birth. Mr. P abuses alcohol, as evidenced by previous driving under the influence charges, but denies illicit drug use. He graduated from high school with average grades and denies a history of disciplinary action at school or home. Although Mr. P was charged with misdemeanors in his late teens, the sexual assault is his first felony charge. Mr. P describes himself as a “charmer.”

After high school, Mr. P worked full-time in construction, where he claims he suffered a traumatic blow to the head. Despite this injury, he continued to work and socialize and never sought treatment at a mental health clinic.

The authors’ observations

Although defendants may legitimately suffer from TBI and resultant complications, many individuals capitalize on a history of minor head injury to support their NGRI defense.¹ Forensic psychiatrists must retain a healthy degree of clinical suspicion for malingering in defendants who claim NGRI as a result of complications from brain injury, especially when the injury and complications are not documented and simply patient-reported.

TBI is a CNS injury that occurs when an outside force traumatically injures the brain and can cause a variety of physical, cognitive, emotional, and behavioral effects ( Table 1 ).² Cognitive deficits include:

• impaired attention
• disrupted insight
• poor judgment
• thought disorders.

Reduced processing speed, distractibility, and deficits in executive functions such as abstract reasoning, planning, problem solving, and multitasking have been documented. Memory loss—the most common cognitive impairment among head-injured people—occurs in 20% to 79% of people with closed head trauma, depending on injury severity.³ People who have suffered TBI may have difficulty understanding or producing spoken or written language, or with more subtle aspects of communication, such as body language.

TBI may cause emotional or behavioral problems and personality changes. Mood and affect changes are common. TBI predisposes patients to obsessive-compulsive disorder, substance abuse, dysthymia, clinical depression, bipolar disorder, phobias, panic disorder, and schizophrenia.⁴ Frontal lobe injuries have been correlated with disinhibition and inappropriate or childish behavior, and temporal lobe injuries with irritability and aggression.⁵

Table 1

TBI symptoms correspond to area of injury

TBI and the insanity defense

The M’Naghten Rule of 1843 requires that for an insanity defense, the defendant must have a mental disease or defect that causes him not to know the nature and quality or the wrongfulness of his act.⁶ TBI is an abnormal condition of the mind leading to a mental disease that can substantially affect control of emotions and behaviors.

Nevertheless, TBI-induced criminality remains controversial.⁷ Theories on the etiology of impulse dyscontrol resulting from TBI have suggested structural damage to the brain and altered neurotransmitters. In TBI, the amygdala—which is located within the anterior temporal lobe and adjoins emotions to thoughts—often is injured. Damage to this structure leads to poor impulse control and violent behavior. Damage to specific neurotransmitter systems that causes elevated norepinephrine and dopamine levels and reduced serotonin levels have also been implicated as a cause of impulse dyscontrol in TBI patients.⁸

In theory, TBI patients potentially could have enough cognitive impairment to have a substantial lack of appreciation of the criminality or wrongfulness of an act. TBI-related impulsivity and cognitive impairment can lead to recklessness and negligence.⁹ The U.S. Supreme Court has acknowledged that CNS dysfunction affects judgment, reality testing, and self-control.¹⁰

EVALUATION: Vague answers

To determine whether Mr. P’s defense is plausible, the forensic psychiatrist must pay attention to the details of the patient’s presentation and history. During the interview, Mr. P quickly shifts from cooperative to obstinate and restricted. He ruminates on the head injury causing him to suffer auditory hallucinations, which he claims he always obeys. Mr. P refuses to provide details of the hallucinations, however, and answers most questions about the head injury or his defense with vague answers, including “I don’t know.”

Because of Mr. P’s reluctance to share information, his lack of psychiatric symptoms other than those he self-reports, and the presence of potential secondary gain from an NGRI defense, the psychiatrist begins to suspect malingering.

The authors’ observations

Malingering is a condition—not a diagnosis—characterized by intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives.¹¹ The presence of external incentives distinguishes malingering from psychiatric illnesses such as factitious and somatoform disorders, in which there is no apparent external incentive. Malingering of psychiatric symptoms occurs in up to 20% of forensic patients, 5% of military recruits, and 1% of mental health patients.⁵ Stimuli for malingering range from seeking food and shelter to avoiding criminal responsibility ( Table 2 ). Malingering is more common in individuals being evaluated for criminal responsibility than for competence to stand trial. The 3 categories of malingering are:

Table 2

Common external incentives for malingering

• pure malingering—feigning a nonexistent disorder
• partial malingering—consciously exaggerating real symptoms

• false imputation—ascribing real symptoms to a cause the individual knows is unrelated to the symptoms.¹²

Determining if a defendant with a history of TBI is malingering requires a multi-step approach that encompasses the clinical interview, a thorough review of collateral data, and focused psychological testing. In interviews, psychiatrists detect approximately 50% of lies, which is no better than would be discovered by chance.¹³ If you suspect a patient is malingering, combine a structured clinical interview with collateral sources such as old hospital records, treatment history, insurance records, police reports, and interviews with close family and friends.

TBI patients’ poor cognition, memory deficits, and inattention will prove challenging. Malingering patients who attempt to capitalize on a pre-existing TBI to evade responsibility for a current criminal charge may grossly exaggerate or even fake intellectual deficits. Be patient with such defendants and remain aware that such people will give vague or hedging answers to straightforward questions, often accompanied by “I don’t know.” Prolonging the interview may be helpful because it may fatigue a defendant who is faking.¹²

Some patients who malinger after sustaining a TBI will attempt to feign psychotic symptoms. Table 3 ¹⁴ illustrates criteria for assessing a patient suspected of malingering psychosis and Table 4 ¹⁴ highlights atypical psychotic symptoms that suggest feigning illness. Malingering of psychosis can be both assessed in the interview and through testing.

Table 3

Criteria for malingered psychosis

Table 4

Atypical psychotic symptoms that suggest malingering

Psychological testing

Several standardized diagnostic instruments can be used to help determine whether a patient is feigning or exaggerating psychotic symptoms or cognitive impairments ( Table 5 ). Testing for a patient such as Mr. P—who attributes any criminal wrongdoing to psychosis and also cites limited cognition as a reason for trouble in the interview—would include personality tests, tests to assess exaggerations of psychosis, and cognitive tests.

In the forensic setting, the preferred personality test is the MMPI-2.¹⁵ It consists of 567 items, with 10 clinical scales and several validity scales. The F scale, “faking good” or “faking bad,” detects people who are answering questions with the goal of appearing better or worse than they actually are. The Personal Assessment Inventory (PAI)¹⁶ is a 344-item test with a 4-point response format. The 22 scales cover a range of important axis I and II psychopathology.

SIRS¹⁷ is the gold standard in detecting malingered psychiatric illness; it includes questions about rare symptoms and uncommon symptom pairing. M-FAST¹⁸ was developed to provide a brief, reliable screen for malingered mental illness. It has shown good validity and high correlation with the SIRS and MMPI-2.

Tests of exaggerated cognitive impairment are extremely important in evaluating patients who claim to suffer from complications following TBI. TOMM¹⁹ —a 50-item recognition test designed to discriminate between true memory-impaired patients and malingerers—is the most studied and valid of such tests. Defendants’ scores that meet the recommended criteria for detecting malingering—≥5 errors on the retention trial—were found to also report a history of head injury.¹

Although not as well validated, the Portland Digit Recognition Test (PDRT)²⁰ is an alternative to the TOMM. This test is a forced-choice measure of recognition designed for assessing the possibility of malingering in individuals claiming mental illness because of head injury. The Victoria Symptoms Validity Test (VSVT)²¹ is used in outpatient and inpatient settings and also uses a forced-choice model to assess possible exaggeration or feigning of cognitive impairments. Finally, the Word Memory Test (WMT)²² is a neuropsychological assessment that evaluates the effort participants put forth.

Table 5

Standardized diagnostic instruments for detecting malingering

OUTCOME: Unsupported claims

Mr. P’s hospital records reveal a very minor head trauma that resulted in no structural brain abnormalities on imaging tests. Collateral interviews with Mr. P’s family and close friends fail to support the defendant’s claim that after the accident he began to experience behavioral changes and periods of psychosis. Mr. P’s SIRS and TOMM scores indicate malingering, and the psychiatrist did not support his NGRI defense.

Related resource

• Williamson DJ. Neurocognitive impairment: feigned, exaggerated, or real? Current Psychiatry. 2007;6(8):19-37.

Disclosure

Dr. Nasrallah receives research grant/research support from Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Otsuka America Pharmaceuticals, Pfizer Inc., Roche, sanofi-aventis, and Shire, is on the advisory board of Abbott Laboratories, AstraZeneca, Janssen, Novartis, Pfizer Inc., and Merck, and is on the speakers’ bureau for Abbott Laboratories, AstraZeneca, Janssen, Novartis, Pfizer Inc., and Merck.

Dr. Farrell reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Self-reported TBI

When charged with raping a 19-year-old woman, Mr. P, age 32, pleads not guilty by reason of insanity (NGRI). He has a self-reported history of traumatic brain injury (TBI) and claims that since suffering a blow to the head 8 years before the rape, he has experienced episodes of personality changes, psychosis, and violent behavior. Mr. P is adamant that any wrongdoing on his part was beyond his control, and he argues that consequences of the brain injury, such as hallucinations and aggressive behavior, had recently emerged. The court asks that a forensic psychiatrist evaluate Mr. P.

An only child, Mr. P was raised by his mother in an inner city area. His father was dependent on alcohol and cocaine and abandoned the family shortly after Mr. P’s birth. Mr. P abuses alcohol, as evidenced by previous driving under the influence charges, but denies illicit drug use. He graduated from high school with average grades and denies a history of disciplinary action at school or home. Although Mr. P was charged with misdemeanors in his late teens, the sexual assault is his first felony charge. Mr. P describes himself as a “charmer.”

After high school, Mr. P worked full-time in construction, where he claims he suffered a traumatic blow to the head. Despite this injury, he continued to work and socialize and never sought treatment at a mental health clinic.

The authors’ observations

Although defendants may legitimately suffer from TBI and resultant complications, many individuals capitalize on a history of minor head injury to support their NGRI defense.¹ Forensic psychiatrists must retain a healthy degree of clinical suspicion for malingering in defendants who claim NGRI as a result of complications from brain injury, especially when the injury and complications are not documented and simply patient-reported.

TBI is a CNS injury that occurs when an outside force traumatically injures the brain and can cause a variety of physical, cognitive, emotional, and behavioral effects ( Table 1 ).² Cognitive deficits include:

• impaired attention
• disrupted insight
• poor judgment
• thought disorders.

Reduced processing speed, distractibility, and deficits in executive functions such as abstract reasoning, planning, problem solving, and multitasking have been documented. Memory loss—the most common cognitive impairment among head-injured people—occurs in 20% to 79% of people with closed head trauma, depending on injury severity.³ People who have suffered TBI may have difficulty understanding or producing spoken or written language, or with more subtle aspects of communication, such as body language.

TBI may cause emotional or behavioral problems and personality changes. Mood and affect changes are common. TBI predisposes patients to obsessive-compulsive disorder, substance abuse, dysthymia, clinical depression, bipolar disorder, phobias, panic disorder, and schizophrenia.⁴ Frontal lobe injuries have been correlated with disinhibition and inappropriate or childish behavior, and temporal lobe injuries with irritability and aggression.⁵

Table 1

TBI symptoms correspond to area of injury

TBI and the insanity defense

The M’Naghten Rule of 1843 requires that for an insanity defense, the defendant must have a mental disease or defect that causes him not to know the nature and quality or the wrongfulness of his act.⁶ TBI is an abnormal condition of the mind leading to a mental disease that can substantially affect control of emotions and behaviors.

Nevertheless, TBI-induced criminality remains controversial.⁷ Theories on the etiology of impulse dyscontrol resulting from TBI have suggested structural damage to the brain and altered neurotransmitters. In TBI, the amygdala—which is located within the anterior temporal lobe and adjoins emotions to thoughts—often is injured. Damage to this structure leads to poor impulse control and violent behavior. Damage to specific neurotransmitter systems that causes elevated norepinephrine and dopamine levels and reduced serotonin levels have also been implicated as a cause of impulse dyscontrol in TBI patients.⁸

In theory, TBI patients potentially could have enough cognitive impairment to have a substantial lack of appreciation of the criminality or wrongfulness of an act. TBI-related impulsivity and cognitive impairment can lead to recklessness and negligence.⁹ The U.S. Supreme Court has acknowledged that CNS dysfunction affects judgment, reality testing, and self-control.¹⁰

EVALUATION: Vague answers

To determine whether Mr. P’s defense is plausible, the forensic psychiatrist must pay attention to the details of the patient’s presentation and history. During the interview, Mr. P quickly shifts from cooperative to obstinate and restricted. He ruminates on the head injury causing him to suffer auditory hallucinations, which he claims he always obeys. Mr. P refuses to provide details of the hallucinations, however, and answers most questions about the head injury or his defense with vague answers, including “I don’t know.”

Because of Mr. P’s reluctance to share information, his lack of psychiatric symptoms other than those he self-reports, and the presence of potential secondary gain from an NGRI defense, the psychiatrist begins to suspect malingering.

The authors’ observations

Malingering is a condition—not a diagnosis—characterized by intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives.¹¹ The presence of external incentives distinguishes malingering from psychiatric illnesses such as factitious and somatoform disorders, in which there is no apparent external incentive. Malingering of psychiatric symptoms occurs in up to 20% of forensic patients, 5% of military recruits, and 1% of mental health patients.⁵ Stimuli for malingering range from seeking food and shelter to avoiding criminal responsibility ( Table 2 ). Malingering is more common in individuals being evaluated for criminal responsibility than for competence to stand trial. The 3 categories of malingering are:

Table 2

Common external incentives for malingering

• pure malingering—feigning a nonexistent disorder
• partial malingering—consciously exaggerating real symptoms

• false imputation—ascribing real symptoms to a cause the individual knows is unrelated to the symptoms.¹²

Determining if a defendant with a history of TBI is malingering requires a multi-step approach that encompasses the clinical interview, a thorough review of collateral data, and focused psychological testing. In interviews, psychiatrists detect approximately 50% of lies, which is no better than would be discovered by chance.¹³ If you suspect a patient is malingering, combine a structured clinical interview with collateral sources such as old hospital records, treatment history, insurance records, police reports, and interviews with close family and friends.

TBI patients’ poor cognition, memory deficits, and inattention will prove challenging. Malingering patients who attempt to capitalize on a pre-existing TBI to evade responsibility for a current criminal charge may grossly exaggerate or even fake intellectual deficits. Be patient with such defendants and remain aware that such people will give vague or hedging answers to straightforward questions, often accompanied by “I don’t know.” Prolonging the interview may be helpful because it may fatigue a defendant who is faking.¹²

Some patients who malinger after sustaining a TBI will attempt to feign psychotic symptoms. Table 3 ¹⁴ illustrates criteria for assessing a patient suspected of malingering psychosis and Table 4 ¹⁴ highlights atypical psychotic symptoms that suggest feigning illness. Malingering of psychosis can be both assessed in the interview and through testing.

Table 3

Criteria for malingered psychosis

Table 4

Atypical psychotic symptoms that suggest malingering

Psychological testing

Several standardized diagnostic instruments can be used to help determine whether a patient is feigning or exaggerating psychotic symptoms or cognitive impairments ( Table 5 ). Testing for a patient such as Mr. P—who attributes any criminal wrongdoing to psychosis and also cites limited cognition as a reason for trouble in the interview—would include personality tests, tests to assess exaggerations of psychosis, and cognitive tests.

In the forensic setting, the preferred personality test is the MMPI-2.¹⁵ It consists of 567 items, with 10 clinical scales and several validity scales. The F scale, “faking good” or “faking bad,” detects people who are answering questions with the goal of appearing better or worse than they actually are. The Personal Assessment Inventory (PAI)¹⁶ is a 344-item test with a 4-point response format. The 22 scales cover a range of important axis I and II psychopathology.

SIRS¹⁷ is the gold standard in detecting malingered psychiatric illness; it includes questions about rare symptoms and uncommon symptom pairing. M-FAST¹⁸ was developed to provide a brief, reliable screen for malingered mental illness. It has shown good validity and high correlation with the SIRS and MMPI-2.

Tests of exaggerated cognitive impairment are extremely important in evaluating patients who claim to suffer from complications following TBI. TOMM¹⁹ —a 50-item recognition test designed to discriminate between true memory-impaired patients and malingerers—is the most studied and valid of such tests. Defendants’ scores that meet the recommended criteria for detecting malingering—≥5 errors on the retention trial—were found to also report a history of head injury.¹

Although not as well validated, the Portland Digit Recognition Test (PDRT)²⁰ is an alternative to the TOMM. This test is a forced-choice measure of recognition designed for assessing the possibility of malingering in individuals claiming mental illness because of head injury. The Victoria Symptoms Validity Test (VSVT)²¹ is used in outpatient and inpatient settings and also uses a forced-choice model to assess possible exaggeration or feigning of cognitive impairments. Finally, the Word Memory Test (WMT)²² is a neuropsychological assessment that evaluates the effort participants put forth.

Table 5

Standardized diagnostic instruments for detecting malingering

OUTCOME: Unsupported claims

Mr. P’s hospital records reveal a very minor head trauma that resulted in no structural brain abnormalities on imaging tests. Collateral interviews with Mr. P’s family and close friends fail to support the defendant’s claim that after the accident he began to experience behavioral changes and periods of psychosis. Mr. P’s SIRS and TOMM scores indicate malingering, and the psychiatrist did not support his NGRI defense.

Related resource

• Williamson DJ. Neurocognitive impairment: feigned, exaggerated, or real? Current Psychiatry. 2007;6(8):19-37.

Disclosure

Dr. Nasrallah receives research grant/research support from Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Otsuka America Pharmaceuticals, Pfizer Inc., Roche, sanofi-aventis, and Shire, is on the advisory board of Abbott Laboratories, AstraZeneca, Janssen, Novartis, Pfizer Inc., and Merck, and is on the speakers’ bureau for Abbott Laboratories, AstraZeneca, Janssen, Novartis, Pfizer Inc., and Merck.

Dr. Farrell reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Self-reported TBI

When charged with raping a 19-year-old woman, Mr. P, age 32, pleads not guilty by reason of insanity (NGRI). He has a self-reported history of traumatic brain injury (TBI) and claims that since suffering a blow to the head 8 years before the rape, he has experienced episodes of personality changes, psychosis, and violent behavior. Mr. P is adamant that any wrongdoing on his part was beyond his control, and he argues that consequences of the brain injury, such as hallucinations and aggressive behavior, had recently emerged. The court asks that a forensic psychiatrist evaluate Mr. P.

An only child, Mr. P was raised by his mother in an inner city area. His father was dependent on alcohol and cocaine and abandoned the family shortly after Mr. P’s birth. Mr. P abuses alcohol, as evidenced by previous driving under the influence charges, but denies illicit drug use. He graduated from high school with average grades and denies a history of disciplinary action at school or home. Although Mr. P was charged with misdemeanors in his late teens, the sexual assault is his first felony charge. Mr. P describes himself as a “charmer.”

After high school, Mr. P worked full-time in construction, where he claims he suffered a traumatic blow to the head. Despite this injury, he continued to work and socialize and never sought treatment at a mental health clinic.

The authors’ observations

Although defendants may legitimately suffer from TBI and resultant complications, many individuals capitalize on a history of minor head injury to support their NGRI defense.¹ Forensic psychiatrists must retain a healthy degree of clinical suspicion for malingering in defendants who claim NGRI as a result of complications from brain injury, especially when the injury and complications are not documented and simply patient-reported.

TBI is a CNS injury that occurs when an outside force traumatically injures the brain and can cause a variety of physical, cognitive, emotional, and behavioral effects ( Table 1 ).² Cognitive deficits include:

• impaired attention
• disrupted insight
• poor judgment
• thought disorders.

Reduced processing speed, distractibility, and deficits in executive functions such as abstract reasoning, planning, problem solving, and multitasking have been documented. Memory loss—the most common cognitive impairment among head-injured people—occurs in 20% to 79% of people with closed head trauma, depending on injury severity.³ People who have suffered TBI may have difficulty understanding or producing spoken or written language, or with more subtle aspects of communication, such as body language.

TBI may cause emotional or behavioral problems and personality changes. Mood and affect changes are common. TBI predisposes patients to obsessive-compulsive disorder, substance abuse, dysthymia, clinical depression, bipolar disorder, phobias, panic disorder, and schizophrenia.⁴ Frontal lobe injuries have been correlated with disinhibition and inappropriate or childish behavior, and temporal lobe injuries with irritability and aggression.⁵

Table 1

TBI symptoms correspond to area of injury

TBI and the insanity defense

The M’Naghten Rule of 1843 requires that for an insanity defense, the defendant must have a mental disease or defect that causes him not to know the nature and quality or the wrongfulness of his act.⁶ TBI is an abnormal condition of the mind leading to a mental disease that can substantially affect control of emotions and behaviors.

Nevertheless, TBI-induced criminality remains controversial.⁷ Theories on the etiology of impulse dyscontrol resulting from TBI have suggested structural damage to the brain and altered neurotransmitters. In TBI, the amygdala—which is located within the anterior temporal lobe and adjoins emotions to thoughts—often is injured. Damage to this structure leads to poor impulse control and violent behavior. Damage to specific neurotransmitter systems that causes elevated norepinephrine and dopamine levels and reduced serotonin levels have also been implicated as a cause of impulse dyscontrol in TBI patients.⁸

In theory, TBI patients potentially could have enough cognitive impairment to have a substantial lack of appreciation of the criminality or wrongfulness of an act. TBI-related impulsivity and cognitive impairment can lead to recklessness and negligence.⁹ The U.S. Supreme Court has acknowledged that CNS dysfunction affects judgment, reality testing, and self-control.¹⁰

EVALUATION: Vague answers

To determine whether Mr. P’s defense is plausible, the forensic psychiatrist must pay attention to the details of the patient’s presentation and history. During the interview, Mr. P quickly shifts from cooperative to obstinate and restricted. He ruminates on the head injury causing him to suffer auditory hallucinations, which he claims he always obeys. Mr. P refuses to provide details of the hallucinations, however, and answers most questions about the head injury or his defense with vague answers, including “I don’t know.”

Because of Mr. P’s reluctance to share information, his lack of psychiatric symptoms other than those he self-reports, and the presence of potential secondary gain from an NGRI defense, the psychiatrist begins to suspect malingering.

The authors’ observations

Malingering is a condition—not a diagnosis—characterized by intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives.¹¹ The presence of external incentives distinguishes malingering from psychiatric illnesses such as factitious and somatoform disorders, in which there is no apparent external incentive. Malingering of psychiatric symptoms occurs in up to 20% of forensic patients, 5% of military recruits, and 1% of mental health patients.⁵ Stimuli for malingering range from seeking food and shelter to avoiding criminal responsibility ( Table 2 ). Malingering is more common in individuals being evaluated for criminal responsibility than for competence to stand trial. The 3 categories of malingering are:

Table 2

Common external incentives for malingering

• pure malingering—feigning a nonexistent disorder
• partial malingering—consciously exaggerating real symptoms

• false imputation—ascribing real symptoms to a cause the individual knows is unrelated to the symptoms.¹²

Determining if a defendant with a history of TBI is malingering requires a multi-step approach that encompasses the clinical interview, a thorough review of collateral data, and focused psychological testing. In interviews, psychiatrists detect approximately 50% of lies, which is no better than would be discovered by chance.¹³ If you suspect a patient is malingering, combine a structured clinical interview with collateral sources such as old hospital records, treatment history, insurance records, police reports, and interviews with close family and friends.

TBI patients’ poor cognition, memory deficits, and inattention will prove challenging. Malingering patients who attempt to capitalize on a pre-existing TBI to evade responsibility for a current criminal charge may grossly exaggerate or even fake intellectual deficits. Be patient with such defendants and remain aware that such people will give vague or hedging answers to straightforward questions, often accompanied by “I don’t know.” Prolonging the interview may be helpful because it may fatigue a defendant who is faking.¹²

Some patients who malinger after sustaining a TBI will attempt to feign psychotic symptoms. Table 3 ¹⁴ illustrates criteria for assessing a patient suspected of malingering psychosis and Table 4 ¹⁴ highlights atypical psychotic symptoms that suggest feigning illness. Malingering of psychosis can be both assessed in the interview and through testing.

Table 3

Criteria for malingered psychosis

Table 4

Atypical psychotic symptoms that suggest malingering

Psychological testing

Several standardized diagnostic instruments can be used to help determine whether a patient is feigning or exaggerating psychotic symptoms or cognitive impairments ( Table 5 ). Testing for a patient such as Mr. P—who attributes any criminal wrongdoing to psychosis and also cites limited cognition as a reason for trouble in the interview—would include personality tests, tests to assess exaggerations of psychosis, and cognitive tests.

In the forensic setting, the preferred personality test is the MMPI-2.¹⁵ It consists of 567 items, with 10 clinical scales and several validity scales. The F scale, “faking good” or “faking bad,” detects people who are answering questions with the goal of appearing better or worse than they actually are. The Personal Assessment Inventory (PAI)¹⁶ is a 344-item test with a 4-point response format. The 22 scales cover a range of important axis I and II psychopathology.

SIRS¹⁷ is the gold standard in detecting malingered psychiatric illness; it includes questions about rare symptoms and uncommon symptom pairing. M-FAST¹⁸ was developed to provide a brief, reliable screen for malingered mental illness. It has shown good validity and high correlation with the SIRS and MMPI-2.

Tests of exaggerated cognitive impairment are extremely important in evaluating patients who claim to suffer from complications following TBI. TOMM¹⁹ —a 50-item recognition test designed to discriminate between true memory-impaired patients and malingerers—is the most studied and valid of such tests. Defendants’ scores that meet the recommended criteria for detecting malingering—≥5 errors on the retention trial—were found to also report a history of head injury.¹

Although not as well validated, the Portland Digit Recognition Test (PDRT)²⁰ is an alternative to the TOMM. This test is a forced-choice measure of recognition designed for assessing the possibility of malingering in individuals claiming mental illness because of head injury. The Victoria Symptoms Validity Test (VSVT)²¹ is used in outpatient and inpatient settings and also uses a forced-choice model to assess possible exaggeration or feigning of cognitive impairments. Finally, the Word Memory Test (WMT)²² is a neuropsychological assessment that evaluates the effort participants put forth.

Table 5

Standardized diagnostic instruments for detecting malingering

OUTCOME: Unsupported claims

Mr. P’s hospital records reveal a very minor head trauma that resulted in no structural brain abnormalities on imaging tests. Collateral interviews with Mr. P’s family and close friends fail to support the defendant’s claim that after the accident he began to experience behavioral changes and periods of psychosis. Mr. P’s SIRS and TOMM scores indicate malingering, and the psychiatrist did not support his NGRI defense.

Related resource

• Williamson DJ. Neurocognitive impairment: feigned, exaggerated, or real? Current Psychiatry. 2007;6(8):19-37.

Disclosure

Dr. Nasrallah receives research grant/research support from Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Otsuka America Pharmaceuticals, Pfizer Inc., Roche, sanofi-aventis, and Shire, is on the advisory board of Abbott Laboratories, AstraZeneca, Janssen, Novartis, Pfizer Inc., and Merck, and is on the speakers’ bureau for Abbott Laboratories, AstraZeneca, Janssen, Novartis, Pfizer Inc., and Merck.

Dr. Farrell reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article

Sammy, age 7, is referred to you by his pediatrician because of a 4-week history of frequent eye blinking. His parents say he blinks a lot when bored but very little when playing baseball. They recall that he also has intermittently sniffed and nodded his head over the last 12 months. Neither Sammy nor his friends seem to be bothered by the blinking. Except for the tics, Sammy’s physical and mental status exams are normal.

Since preschool, Sammy’s teachers have complained that his backpack and desk are always a mess. Sammy is well-meaning but forgetful in his chores at home. A paternal uncle has head-turning movements, counts his steps, and becomes distressed if books on his shelf are not in alphabetical order.

Tics, such as strong eye blinks or repetitive shoulder shrugs, can distress a child or his/her parents, but the conditions associated with tic disorders often are more problematic than the tic disorder itself. High rates of comorbid conditions are recognized in persons with Tourette syndrome, including:

• obsessive-compulsive disorder (OCD) in >80%¹
• attention-deficit/hyperactivity disorder (ADHD) in ≤70%²
• anxiety disorders in 30%³
• rage, aggression, learning disabilities, and autism less commonly.

The strategy we recommend for managing tic disorders includes assessing tic severity, educating the family about the illness, determining whether a comorbid condition is present, and managing these conditions appropriately. Above all, we emphasize a risk-benefit analysis guided by the Hippocratic principle of “do no harm.”

Characteristics of tic disorders

You diagnose Sammy with Tourette syndrome because he meets DSM-IV-TR criteria of at least 2 motor tics and 1 vocal tic that have persisted for 1 year without more than a 3-month hiatus, with tic onset before age 18. Because tics may resemble other movement disorders, you rule out stereotypies, dystonia, chorea, ballism, and myoclonus (Table 1). You explain to his parents that Sammy’s condition is a heritable, neurobehavioral disorder that typically begins in childhood and is associated in families with OCD, ADHD, and autism spectrum disorders.

His parents ask about the difference between tics and other movements. You explain that eye-blinking tics—like other motor tics—appear as sudden, repetitive, stereotyped, nonrhythmic movements that involve discrete muscle groups. (View a video of a patient with tics.) Simple motor tics are focal movements involving 1 group of muscles, whereas complex tics are sequential patterns of movement that involve >1 muscle group or resemble purposeful movements (Table 2).

Table 1

Features of 5 movement disorders that may resemble tics

Table 2

Characteristics of simple and complex motor and vocal tics*

Older children frequently describe a premonitory urge prior to the tic. Patients typically can suppress tics for a transient period of time, although during tic suppression they usually feel restless and anticipate performing their tic. The ultimate performance of the tic brings relief. Tic suppression also occurs during focused activity. Emotional stress, fatigue, illness, or boredom can exacerbate tics.

To begin monitoring Sammy’s clinical course, you administer 3 assessment tools described inTable 3. You explain to Sammy’s parents that these tests will be repeated yearly or when tics worsen. However, you tell his parents that these scores alone will not determine present or future clinical decisions, including treatments. You also recommend that they connect with support groups on the Tourette Syndrome Association (TSA) Web site.

CASE CONTINUED: Changes over time

Sammy’s parents appreciate your explanation and say they will share information from the TSA Web site with Sammy’s principal, teachers, and classmates. The family agrees to return in 6 months or sooner if the tics worsen.

By age 8, Sammy develops multiple tics: facial grimacing, looking upwards, punching movements, whistling, and throat clearing. He is slightly bothered by these tics, and his friends have asked him about them. He tells them he has Tourette syndrome, and that usually ends the questioning. He returns for a follow-up visit because his parents notice a dramatic increase in his tics after Sammy’s father loses his job.

Treatment options

When deciding to treat a child’s tics, the first step is to determine whether to pursue a nonpharmacologic or pharmacologic approach (Algorithm). To tailor an approach most suited for an individual child, discuss with the family their feelings about therapy and medications. This information—along with tic severity—will help determine a treatment plan.

Behavior therapy and medication are management strategies; neither can cure a tic disorder. The most conservative approach to tic treatment is to:

• provide the child and family with basic guidelines for managing tics
• help alleviate environmental stress and other potential triggers.

Algorithm: Recommended treatment of tics in children and adolescents

CASE CONTINUED: A first intervention

You discuss treatment options with Sammy’s family, and they view medication as a last resort. Sammy does not seem to be bothered by his tics, and his parents do not wish to start him on daily medications. Given this situation, habit reversal therapy (HRT) is appropriate for Sammy because he is old enough to participate in HRT to reduce his tics.

HRT is an effective nonpharmacologic approach to help children with tics.⁴ Its 3 components are:

• awareness training
• competing response training
• social support.⁵

This simplified version of the original HRT can be completed in eight 1-hour sessions. Good candidates are patients who are cognitively mature enough to understand the therapy’s goals and compliant with frequent clinic visits. They also must practice the strategies at home.

It should not be difficult for psychiatrists to learn HRT—or refer to therapists who are willing to learn it—with the available instructional manual.

CASE CONTINUED: Practicing alternatives

You ask Sammy to imitate his tics. After helping him become more aware of his tics, you encourage him to develop a more socially appropriate movement to engage in whenever he feels the urge to punch. Sammy chooses to clench his fist in his pocket. He also learns to breathe in whenever he has an urge to whistle. you advise Sammy’s parents to reward his efforts to suppress the tics. He practices the strategies daily.

At age 12, Sammy returns to your office. He has begun to have frequent neck-jerking tics, which cause neck pain and daily headaches. He also is slapping his thigh and having frequent vocal tics characterized by loud shrieking. The vocal tics are disruptive in class, even though Sammy sits toward the back of the room. Sammy’s classmates tease him, and he is very frustrated.

Medication approach

The decision to start a medication for tics is complex. Scores from the YGTSS, PUTS, and GTS-QOL scales (Table 3) provide only a partial clinical picture. This decision should be reached after a detailed discussion with the family about benefits and risks of medications and ensuring that everyone’s expectations are reasonable.

A variety of medications are available to treat patients with tics (Table 4). No medication can completely eliminate tics, however, and many have substantial side effects. Before initiating medical treatment, consider 3 questions:

• Is moderate or severe pain involved?
• Is there significant functional interference?
• Is there significant social disruption despite efforts to optimize the social environment for the child?

Sammy’s frequent neck-jerking tics now cause chronic daily headaches, and his shrieking vocal tics are interfering with classroom activities, so we recommended a 3-month trial of guanfacine following the dosing schedule in Table 4.

Table 3

3 scales for assessing tic severity and impact on functioning

Table 4

Medications with evidence of tic-suppressing effects*

The first-line pharmacologic agent for tic suppression generally is an alpha-adrenergic medication, unless the tics are severe.⁶

Clonidine and guanfacine usually are started at low doses and increased gradually. Although not as effective as neuroleptics, alpha-adrenergics have a lower potential for side effects and are easier to use because no laboratory tests need to be monitored. Adverse effects associated with alpha-adrenergic medications include sedation, dry mouth, dizziness, headache, and rebound hypertension if discontinued abruptly.

If tics are causing pain, some clinicians prefer conservative measures such as heat or ice, massage, analgesics, relaxation therapy, and reassurance.

Second-line agents include typical and atypical antipsychotics. Haloperidol and pimozide have shown efficacy in reducing tics in placebo- controlled studies,^7,8 as have risperidone (in 4 randomized controlled trials [RCTs]) and ziprasidone (in 1 RCT).^9,10 The emergence of serious side effects is a risk for both typical and atypical antipsychotics (Table 5).

Table 5

Potential adverse effects of antipsychotic treatment in children*

As part of your informed consent discussion, weigh the risk of side effects against the benefits of treatment. Point out to patients and their families that they can expect to see a decrease in tic frequency, but symptoms will not necessarily disappear with any medication. We tell our patients that with antipsychotics the best we can hope for is to reduce tic frequency by approximately one-half.⁶

When treating tics, start with 1 medication. However, if the tics are severe enough to require more than 1 medication, check for drug interactions.

Third-line agents. Agents that have not been tested in placebo-controlled trials can be considered third line; these are listed as category C (supported by open-label studies) in Table 4. Botulinum toxin injection has been found to be effective for motor and vocal tics.^11,12 Botulinum toxin and implantation of deep brain stimulators¹³ are invasive options and generally are reserved for severe, treatment-resistant tics.

CASE CONTINUED: Managing antipsychotics

After trying guanfacine for 12 weeks, Sammy notices no tic reduction. His parents consent to a low dose of risperidone. you review with them the American Psychiatric Association (APA)/American Diabetes Association (ADA) guidelines¹⁴ for managing metabolic problems in patients treated with atypical antipsychotics.

As instructed in the APA/ADA guidelines, obtain baseline measurements and monitor for metabolic effects of antipsychotic therapy over time (Table 6). Sammy starts risperidone at 0.5 mg once daily. After 2 weeks, he notices a decrease in his tics. At the 3-month visit after starting risperidone, he is happy with his risperidone dose and does not want to increase it. He has gained 3 pounds, and you instruct him to eat a well-balanced diet and exercise routinely. At the 6-month visit, his tics are minimal and his weight has stabilized.

Table 6

Children receiving antipsychotics: monitoring recommendations

You recommend that Sammy remain on risperidone for another 3 months of stability and then begin to taper this medication. You review the risks and benefits of long-term treatment with risperidone, pointing out that it may lead to abnormal movements upon withdrawal, and explain that you typically do not treat children with antipsychotics for more than one year continuously.

CASE CONTINUED: Comorbid symptoms

Since starting 7th grade, Sammy has worried excessively about making mistakes. He spends 6 hours each night on homework, which he often does not turn in because of anxiety about not getting answers perfectly right. Classmates notice that Sammy taps the door 3 times when he comes into the classroom and that he steps over the black tiles in the hallway.

Consider the presence and impact of comorbid OCD or ADHD, which can impair children’s quality of life more than tics themselves.¹⁵ Assessment scales can help you make a diagnosis and monitor treatment.

If you suspect OCD, the clinician-rated Children’s Yale Brown Obsessive Compulsive Scale is the gold standard for describing the phenomenology and measuring symptom severity. Additional scales to measure symptoms’ impact on family life include the Leyton Obsessional Inventory—child version, Family Accommodation Scale for OCD, and Child OCD Impact Scale.

ADHD scales include the Conners Parent Rating Scale—Revised, Conners Teacher Rating Scale—Revised, Swanson, Nolan, and Pelham, or the Vanderbilt ADHD Diagnostic Parent and Teacher Rating Scales. Because ADHD symptoms must be present in more than 1 environment to meet diagnostic criteria, ask parents and teachers to complete the Conners or Vanderbilt scales.

In children who present with a tic disorder plus a comorbid condition, prioritize treatment by determining which symptoms interfere with the child’s ability to function at school, at home, and in the social arena. Children who require treatment for >1 disorder often are referred initially for cognitive-behavioral therapy for OCD symptoms while receiving pharmacologic treatment for ADHD and/or Tourette syndrome. When necessary, it is usually safe to combine antipsychotics, stimulants, and selective serotonin reuptake inhibitors, although medication interactions should be reviewed in each specific case.

Related resources

• Woods DW. Managing Tourette syndrome: a behavioral intervention for children and adults. Therapist guide. New York, NY: Oxford University Press; 2008.
• Tourette Syndrome Association. www.tsa-usa.org.
• International OCD Foundation. www.ocfoundation.org.

Drug brand names

• Baclofen • Lioresal
• Botulinum toxin • Botox, Myobloc
• Clomipramine • Anafranil
• Clonidine • Catapres
• Guanfacine • Tenex
• Fluphenazine • Prolixin
• Flutamide • Eulexin
• Haloperidol • Haldol
• Mecamylamine • Inversine
• Nicotine patch • NicoDerm
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Tetrabenazine • Xenazine
• Ziprasidone • Geodon

Disclosures

Dr. Harris has received research support from the Translational Research Initiative at Cincinnati Children’s Hospital Medical Center.

Dr. Wu reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article

Sammy, age 7, is referred to you by his pediatrician because of a 4-week history of frequent eye blinking. His parents say he blinks a lot when bored but very little when playing baseball. They recall that he also has intermittently sniffed and nodded his head over the last 12 months. Neither Sammy nor his friends seem to be bothered by the blinking. Except for the tics, Sammy’s physical and mental status exams are normal.

Since preschool, Sammy’s teachers have complained that his backpack and desk are always a mess. Sammy is well-meaning but forgetful in his chores at home. A paternal uncle has head-turning movements, counts his steps, and becomes distressed if books on his shelf are not in alphabetical order.

Tics, such as strong eye blinks or repetitive shoulder shrugs, can distress a child or his/her parents, but the conditions associated with tic disorders often are more problematic than the tic disorder itself. High rates of comorbid conditions are recognized in persons with Tourette syndrome, including:

• obsessive-compulsive disorder (OCD) in >80%¹
• attention-deficit/hyperactivity disorder (ADHD) in ≤70%²
• anxiety disorders in 30%³
• rage, aggression, learning disabilities, and autism less commonly.

The strategy we recommend for managing tic disorders includes assessing tic severity, educating the family about the illness, determining whether a comorbid condition is present, and managing these conditions appropriately. Above all, we emphasize a risk-benefit analysis guided by the Hippocratic principle of “do no harm.”

Characteristics of tic disorders

You diagnose Sammy with Tourette syndrome because he meets DSM-IV-TR criteria of at least 2 motor tics and 1 vocal tic that have persisted for 1 year without more than a 3-month hiatus, with tic onset before age 18. Because tics may resemble other movement disorders, you rule out stereotypies, dystonia, chorea, ballism, and myoclonus (Table 1). You explain to his parents that Sammy’s condition is a heritable, neurobehavioral disorder that typically begins in childhood and is associated in families with OCD, ADHD, and autism spectrum disorders.

His parents ask about the difference between tics and other movements. You explain that eye-blinking tics—like other motor tics—appear as sudden, repetitive, stereotyped, nonrhythmic movements that involve discrete muscle groups. (View a video of a patient with tics.) Simple motor tics are focal movements involving 1 group of muscles, whereas complex tics are sequential patterns of movement that involve >1 muscle group or resemble purposeful movements (Table 2).

Table 1

Features of 5 movement disorders that may resemble tics

Table 2

Characteristics of simple and complex motor and vocal tics*

Older children frequently describe a premonitory urge prior to the tic. Patients typically can suppress tics for a transient period of time, although during tic suppression they usually feel restless and anticipate performing their tic. The ultimate performance of the tic brings relief. Tic suppression also occurs during focused activity. Emotional stress, fatigue, illness, or boredom can exacerbate tics.

To begin monitoring Sammy’s clinical course, you administer 3 assessment tools described inTable 3. You explain to Sammy’s parents that these tests will be repeated yearly or when tics worsen. However, you tell his parents that these scores alone will not determine present or future clinical decisions, including treatments. You also recommend that they connect with support groups on the Tourette Syndrome Association (TSA) Web site.

CASE CONTINUED: Changes over time

Sammy’s parents appreciate your explanation and say they will share information from the TSA Web site with Sammy’s principal, teachers, and classmates. The family agrees to return in 6 months or sooner if the tics worsen.

By age 8, Sammy develops multiple tics: facial grimacing, looking upwards, punching movements, whistling, and throat clearing. He is slightly bothered by these tics, and his friends have asked him about them. He tells them he has Tourette syndrome, and that usually ends the questioning. He returns for a follow-up visit because his parents notice a dramatic increase in his tics after Sammy’s father loses his job.

Treatment options

When deciding to treat a child’s tics, the first step is to determine whether to pursue a nonpharmacologic or pharmacologic approach (Algorithm). To tailor an approach most suited for an individual child, discuss with the family their feelings about therapy and medications. This information—along with tic severity—will help determine a treatment plan.

Behavior therapy and medication are management strategies; neither can cure a tic disorder. The most conservative approach to tic treatment is to:

• provide the child and family with basic guidelines for managing tics
• help alleviate environmental stress and other potential triggers.

Algorithm: Recommended treatment of tics in children and adolescents

CASE CONTINUED: A first intervention

You discuss treatment options with Sammy’s family, and they view medication as a last resort. Sammy does not seem to be bothered by his tics, and his parents do not wish to start him on daily medications. Given this situation, habit reversal therapy (HRT) is appropriate for Sammy because he is old enough to participate in HRT to reduce his tics.

HRT is an effective nonpharmacologic approach to help children with tics.⁴ Its 3 components are:

• awareness training
• competing response training
• social support.⁵

This simplified version of the original HRT can be completed in eight 1-hour sessions. Good candidates are patients who are cognitively mature enough to understand the therapy’s goals and compliant with frequent clinic visits. They also must practice the strategies at home.

It should not be difficult for psychiatrists to learn HRT—or refer to therapists who are willing to learn it—with the available instructional manual.

CASE CONTINUED: Practicing alternatives

You ask Sammy to imitate his tics. After helping him become more aware of his tics, you encourage him to develop a more socially appropriate movement to engage in whenever he feels the urge to punch. Sammy chooses to clench his fist in his pocket. He also learns to breathe in whenever he has an urge to whistle. you advise Sammy’s parents to reward his efforts to suppress the tics. He practices the strategies daily.

At age 12, Sammy returns to your office. He has begun to have frequent neck-jerking tics, which cause neck pain and daily headaches. He also is slapping his thigh and having frequent vocal tics characterized by loud shrieking. The vocal tics are disruptive in class, even though Sammy sits toward the back of the room. Sammy’s classmates tease him, and he is very frustrated.

Medication approach

The decision to start a medication for tics is complex. Scores from the YGTSS, PUTS, and GTS-QOL scales (Table 3) provide only a partial clinical picture. This decision should be reached after a detailed discussion with the family about benefits and risks of medications and ensuring that everyone’s expectations are reasonable.

A variety of medications are available to treat patients with tics (Table 4). No medication can completely eliminate tics, however, and many have substantial side effects. Before initiating medical treatment, consider 3 questions:

• Is moderate or severe pain involved?
• Is there significant functional interference?
• Is there significant social disruption despite efforts to optimize the social environment for the child?

Sammy’s frequent neck-jerking tics now cause chronic daily headaches, and his shrieking vocal tics are interfering with classroom activities, so we recommended a 3-month trial of guanfacine following the dosing schedule in Table 4.

Table 3

3 scales for assessing tic severity and impact on functioning

Table 4

Medications with evidence of tic-suppressing effects*

The first-line pharmacologic agent for tic suppression generally is an alpha-adrenergic medication, unless the tics are severe.⁶

Clonidine and guanfacine usually are started at low doses and increased gradually. Although not as effective as neuroleptics, alpha-adrenergics have a lower potential for side effects and are easier to use because no laboratory tests need to be monitored. Adverse effects associated with alpha-adrenergic medications include sedation, dry mouth, dizziness, headache, and rebound hypertension if discontinued abruptly.

If tics are causing pain, some clinicians prefer conservative measures such as heat or ice, massage, analgesics, relaxation therapy, and reassurance.

Second-line agents include typical and atypical antipsychotics. Haloperidol and pimozide have shown efficacy in reducing tics in placebo- controlled studies,^7,8 as have risperidone (in 4 randomized controlled trials [RCTs]) and ziprasidone (in 1 RCT).^9,10 The emergence of serious side effects is a risk for both typical and atypical antipsychotics (Table 5).

Table 5

Potential adverse effects of antipsychotic treatment in children*

As part of your informed consent discussion, weigh the risk of side effects against the benefits of treatment. Point out to patients and their families that they can expect to see a decrease in tic frequency, but symptoms will not necessarily disappear with any medication. We tell our patients that with antipsychotics the best we can hope for is to reduce tic frequency by approximately one-half.⁶

When treating tics, start with 1 medication. However, if the tics are severe enough to require more than 1 medication, check for drug interactions.

Third-line agents. Agents that have not been tested in placebo-controlled trials can be considered third line; these are listed as category C (supported by open-label studies) in Table 4. Botulinum toxin injection has been found to be effective for motor and vocal tics.^11,12 Botulinum toxin and implantation of deep brain stimulators¹³ are invasive options and generally are reserved for severe, treatment-resistant tics.

CASE CONTINUED: Managing antipsychotics

After trying guanfacine for 12 weeks, Sammy notices no tic reduction. His parents consent to a low dose of risperidone. you review with them the American Psychiatric Association (APA)/American Diabetes Association (ADA) guidelines¹⁴ for managing metabolic problems in patients treated with atypical antipsychotics.

As instructed in the APA/ADA guidelines, obtain baseline measurements and monitor for metabolic effects of antipsychotic therapy over time (Table 6). Sammy starts risperidone at 0.5 mg once daily. After 2 weeks, he notices a decrease in his tics. At the 3-month visit after starting risperidone, he is happy with his risperidone dose and does not want to increase it. He has gained 3 pounds, and you instruct him to eat a well-balanced diet and exercise routinely. At the 6-month visit, his tics are minimal and his weight has stabilized.

Table 6

Children receiving antipsychotics: monitoring recommendations

You recommend that Sammy remain on risperidone for another 3 months of stability and then begin to taper this medication. You review the risks and benefits of long-term treatment with risperidone, pointing out that it may lead to abnormal movements upon withdrawal, and explain that you typically do not treat children with antipsychotics for more than one year continuously.

CASE CONTINUED: Comorbid symptoms

Since starting 7th grade, Sammy has worried excessively about making mistakes. He spends 6 hours each night on homework, which he often does not turn in because of anxiety about not getting answers perfectly right. Classmates notice that Sammy taps the door 3 times when he comes into the classroom and that he steps over the black tiles in the hallway.

Consider the presence and impact of comorbid OCD or ADHD, which can impair children’s quality of life more than tics themselves.¹⁵ Assessment scales can help you make a diagnosis and monitor treatment.

If you suspect OCD, the clinician-rated Children’s Yale Brown Obsessive Compulsive Scale is the gold standard for describing the phenomenology and measuring symptom severity. Additional scales to measure symptoms’ impact on family life include the Leyton Obsessional Inventory—child version, Family Accommodation Scale for OCD, and Child OCD Impact Scale.

ADHD scales include the Conners Parent Rating Scale—Revised, Conners Teacher Rating Scale—Revised, Swanson, Nolan, and Pelham, or the Vanderbilt ADHD Diagnostic Parent and Teacher Rating Scales. Because ADHD symptoms must be present in more than 1 environment to meet diagnostic criteria, ask parents and teachers to complete the Conners or Vanderbilt scales.

In children who present with a tic disorder plus a comorbid condition, prioritize treatment by determining which symptoms interfere with the child’s ability to function at school, at home, and in the social arena. Children who require treatment for >1 disorder often are referred initially for cognitive-behavioral therapy for OCD symptoms while receiving pharmacologic treatment for ADHD and/or Tourette syndrome. When necessary, it is usually safe to combine antipsychotics, stimulants, and selective serotonin reuptake inhibitors, although medication interactions should be reviewed in each specific case.

Related resources

• Woods DW. Managing Tourette syndrome: a behavioral intervention for children and adults. Therapist guide. New York, NY: Oxford University Press; 2008.
• Tourette Syndrome Association. www.tsa-usa.org.
• International OCD Foundation. www.ocfoundation.org.

Drug brand names

• Baclofen • Lioresal
• Botulinum toxin • Botox, Myobloc
• Clomipramine • Anafranil
• Clonidine • Catapres
• Guanfacine • Tenex
• Fluphenazine • Prolixin
• Flutamide • Eulexin
• Haloperidol • Haldol
• Mecamylamine • Inversine
• Nicotine patch • NicoDerm
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Tetrabenazine • Xenazine
• Ziprasidone • Geodon

Disclosures

Dr. Harris has received research support from the Translational Research Initiative at Cincinnati Children’s Hospital Medical Center.

Dr. Wu reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article

Sammy, age 7, is referred to you by his pediatrician because of a 4-week history of frequent eye blinking. His parents say he blinks a lot when bored but very little when playing baseball. They recall that he also has intermittently sniffed and nodded his head over the last 12 months. Neither Sammy nor his friends seem to be bothered by the blinking. Except for the tics, Sammy’s physical and mental status exams are normal.

Since preschool, Sammy’s teachers have complained that his backpack and desk are always a mess. Sammy is well-meaning but forgetful in his chores at home. A paternal uncle has head-turning movements, counts his steps, and becomes distressed if books on his shelf are not in alphabetical order.

Tics, such as strong eye blinks or repetitive shoulder shrugs, can distress a child or his/her parents, but the conditions associated with tic disorders often are more problematic than the tic disorder itself. High rates of comorbid conditions are recognized in persons with Tourette syndrome, including:

• obsessive-compulsive disorder (OCD) in >80%¹
• attention-deficit/hyperactivity disorder (ADHD) in ≤70%²
• anxiety disorders in 30%³
• rage, aggression, learning disabilities, and autism less commonly.

The strategy we recommend for managing tic disorders includes assessing tic severity, educating the family about the illness, determining whether a comorbid condition is present, and managing these conditions appropriately. Above all, we emphasize a risk-benefit analysis guided by the Hippocratic principle of “do no harm.”

Characteristics of tic disorders

You diagnose Sammy with Tourette syndrome because he meets DSM-IV-TR criteria of at least 2 motor tics and 1 vocal tic that have persisted for 1 year without more than a 3-month hiatus, with tic onset before age 18. Because tics may resemble other movement disorders, you rule out stereotypies, dystonia, chorea, ballism, and myoclonus (Table 1). You explain to his parents that Sammy’s condition is a heritable, neurobehavioral disorder that typically begins in childhood and is associated in families with OCD, ADHD, and autism spectrum disorders.

His parents ask about the difference between tics and other movements. You explain that eye-blinking tics—like other motor tics—appear as sudden, repetitive, stereotyped, nonrhythmic movements that involve discrete muscle groups. (View a video of a patient with tics.) Simple motor tics are focal movements involving 1 group of muscles, whereas complex tics are sequential patterns of movement that involve >1 muscle group or resemble purposeful movements (Table 2).

Table 1

Features of 5 movement disorders that may resemble tics

Table 2

Characteristics of simple and complex motor and vocal tics*

Older children frequently describe a premonitory urge prior to the tic. Patients typically can suppress tics for a transient period of time, although during tic suppression they usually feel restless and anticipate performing their tic. The ultimate performance of the tic brings relief. Tic suppression also occurs during focused activity. Emotional stress, fatigue, illness, or boredom can exacerbate tics.

To begin monitoring Sammy’s clinical course, you administer 3 assessment tools described inTable 3. You explain to Sammy’s parents that these tests will be repeated yearly or when tics worsen. However, you tell his parents that these scores alone will not determine present or future clinical decisions, including treatments. You also recommend that they connect with support groups on the Tourette Syndrome Association (TSA) Web site.

CASE CONTINUED: Changes over time

Sammy’s parents appreciate your explanation and say they will share information from the TSA Web site with Sammy’s principal, teachers, and classmates. The family agrees to return in 6 months or sooner if the tics worsen.

By age 8, Sammy develops multiple tics: facial grimacing, looking upwards, punching movements, whistling, and throat clearing. He is slightly bothered by these tics, and his friends have asked him about them. He tells them he has Tourette syndrome, and that usually ends the questioning. He returns for a follow-up visit because his parents notice a dramatic increase in his tics after Sammy’s father loses his job.

Treatment options

When deciding to treat a child’s tics, the first step is to determine whether to pursue a nonpharmacologic or pharmacologic approach (Algorithm). To tailor an approach most suited for an individual child, discuss with the family their feelings about therapy and medications. This information—along with tic severity—will help determine a treatment plan.

Behavior therapy and medication are management strategies; neither can cure a tic disorder. The most conservative approach to tic treatment is to:

• provide the child and family with basic guidelines for managing tics
• help alleviate environmental stress and other potential triggers.

Algorithm: Recommended treatment of tics in children and adolescents

CASE CONTINUED: A first intervention

You discuss treatment options with Sammy’s family, and they view medication as a last resort. Sammy does not seem to be bothered by his tics, and his parents do not wish to start him on daily medications. Given this situation, habit reversal therapy (HRT) is appropriate for Sammy because he is old enough to participate in HRT to reduce his tics.

HRT is an effective nonpharmacologic approach to help children with tics.⁴ Its 3 components are:

• awareness training
• competing response training
• social support.⁵

This simplified version of the original HRT can be completed in eight 1-hour sessions. Good candidates are patients who are cognitively mature enough to understand the therapy’s goals and compliant with frequent clinic visits. They also must practice the strategies at home.

It should not be difficult for psychiatrists to learn HRT—or refer to therapists who are willing to learn it—with the available instructional manual.

CASE CONTINUED: Practicing alternatives

You ask Sammy to imitate his tics. After helping him become more aware of his tics, you encourage him to develop a more socially appropriate movement to engage in whenever he feels the urge to punch. Sammy chooses to clench his fist in his pocket. He also learns to breathe in whenever he has an urge to whistle. you advise Sammy’s parents to reward his efforts to suppress the tics. He practices the strategies daily.

At age 12, Sammy returns to your office. He has begun to have frequent neck-jerking tics, which cause neck pain and daily headaches. He also is slapping his thigh and having frequent vocal tics characterized by loud shrieking. The vocal tics are disruptive in class, even though Sammy sits toward the back of the room. Sammy’s classmates tease him, and he is very frustrated.

Medication approach

The decision to start a medication for tics is complex. Scores from the YGTSS, PUTS, and GTS-QOL scales (Table 3) provide only a partial clinical picture. This decision should be reached after a detailed discussion with the family about benefits and risks of medications and ensuring that everyone’s expectations are reasonable.

A variety of medications are available to treat patients with tics (Table 4). No medication can completely eliminate tics, however, and many have substantial side effects. Before initiating medical treatment, consider 3 questions:

• Is moderate or severe pain involved?
• Is there significant functional interference?
• Is there significant social disruption despite efforts to optimize the social environment for the child?

Sammy’s frequent neck-jerking tics now cause chronic daily headaches, and his shrieking vocal tics are interfering with classroom activities, so we recommended a 3-month trial of guanfacine following the dosing schedule in Table 4.

Table 3

3 scales for assessing tic severity and impact on functioning

Table 4

Medications with evidence of tic-suppressing effects*

The first-line pharmacologic agent for tic suppression generally is an alpha-adrenergic medication, unless the tics are severe.⁶

Clonidine and guanfacine usually are started at low doses and increased gradually. Although not as effective as neuroleptics, alpha-adrenergics have a lower potential for side effects and are easier to use because no laboratory tests need to be monitored. Adverse effects associated with alpha-adrenergic medications include sedation, dry mouth, dizziness, headache, and rebound hypertension if discontinued abruptly.

If tics are causing pain, some clinicians prefer conservative measures such as heat or ice, massage, analgesics, relaxation therapy, and reassurance.

Second-line agents include typical and atypical antipsychotics. Haloperidol and pimozide have shown efficacy in reducing tics in placebo- controlled studies,^7,8 as have risperidone (in 4 randomized controlled trials [RCTs]) and ziprasidone (in 1 RCT).^9,10 The emergence of serious side effects is a risk for both typical and atypical antipsychotics (Table 5).

Table 5

Potential adverse effects of antipsychotic treatment in children*

As part of your informed consent discussion, weigh the risk of side effects against the benefits of treatment. Point out to patients and their families that they can expect to see a decrease in tic frequency, but symptoms will not necessarily disappear with any medication. We tell our patients that with antipsychotics the best we can hope for is to reduce tic frequency by approximately one-half.⁶

When treating tics, start with 1 medication. However, if the tics are severe enough to require more than 1 medication, check for drug interactions.

Third-line agents. Agents that have not been tested in placebo-controlled trials can be considered third line; these are listed as category C (supported by open-label studies) in Table 4. Botulinum toxin injection has been found to be effective for motor and vocal tics.^11,12 Botulinum toxin and implantation of deep brain stimulators¹³ are invasive options and generally are reserved for severe, treatment-resistant tics.

CASE CONTINUED: Managing antipsychotics

After trying guanfacine for 12 weeks, Sammy notices no tic reduction. His parents consent to a low dose of risperidone. you review with them the American Psychiatric Association (APA)/American Diabetes Association (ADA) guidelines¹⁴ for managing metabolic problems in patients treated with atypical antipsychotics.

As instructed in the APA/ADA guidelines, obtain baseline measurements and monitor for metabolic effects of antipsychotic therapy over time (Table 6). Sammy starts risperidone at 0.5 mg once daily. After 2 weeks, he notices a decrease in his tics. At the 3-month visit after starting risperidone, he is happy with his risperidone dose and does not want to increase it. He has gained 3 pounds, and you instruct him to eat a well-balanced diet and exercise routinely. At the 6-month visit, his tics are minimal and his weight has stabilized.

Table 6

Children receiving antipsychotics: monitoring recommendations

You recommend that Sammy remain on risperidone for another 3 months of stability and then begin to taper this medication. You review the risks and benefits of long-term treatment with risperidone, pointing out that it may lead to abnormal movements upon withdrawal, and explain that you typically do not treat children with antipsychotics for more than one year continuously.

CASE CONTINUED: Comorbid symptoms

Since starting 7th grade, Sammy has worried excessively about making mistakes. He spends 6 hours each night on homework, which he often does not turn in because of anxiety about not getting answers perfectly right. Classmates notice that Sammy taps the door 3 times when he comes into the classroom and that he steps over the black tiles in the hallway.

Consider the presence and impact of comorbid OCD or ADHD, which can impair children’s quality of life more than tics themselves.¹⁵ Assessment scales can help you make a diagnosis and monitor treatment.

If you suspect OCD, the clinician-rated Children’s Yale Brown Obsessive Compulsive Scale is the gold standard for describing the phenomenology and measuring symptom severity. Additional scales to measure symptoms’ impact on family life include the Leyton Obsessional Inventory—child version, Family Accommodation Scale for OCD, and Child OCD Impact Scale.

ADHD scales include the Conners Parent Rating Scale—Revised, Conners Teacher Rating Scale—Revised, Swanson, Nolan, and Pelham, or the Vanderbilt ADHD Diagnostic Parent and Teacher Rating Scales. Because ADHD symptoms must be present in more than 1 environment to meet diagnostic criteria, ask parents and teachers to complete the Conners or Vanderbilt scales.

In children who present with a tic disorder plus a comorbid condition, prioritize treatment by determining which symptoms interfere with the child’s ability to function at school, at home, and in the social arena. Children who require treatment for >1 disorder often are referred initially for cognitive-behavioral therapy for OCD symptoms while receiving pharmacologic treatment for ADHD and/or Tourette syndrome. When necessary, it is usually safe to combine antipsychotics, stimulants, and selective serotonin reuptake inhibitors, although medication interactions should be reviewed in each specific case.

Related resources

• Woods DW. Managing Tourette syndrome: a behavioral intervention for children and adults. Therapist guide. New York, NY: Oxford University Press; 2008.
• Tourette Syndrome Association. www.tsa-usa.org.
• International OCD Foundation. www.ocfoundation.org.

Drug brand names

• Baclofen • Lioresal
• Botulinum toxin • Botox, Myobloc
• Clomipramine • Anafranil
• Clonidine • Catapres
• Guanfacine • Tenex
• Fluphenazine • Prolixin
• Flutamide • Eulexin
• Haloperidol • Haldol
• Mecamylamine • Inversine
• Nicotine patch • NicoDerm
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Tetrabenazine • Xenazine
• Ziprasidone • Geodon

Disclosures

Dr. Harris has received research support from the Translational Research Initiative at Cincinnati Children’s Hospital Medical Center.

Dr. Wu reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article

Most psychiatrists have encountered patients who report distressing symptoms when they have forgotten to take their antidepressant for a few days or during changes in the medication regimen. A discontinuation syndrome can occur with almost any antidepressant, highlighting the need to slowly taper these medications when discontinuation is part of a treatment plan.

This article discusses antidepressant discontinuation syndrome (ADS) in a patient who experienced substantial distress after a rapid antidepressant taper in preparation for electroconvulsive therapy (ECT). My goal is to raise awareness of ADS, promote early detection of the syndrome, and address proper prevention and management strategies.

CASE REPORT: Feeling ‘worse than ever’

Mr. J, a 32-year-old tax accountant, is hospitalized for a major depressive episode (MDE) associated with deteriorating function and suicidal ideation. This second lifetime MDE started 8 months before his admission to an inpatient mood disorders unit.

Mr. J initially was treated with fluoxetine, up to 40 mg/d across 14 weeks, with good tolerability but no significant benefit. His psychiatrist switched Mr. J to bupropion but stopped it after 4 weeks because of side effects—including headaches, insomnia, and tremor—and limited antidepressant benefit. Venlafaxine XR was initiated next, at 150 mg/d within the first 2 weeks, increased to 225 mg/d at week 6, then titrated to 300 mg/d at week 10. After 10 weeks, aripiprazole, 5 mg/d, was added because Mr. J showed only partial, limited response to venlafaxine XR and this antipsychotic is indicated for adjunctive treatment of major depressive disorder.

Mr. J reported mild, transient restlessness but otherwise he tolerated the medications well, and he claimed excellent adherence. After 6 additional weeks of treatment, however, Mr. J was hospitalized because of persistent severely depressed mood, increasing suicidal ideation, and inability to function at work.

On admission, Mr. J is evaluated and agrees to ECT. To meet the ECT service’s protocol, venlafaxine XR is reduced to 150 mg/d for 2 days and then stopped when ECT is started. Aripiprazole is continued at 5 mg/d.

Mr. J tolerates the first ECT treatment well, but the morning before his second treatment he complains of feeling “worse than ever.” An agitated Mr. J reports dramatically intensified suicidal ideation—much more intrusive than before he was hospitalized. He also complains of diffuse muscle aches and cramps, runny nose, nausea, headache, and burning sensations in both arms and hands. He withdraws consent for ECT and returns to the mood disorders unit for ongoing treatment.

Could this be ADS?

Yes, it could. In this case, the inpatient psychiatrist and treatment team were lulled into a false sense of security by Mr. J’s history of few side effects with various treatments and medication changes. The ECT service wanted the patient off venlafaxine XR before beginning ECT, and the treatment team believed a quick taper would not cause discontinuation symptoms because Mr. J was taking an “extended-release” medication.

Within 72 hours, Mr. J went from taking 300 mg/d of venlafaxine XR to none. Within 2 days of cessation, he complained of symptoms that could characterize a discontinuation syndrome. A potential red herring in this case is that the patient complained of feeling worse after his first ECT treatment, and one might erroneously think the myalgias, headache, and other somatic symptoms were side effects of ECT and/or anesthesia.

Typical ADS symptoms

Nearly all antidepressant classes are associated with ADS. Symptoms vary from patient to patient but typically include the “FINISH” syndrome: flu-like symptoms, ###bold/bold###nsomnia, nausea, ###bold/bold###mbalance, sensory disturbances, and hyperarousal (anxiety/agitation) (Table 1).¹

Adverse effects after stopping tricyclic antidepressants have been well documented. They may include FINISH syndrome features as well as cholinergic overdrive or “rebound” such as abdominal cramping and diarrhea.^2-4 Reports of ADS after patients stopped selective serotonin reuptake inhibitors (SSRIs) emerged soon after these agents were introduced.^5-7 Similarly, ADS has been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine,^8-10 venlafaxine XR,¹¹ and duloxetine.¹² ADS symptoms are similar with SSRIs and SNRIs, generally without the anticholinergic effects associated with tricyclic antidepressant discontinuation.

Fewer reports of discontinuation syndrome exist for bupropion, mirtazapine, monoamine oxidase inhibitors (MAOIs), and nefazodone.^13-17 Discontinuation-emergent syndromes with these non-SSRI/non-SNRI antidepressants tend to present differently. With MAOIs, for example, neuropsychiatric symptoms such as severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, delirium, and paranoid psychosis can be prominent.¹⁷

The prevalence of ADS is unclear, and published estimates vary widely because of the lack of large controlled studies. ADS rates with SSRIs/SNRIs have been reported from as low as 0% for fluoxetine to higher rates for shorter half-life antidepressants:

• 2.2% with sertraline
• 14% with fluvoxamine
• 20% with paroxetine
• 30.8% with clomipramine.

These rates come from a retrospective case note review of patients who discontinued antidepressants under supervision.¹⁸ In a small cohort of outpatients being treated for major depressive disorder, stopping venlafaxine XR was associated with discontinuation symptoms for the next 3 days in 7 of 9 patients (78%), compared with 2 of 9 patients (22%) stopping placebo.¹¹

Diagnostic criteria have been proposed for ADS associated with serotonin (5-HT) reuptake inhibitors.^19-22 Proposed ADS definitions differ somewhat, but essentially 3 features guide the diagnosis:

• appearance of characteristic symptoms (Table 2)^21,23
• timing of those symptoms, which usually emerge within 1 week of abrupt cessation or marked reduction of the antidepressant
• symptoms generally are mild, short-lived, self-limiting, and/or rapidly reversed by restarting the original antidepressant.

Evidence suggests shorter half-life antidepressants may be associated with the highest risk for ADS, but other risk factors remain presumptive (Table 3).

Table 1

FINISH: Symptoms of antidepressant discontinuation syndrome

Table 2

ADS symptoms can range across a variety of system clusters

Table 3

Possible patient risk factors for developing ADS*

What causes ADS?

Although the exact cause of ADS is unknown, the literature proposes several theories.

Because of the central serotonin system’s complex connections, acute reduction in synaptic serotonin when an SSRI or SNRI is abruptly or too quickly stopped may be the first in a cascade of steps affecting transmission of multiple monoamines. Parallels have been drawn between the phenomenon observed with rapid depletion of tryptophan—the essential amino acid precursor for the synthesis of 5-HT—and ADS seen with abrupt discontinuation of serotonergic antidepressants. This suggests that acute drops in neurotransmitter levels can precipitate neuropsychiatric and somatic manifestations of ADS.²⁴

Patients’ uncomfortable symptoms likely are caused by the serotonin, norepinephrine, and cholinergic systems and their complex interactions.²⁵ Individual genetic factors may influence patients’ vulnerability for ADS.

Managing ADS

Awareness and prevention. ADS can be misinterpreted as side effects of newly started treatment after an antidepressant is stopped. In Mr. J’s case, the appearance of muscle aches, headaches, and other ADS symptoms after ECT was started easily could have been perceived as adverse effects of ECT. Mr. J’s agitation and increased suicidal ideation could lead a clinician to mistakenly think that MDE was worsening because the antidepressant was stopped before ECT became effective. Being aware of ADS can prevent misdiagnosis and allow you to quickly identify the condition, manage the reversible syndrome, and continue with new treatment plan—in this case, ECT.

You can help prevent ADS by educating patients about the need to adhere to antidepressant regimens and to avoid missing doses. Consider ADS risk factors—particularly medications’ half-lives—before you start, change, or stop antidepressant therapy. Gradually taper all antidepressants being discontinued, with the possible exception of fluoxetine (which, including its active metabolite, has an elimination half-life of approximately 1 to 2 weeks).

Tapering antidepressants is more art than science because we have no controlled data to support any particular tapering regimen. Tailor the taper duration based on each patient’s response to sequential dosage reductions. Antidepressants with shorter half-lives—such as venlafaxine or paroxetine—may need to be tapered more slowly, perhaps by reducing the dosage by 25% every 4 to 6 weeks. If you plan to switch medications, this process may be expedited during a cross-taper to another antidepressant. You still may see discontinuation symptoms, however, depending on which new agent is chosen and which is being stopped.

Treating ADS. Appropriately recognizing ADS risk and slowly tapering antidepressants as needed usually prevents clinically significant distress associated with discontinuation. For some patients, however, ADS may be particularly severe or prolonged, or may emerge at the end of a slow taper.

Challenging cases may be more likely with paroxetine or venlafaxine—even the extended-release or controlled-release preparations. The elimination half-life of paroxetine is 15 to 20 hours, and the half-lives of venlafaxine and venlafaxine XR are 5 to 11 hours. Desvenlafaxine’s half-life is 11 hours, and product labeling of this enantiomer of racemic venlafaxine notes that discontinuation symptoms have occurred.²⁶ ADS treatment depends on the severity of the reaction and whether or not further antidepressant therapy is necessary.

For mild ADS, reassurance and treatment focused on specific symptoms—such as sedative-hypnotics for insomnia or benzodiazepines for anxiety—may be all that is needed, because ADS tends to gradually resolve over an average of 10 days.²⁷

For more severe ADS, or when ongoing antidepressant therapy is indicated, restarting the recently withdrawn antidepressant at the pre-ADS dosage typically resolves the syndrome within 24 hours. Then employ a slower, more cautious taper when next attempting to discontinue that antidepressant.

Another option. An alternate management strategy is to substitute fluoxetine to suppress ADS associated with shorter half-life SSRIs or SNRIs. Case reports^18,20,28 suggest that fluoxetine, 5 to 20 mg/d, can be used to ameliorate venlafaxine-induced ADS. Fluoxetine can be tried as monotherapy for 1 to 2 weeks and then rapidly tapered or stopped. Others have suggested combination therapy, such as:

• restarting venlafaxine at the pre-ADS dose plus fluoxetine, 20 mg/d
• tapering venlafaxine by 50% every 5 days until stopped
• reducing fluoxetine 1 week later to 10 mg/d for 5 days
• then stopping fluoxetine.²⁸

In general, SSRIs should not be co-administered with SNRIs long-term because of potential additive adverse effects such as serotonin syndrome. Combining fluoxetine with an SNRI such as venlafaxine for the purpose of tapering off venlafaxine and reducing ADS risk probably is safe, however, as long as the fluoxetine dose is low (5 to 20 mg) and SNRI reduction begins immediately, with a plan for complete tapering.

CASE CONTINUED: ECT treatment proceeds

Venlafaxine XR is not restarted to address Mr. J’s suspected ADS because of concerns about potential increased risk for cardiac events (asystole, prolonged bradycardia) during ECT with concomitant venlafaxine use.^29,30 Fluoxetine, which rarely may prolong ECT-induced seizures, is deemed a safer choice and is started immediately at 20 mg/d.

Because of Mr. J’s other symptoms, we prescribe lorazepam, 0.5 mg bid, for anxiety for 2 days; increase aripiprazole to 5 mg bid for agitation; and add zolpidem, 10 mg at bedtime, for insomnia. The following day, Mr. J reports substantial relief from ADS symptoms, including myalgias, paresthesias, and suicidal ideation.^21,23

His second ECT treatment is administered the next day, followed by a successful course of 9 treatments and partial remission of the MDE within 3 weeks. Fluoxetine is reduced to 10 mg/d one week into the ECT series, then discontinued one week later. No signs of emergent ADS are seen at discharge or 2-week outpatient follow-up. Mr. J achieves full remission with maintenance ECT plus bedtime doses of mirtazapine, 30 mg, and aripiprazole, 7.5 mg, across 6 months of follow-up care.

Related resources

• Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(suppl 4):27-30.
• American Family Physician. Patient handout on antidepressant discontinuation. www.aafp.org/afp/2006/0801/p457.html.
• Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77-87. See appendix for discontinuation-emergent signs and symptoms checklist.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Clomipramine • Anafranil
• Desvenlafaxine • Pristiq
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor
• Venlafaxine extended-release • Effexor XR
• Zolpidem • Ambien

Disclosure

Dr. Muzina reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

When Dr. Muzina submitted this article to Current Psychiatry, he was director, Center for Mood Disorders Treatment and Research, Cleveland Clinic Neurological Institute, Cleveland, OH.

Discuss this article

Most psychiatrists have encountered patients who report distressing symptoms when they have forgotten to take their antidepressant for a few days or during changes in the medication regimen. A discontinuation syndrome can occur with almost any antidepressant, highlighting the need to slowly taper these medications when discontinuation is part of a treatment plan.

This article discusses antidepressant discontinuation syndrome (ADS) in a patient who experienced substantial distress after a rapid antidepressant taper in preparation for electroconvulsive therapy (ECT). My goal is to raise awareness of ADS, promote early detection of the syndrome, and address proper prevention and management strategies.

CASE REPORT: Feeling ‘worse than ever’

Mr. J, a 32-year-old tax accountant, is hospitalized for a major depressive episode (MDE) associated with deteriorating function and suicidal ideation. This second lifetime MDE started 8 months before his admission to an inpatient mood disorders unit.

Mr. J initially was treated with fluoxetine, up to 40 mg/d across 14 weeks, with good tolerability but no significant benefit. His psychiatrist switched Mr. J to bupropion but stopped it after 4 weeks because of side effects—including headaches, insomnia, and tremor—and limited antidepressant benefit. Venlafaxine XR was initiated next, at 150 mg/d within the first 2 weeks, increased to 225 mg/d at week 6, then titrated to 300 mg/d at week 10. After 10 weeks, aripiprazole, 5 mg/d, was added because Mr. J showed only partial, limited response to venlafaxine XR and this antipsychotic is indicated for adjunctive treatment of major depressive disorder.

Mr. J reported mild, transient restlessness but otherwise he tolerated the medications well, and he claimed excellent adherence. After 6 additional weeks of treatment, however, Mr. J was hospitalized because of persistent severely depressed mood, increasing suicidal ideation, and inability to function at work.

On admission, Mr. J is evaluated and agrees to ECT. To meet the ECT service’s protocol, venlafaxine XR is reduced to 150 mg/d for 2 days and then stopped when ECT is started. Aripiprazole is continued at 5 mg/d.

Mr. J tolerates the first ECT treatment well, but the morning before his second treatment he complains of feeling “worse than ever.” An agitated Mr. J reports dramatically intensified suicidal ideation—much more intrusive than before he was hospitalized. He also complains of diffuse muscle aches and cramps, runny nose, nausea, headache, and burning sensations in both arms and hands. He withdraws consent for ECT and returns to the mood disorders unit for ongoing treatment.

Could this be ADS?

Yes, it could. In this case, the inpatient psychiatrist and treatment team were lulled into a false sense of security by Mr. J’s history of few side effects with various treatments and medication changes. The ECT service wanted the patient off venlafaxine XR before beginning ECT, and the treatment team believed a quick taper would not cause discontinuation symptoms because Mr. J was taking an “extended-release” medication.

Within 72 hours, Mr. J went from taking 300 mg/d of venlafaxine XR to none. Within 2 days of cessation, he complained of symptoms that could characterize a discontinuation syndrome. A potential red herring in this case is that the patient complained of feeling worse after his first ECT treatment, and one might erroneously think the myalgias, headache, and other somatic symptoms were side effects of ECT and/or anesthesia.

Typical ADS symptoms

Nearly all antidepressant classes are associated with ADS. Symptoms vary from patient to patient but typically include the “FINISH” syndrome: flu-like symptoms, ###bold/bold###nsomnia, nausea, ###bold/bold###mbalance, sensory disturbances, and hyperarousal (anxiety/agitation) (Table 1).¹

Adverse effects after stopping tricyclic antidepressants have been well documented. They may include FINISH syndrome features as well as cholinergic overdrive or “rebound” such as abdominal cramping and diarrhea.^2-4 Reports of ADS after patients stopped selective serotonin reuptake inhibitors (SSRIs) emerged soon after these agents were introduced.^5-7 Similarly, ADS has been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine,^8-10 venlafaxine XR,¹¹ and duloxetine.¹² ADS symptoms are similar with SSRIs and SNRIs, generally without the anticholinergic effects associated with tricyclic antidepressant discontinuation.

Fewer reports of discontinuation syndrome exist for bupropion, mirtazapine, monoamine oxidase inhibitors (MAOIs), and nefazodone.^13-17 Discontinuation-emergent syndromes with these non-SSRI/non-SNRI antidepressants tend to present differently. With MAOIs, for example, neuropsychiatric symptoms such as severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, delirium, and paranoid psychosis can be prominent.¹⁷

The prevalence of ADS is unclear, and published estimates vary widely because of the lack of large controlled studies. ADS rates with SSRIs/SNRIs have been reported from as low as 0% for fluoxetine to higher rates for shorter half-life antidepressants:

• 2.2% with sertraline
• 14% with fluvoxamine
• 20% with paroxetine
• 30.8% with clomipramine.

These rates come from a retrospective case note review of patients who discontinued antidepressants under supervision.¹⁸ In a small cohort of outpatients being treated for major depressive disorder, stopping venlafaxine XR was associated with discontinuation symptoms for the next 3 days in 7 of 9 patients (78%), compared with 2 of 9 patients (22%) stopping placebo.¹¹

Diagnostic criteria have been proposed for ADS associated with serotonin (5-HT) reuptake inhibitors.^19-22 Proposed ADS definitions differ somewhat, but essentially 3 features guide the diagnosis:

• appearance of characteristic symptoms (Table 2)^21,23
• timing of those symptoms, which usually emerge within 1 week of abrupt cessation or marked reduction of the antidepressant
• symptoms generally are mild, short-lived, self-limiting, and/or rapidly reversed by restarting the original antidepressant.

Evidence suggests shorter half-life antidepressants may be associated with the highest risk for ADS, but other risk factors remain presumptive (Table 3).

Table 1

FINISH: Symptoms of antidepressant discontinuation syndrome

Table 2

ADS symptoms can range across a variety of system clusters

Table 3

Possible patient risk factors for developing ADS*

What causes ADS?

Although the exact cause of ADS is unknown, the literature proposes several theories.

Because of the central serotonin system’s complex connections, acute reduction in synaptic serotonin when an SSRI or SNRI is abruptly or too quickly stopped may be the first in a cascade of steps affecting transmission of multiple monoamines. Parallels have been drawn between the phenomenon observed with rapid depletion of tryptophan—the essential amino acid precursor for the synthesis of 5-HT—and ADS seen with abrupt discontinuation of serotonergic antidepressants. This suggests that acute drops in neurotransmitter levels can precipitate neuropsychiatric and somatic manifestations of ADS.²⁴

Patients’ uncomfortable symptoms likely are caused by the serotonin, norepinephrine, and cholinergic systems and their complex interactions.²⁵ Individual genetic factors may influence patients’ vulnerability for ADS.

Managing ADS

Awareness and prevention. ADS can be misinterpreted as side effects of newly started treatment after an antidepressant is stopped. In Mr. J’s case, the appearance of muscle aches, headaches, and other ADS symptoms after ECT was started easily could have been perceived as adverse effects of ECT. Mr. J’s agitation and increased suicidal ideation could lead a clinician to mistakenly think that MDE was worsening because the antidepressant was stopped before ECT became effective. Being aware of ADS can prevent misdiagnosis and allow you to quickly identify the condition, manage the reversible syndrome, and continue with new treatment plan—in this case, ECT.

You can help prevent ADS by educating patients about the need to adhere to antidepressant regimens and to avoid missing doses. Consider ADS risk factors—particularly medications’ half-lives—before you start, change, or stop antidepressant therapy. Gradually taper all antidepressants being discontinued, with the possible exception of fluoxetine (which, including its active metabolite, has an elimination half-life of approximately 1 to 2 weeks).

Tapering antidepressants is more art than science because we have no controlled data to support any particular tapering regimen. Tailor the taper duration based on each patient’s response to sequential dosage reductions. Antidepressants with shorter half-lives—such as venlafaxine or paroxetine—may need to be tapered more slowly, perhaps by reducing the dosage by 25% every 4 to 6 weeks. If you plan to switch medications, this process may be expedited during a cross-taper to another antidepressant. You still may see discontinuation symptoms, however, depending on which new agent is chosen and which is being stopped.

Treating ADS. Appropriately recognizing ADS risk and slowly tapering antidepressants as needed usually prevents clinically significant distress associated with discontinuation. For some patients, however, ADS may be particularly severe or prolonged, or may emerge at the end of a slow taper.

Challenging cases may be more likely with paroxetine or venlafaxine—even the extended-release or controlled-release preparations. The elimination half-life of paroxetine is 15 to 20 hours, and the half-lives of venlafaxine and venlafaxine XR are 5 to 11 hours. Desvenlafaxine’s half-life is 11 hours, and product labeling of this enantiomer of racemic venlafaxine notes that discontinuation symptoms have occurred.²⁶ ADS treatment depends on the severity of the reaction and whether or not further antidepressant therapy is necessary.

For mild ADS, reassurance and treatment focused on specific symptoms—such as sedative-hypnotics for insomnia or benzodiazepines for anxiety—may be all that is needed, because ADS tends to gradually resolve over an average of 10 days.²⁷

For more severe ADS, or when ongoing antidepressant therapy is indicated, restarting the recently withdrawn antidepressant at the pre-ADS dosage typically resolves the syndrome within 24 hours. Then employ a slower, more cautious taper when next attempting to discontinue that antidepressant.

Another option. An alternate management strategy is to substitute fluoxetine to suppress ADS associated with shorter half-life SSRIs or SNRIs. Case reports^18,20,28 suggest that fluoxetine, 5 to 20 mg/d, can be used to ameliorate venlafaxine-induced ADS. Fluoxetine can be tried as monotherapy for 1 to 2 weeks and then rapidly tapered or stopped. Others have suggested combination therapy, such as:

• restarting venlafaxine at the pre-ADS dose plus fluoxetine, 20 mg/d
• tapering venlafaxine by 50% every 5 days until stopped
• reducing fluoxetine 1 week later to 10 mg/d for 5 days
• then stopping fluoxetine.²⁸

In general, SSRIs should not be co-administered with SNRIs long-term because of potential additive adverse effects such as serotonin syndrome. Combining fluoxetine with an SNRI such as venlafaxine for the purpose of tapering off venlafaxine and reducing ADS risk probably is safe, however, as long as the fluoxetine dose is low (5 to 20 mg) and SNRI reduction begins immediately, with a plan for complete tapering.

CASE CONTINUED: ECT treatment proceeds

Venlafaxine XR is not restarted to address Mr. J’s suspected ADS because of concerns about potential increased risk for cardiac events (asystole, prolonged bradycardia) during ECT with concomitant venlafaxine use.^29,30 Fluoxetine, which rarely may prolong ECT-induced seizures, is deemed a safer choice and is started immediately at 20 mg/d.

Because of Mr. J’s other symptoms, we prescribe lorazepam, 0.5 mg bid, for anxiety for 2 days; increase aripiprazole to 5 mg bid for agitation; and add zolpidem, 10 mg at bedtime, for insomnia. The following day, Mr. J reports substantial relief from ADS symptoms, including myalgias, paresthesias, and suicidal ideation.^21,23

His second ECT treatment is administered the next day, followed by a successful course of 9 treatments and partial remission of the MDE within 3 weeks. Fluoxetine is reduced to 10 mg/d one week into the ECT series, then discontinued one week later. No signs of emergent ADS are seen at discharge or 2-week outpatient follow-up. Mr. J achieves full remission with maintenance ECT plus bedtime doses of mirtazapine, 30 mg, and aripiprazole, 7.5 mg, across 6 months of follow-up care.

Related resources

• Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(suppl 4):27-30.
• American Family Physician. Patient handout on antidepressant discontinuation. www.aafp.org/afp/2006/0801/p457.html.
• Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77-87. See appendix for discontinuation-emergent signs and symptoms checklist.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Clomipramine • Anafranil
• Desvenlafaxine • Pristiq
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor
• Venlafaxine extended-release • Effexor XR
• Zolpidem • Ambien

Disclosure

Dr. Muzina reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

When Dr. Muzina submitted this article to Current Psychiatry, he was director, Center for Mood Disorders Treatment and Research, Cleveland Clinic Neurological Institute, Cleveland, OH.

Discuss this article

Most psychiatrists have encountered patients who report distressing symptoms when they have forgotten to take their antidepressant for a few days or during changes in the medication regimen. A discontinuation syndrome can occur with almost any antidepressant, highlighting the need to slowly taper these medications when discontinuation is part of a treatment plan.

This article discusses antidepressant discontinuation syndrome (ADS) in a patient who experienced substantial distress after a rapid antidepressant taper in preparation for electroconvulsive therapy (ECT). My goal is to raise awareness of ADS, promote early detection of the syndrome, and address proper prevention and management strategies.

CASE REPORT: Feeling ‘worse than ever’

Mr. J, a 32-year-old tax accountant, is hospitalized for a major depressive episode (MDE) associated with deteriorating function and suicidal ideation. This second lifetime MDE started 8 months before his admission to an inpatient mood disorders unit.

Mr. J initially was treated with fluoxetine, up to 40 mg/d across 14 weeks, with good tolerability but no significant benefit. His psychiatrist switched Mr. J to bupropion but stopped it after 4 weeks because of side effects—including headaches, insomnia, and tremor—and limited antidepressant benefit. Venlafaxine XR was initiated next, at 150 mg/d within the first 2 weeks, increased to 225 mg/d at week 6, then titrated to 300 mg/d at week 10. After 10 weeks, aripiprazole, 5 mg/d, was added because Mr. J showed only partial, limited response to venlafaxine XR and this antipsychotic is indicated for adjunctive treatment of major depressive disorder.

Mr. J reported mild, transient restlessness but otherwise he tolerated the medications well, and he claimed excellent adherence. After 6 additional weeks of treatment, however, Mr. J was hospitalized because of persistent severely depressed mood, increasing suicidal ideation, and inability to function at work.

On admission, Mr. J is evaluated and agrees to ECT. To meet the ECT service’s protocol, venlafaxine XR is reduced to 150 mg/d for 2 days and then stopped when ECT is started. Aripiprazole is continued at 5 mg/d.

Mr. J tolerates the first ECT treatment well, but the morning before his second treatment he complains of feeling “worse than ever.” An agitated Mr. J reports dramatically intensified suicidal ideation—much more intrusive than before he was hospitalized. He also complains of diffuse muscle aches and cramps, runny nose, nausea, headache, and burning sensations in both arms and hands. He withdraws consent for ECT and returns to the mood disorders unit for ongoing treatment.

Could this be ADS?

Yes, it could. In this case, the inpatient psychiatrist and treatment team were lulled into a false sense of security by Mr. J’s history of few side effects with various treatments and medication changes. The ECT service wanted the patient off venlafaxine XR before beginning ECT, and the treatment team believed a quick taper would not cause discontinuation symptoms because Mr. J was taking an “extended-release” medication.

Within 72 hours, Mr. J went from taking 300 mg/d of venlafaxine XR to none. Within 2 days of cessation, he complained of symptoms that could characterize a discontinuation syndrome. A potential red herring in this case is that the patient complained of feeling worse after his first ECT treatment, and one might erroneously think the myalgias, headache, and other somatic symptoms were side effects of ECT and/or anesthesia.

Typical ADS symptoms

Nearly all antidepressant classes are associated with ADS. Symptoms vary from patient to patient but typically include the “FINISH” syndrome: flu-like symptoms, ###bold/bold###nsomnia, nausea, ###bold/bold###mbalance, sensory disturbances, and hyperarousal (anxiety/agitation) (Table 1).¹

Adverse effects after stopping tricyclic antidepressants have been well documented. They may include FINISH syndrome features as well as cholinergic overdrive or “rebound” such as abdominal cramping and diarrhea.^2-4 Reports of ADS after patients stopped selective serotonin reuptake inhibitors (SSRIs) emerged soon after these agents were introduced.^5-7 Similarly, ADS has been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine,^8-10 venlafaxine XR,¹¹ and duloxetine.¹² ADS symptoms are similar with SSRIs and SNRIs, generally without the anticholinergic effects associated with tricyclic antidepressant discontinuation.

Fewer reports of discontinuation syndrome exist for bupropion, mirtazapine, monoamine oxidase inhibitors (MAOIs), and nefazodone.^13-17 Discontinuation-emergent syndromes with these non-SSRI/non-SNRI antidepressants tend to present differently. With MAOIs, for example, neuropsychiatric symptoms such as severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, delirium, and paranoid psychosis can be prominent.¹⁷

The prevalence of ADS is unclear, and published estimates vary widely because of the lack of large controlled studies. ADS rates with SSRIs/SNRIs have been reported from as low as 0% for fluoxetine to higher rates for shorter half-life antidepressants:

• 2.2% with sertraline
• 14% with fluvoxamine
• 20% with paroxetine
• 30.8% with clomipramine.

These rates come from a retrospective case note review of patients who discontinued antidepressants under supervision.¹⁸ In a small cohort of outpatients being treated for major depressive disorder, stopping venlafaxine XR was associated with discontinuation symptoms for the next 3 days in 7 of 9 patients (78%), compared with 2 of 9 patients (22%) stopping placebo.¹¹

Diagnostic criteria have been proposed for ADS associated with serotonin (5-HT) reuptake inhibitors.^19-22 Proposed ADS definitions differ somewhat, but essentially 3 features guide the diagnosis:

• appearance of characteristic symptoms (Table 2)^21,23
• timing of those symptoms, which usually emerge within 1 week of abrupt cessation or marked reduction of the antidepressant
• symptoms generally are mild, short-lived, self-limiting, and/or rapidly reversed by restarting the original antidepressant.

Evidence suggests shorter half-life antidepressants may be associated with the highest risk for ADS, but other risk factors remain presumptive (Table 3).

Table 1

FINISH: Symptoms of antidepressant discontinuation syndrome

Table 2

ADS symptoms can range across a variety of system clusters

Table 3

Possible patient risk factors for developing ADS*

What causes ADS?

Although the exact cause of ADS is unknown, the literature proposes several theories.

Because of the central serotonin system’s complex connections, acute reduction in synaptic serotonin when an SSRI or SNRI is abruptly or too quickly stopped may be the first in a cascade of steps affecting transmission of multiple monoamines. Parallels have been drawn between the phenomenon observed with rapid depletion of tryptophan—the essential amino acid precursor for the synthesis of 5-HT—and ADS seen with abrupt discontinuation of serotonergic antidepressants. This suggests that acute drops in neurotransmitter levels can precipitate neuropsychiatric and somatic manifestations of ADS.²⁴

Patients’ uncomfortable symptoms likely are caused by the serotonin, norepinephrine, and cholinergic systems and their complex interactions.²⁵ Individual genetic factors may influence patients’ vulnerability for ADS.

Managing ADS

Awareness and prevention. ADS can be misinterpreted as side effects of newly started treatment after an antidepressant is stopped. In Mr. J’s case, the appearance of muscle aches, headaches, and other ADS symptoms after ECT was started easily could have been perceived as adverse effects of ECT. Mr. J’s agitation and increased suicidal ideation could lead a clinician to mistakenly think that MDE was worsening because the antidepressant was stopped before ECT became effective. Being aware of ADS can prevent misdiagnosis and allow you to quickly identify the condition, manage the reversible syndrome, and continue with new treatment plan—in this case, ECT.

You can help prevent ADS by educating patients about the need to adhere to antidepressant regimens and to avoid missing doses. Consider ADS risk factors—particularly medications’ half-lives—before you start, change, or stop antidepressant therapy. Gradually taper all antidepressants being discontinued, with the possible exception of fluoxetine (which, including its active metabolite, has an elimination half-life of approximately 1 to 2 weeks).

Tapering antidepressants is more art than science because we have no controlled data to support any particular tapering regimen. Tailor the taper duration based on each patient’s response to sequential dosage reductions. Antidepressants with shorter half-lives—such as venlafaxine or paroxetine—may need to be tapered more slowly, perhaps by reducing the dosage by 25% every 4 to 6 weeks. If you plan to switch medications, this process may be expedited during a cross-taper to another antidepressant. You still may see discontinuation symptoms, however, depending on which new agent is chosen and which is being stopped.

Treating ADS. Appropriately recognizing ADS risk and slowly tapering antidepressants as needed usually prevents clinically significant distress associated with discontinuation. For some patients, however, ADS may be particularly severe or prolonged, or may emerge at the end of a slow taper.

Challenging cases may be more likely with paroxetine or venlafaxine—even the extended-release or controlled-release preparations. The elimination half-life of paroxetine is 15 to 20 hours, and the half-lives of venlafaxine and venlafaxine XR are 5 to 11 hours. Desvenlafaxine’s half-life is 11 hours, and product labeling of this enantiomer of racemic venlafaxine notes that discontinuation symptoms have occurred.²⁶ ADS treatment depends on the severity of the reaction and whether or not further antidepressant therapy is necessary.

For mild ADS, reassurance and treatment focused on specific symptoms—such as sedative-hypnotics for insomnia or benzodiazepines for anxiety—may be all that is needed, because ADS tends to gradually resolve over an average of 10 days.²⁷

For more severe ADS, or when ongoing antidepressant therapy is indicated, restarting the recently withdrawn antidepressant at the pre-ADS dosage typically resolves the syndrome within 24 hours. Then employ a slower, more cautious taper when next attempting to discontinue that antidepressant.

Another option. An alternate management strategy is to substitute fluoxetine to suppress ADS associated with shorter half-life SSRIs or SNRIs. Case reports^18,20,28 suggest that fluoxetine, 5 to 20 mg/d, can be used to ameliorate venlafaxine-induced ADS. Fluoxetine can be tried as monotherapy for 1 to 2 weeks and then rapidly tapered or stopped. Others have suggested combination therapy, such as:

• restarting venlafaxine at the pre-ADS dose plus fluoxetine, 20 mg/d
• tapering venlafaxine by 50% every 5 days until stopped
• reducing fluoxetine 1 week later to 10 mg/d for 5 days
• then stopping fluoxetine.²⁸

In general, SSRIs should not be co-administered with SNRIs long-term because of potential additive adverse effects such as serotonin syndrome. Combining fluoxetine with an SNRI such as venlafaxine for the purpose of tapering off venlafaxine and reducing ADS risk probably is safe, however, as long as the fluoxetine dose is low (5 to 20 mg) and SNRI reduction begins immediately, with a plan for complete tapering.

CASE CONTINUED: ECT treatment proceeds

Venlafaxine XR is not restarted to address Mr. J’s suspected ADS because of concerns about potential increased risk for cardiac events (asystole, prolonged bradycardia) during ECT with concomitant venlafaxine use.^29,30 Fluoxetine, which rarely may prolong ECT-induced seizures, is deemed a safer choice and is started immediately at 20 mg/d.

Because of Mr. J’s other symptoms, we prescribe lorazepam, 0.5 mg bid, for anxiety for 2 days; increase aripiprazole to 5 mg bid for agitation; and add zolpidem, 10 mg at bedtime, for insomnia. The following day, Mr. J reports substantial relief from ADS symptoms, including myalgias, paresthesias, and suicidal ideation.^21,23

His second ECT treatment is administered the next day, followed by a successful course of 9 treatments and partial remission of the MDE within 3 weeks. Fluoxetine is reduced to 10 mg/d one week into the ECT series, then discontinued one week later. No signs of emergent ADS are seen at discharge or 2-week outpatient follow-up. Mr. J achieves full remission with maintenance ECT plus bedtime doses of mirtazapine, 30 mg, and aripiprazole, 7.5 mg, across 6 months of follow-up care.

Related resources

• Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(suppl 4):27-30.
• American Family Physician. Patient handout on antidepressant discontinuation. www.aafp.org/afp/2006/0801/p457.html.
• Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77-87. See appendix for discontinuation-emergent signs and symptoms checklist.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Clomipramine • Anafranil
• Desvenlafaxine • Pristiq
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor
• Venlafaxine extended-release • Effexor XR
• Zolpidem • Ambien

Disclosure

Dr. Muzina reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

When Dr. Muzina submitted this article to Current Psychiatry, he was director, Center for Mood Disorders Treatment and Research, Cleveland Clinic Neurological Institute, Cleveland, OH.

Paliperidone palmitate (9-hydroxyrisperidone) is an injectable, once-monthly atypical antipsychotic medication, FDA-approved in July 2009 for acute and/or maintenance treatment of schizophrenia. This aqueous-based, extremely slowly dissolving depot medication is well tolerated and causes few drug-drug interactions.¹ Clinically, paliperidone palmitate and its parent drug, intramuscular (IM) risperidone, have similarities and differences.

Clinical information

Paliperidone palmitate is available in 39-mg, 78-mg, 117-mg, 156-mg, and 234-mg formulations. Once administered, it hydrolyzes and diffuses slowly and provides paliperidone doses equivalent to 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg, respectively. The 234-mg dose of paliperidone palmitate is equivalent to 12 mg oral paliperidone, 117 mg to 6 mg, and 39 to 78 mg to 3 mg, respectively (visit this article at CurrentPsychiatry.com to learn more about paliperidone palmitate).

Pharmacokinetics. This palmitate ester of paliperidone is an aqueous suspension utilizing nanocrystal molecules. The increased surface area leads to rapid medication release and a short time to steady state. Active paliperidone plasma levels were detected at day 1, meaning co-administration with the oral formulation is not necessary. Paliperidone palmitate’s slow dissolution rate results in a half-life of 25 to 49 days. The fast onset of action and long half-life simplifies administration.

Co-administration with carbamazepine decreases paliperidone levels, whereas divalproex causes an increase. Up to 60% of paliperidone is excreted unchanged through the kidneys, which means patients with impaired renal function require a lower dosage. Because the liver has only a minimal role in paliperidone palmitate’s metabolism, dose adjustment is needed only for patients with severe hepatic dysfunction.¹

Administration. Before starting this medication, test for allergy with a dose of oral paliperidone. Then administer 2 consecutive loading doses of paliperidone palmitate by deltoid IM injection; first 234 mg, and then a 156-mg dose after 7 to 10 days. Monthly injections of 117 mg are recommended, although higher or lower dosages can be used depending on the clinical situation. The first 2 injections should be in the deltoid muscle because plasma concentrations are 28% higher with deltoid vs gluteal administration. Subsequent injections can alternate between gluteal and deltoid sites.

If a dose is missed within 6 weeks of the last injection, administer the most recently used dosage. For discontinuation of 6 weeks to 6 months, administer 2 injections of the previously stabilized dose separated by 1 week, followed by the regular monthly dosage. After >6 months, begin the initial loading dose regimen.¹

Paliperidone palmitate is available in prefilled syringes that do not require refrigeration or reconstitution. Use a 22-gauge needle for deltoid injections and for patients weighing >200 lbs. Use a 23-gauge needle for gluteal injections in non-obese individuals. Do not inject into a blood vessel, and alternate injection sites between sides of the body each month.¹

Table

Paliperidone palmitate: Fast facts

Efficacy

In a 9-week, phase II, double-blind study, mean Positive and Negative Syndrome Scale (PANSS) scores improved in patients receiving paliperidone, 78 mg or 156 mg (mean change -5.2 and -7.8, respectively) compared with placebo (6.2). Two percent of the paliperidone group discontinued the agent, compared with 10% of placebo. Although extrapyramidal symptoms were comparable in all groups (1%), 5% of patients receiving 78 mg and 8% of patients receiving 156 mg reported parkinsonian adverse events, compared with 1% with placebo.²

In other double-blind, placebo-controlled trials, paliperidone dosages from 25 mg to 150 mg were associated with a decrease in positive and negative symptoms in 1,540 subjects.¹ During a 1-year study, 18% of patients taking paliperidone palmitate relapsed, compared with 48% for placebo.¹

In a 53-week study, both paliperidone palmitate and IM risperidone were effective in decreasing positive and negative symptoms; however, risperidone-treated patients showed greater therapeutic response.³ Mean PANSS score changes in patients receiving paliperidone were -11.6, compared with -14.4 with risperidone. Psychotic relapse occurred in 14% of IM risperidone patients and 18% of paliperidone palmitate patients.³

In an unpublished 13-week, randomized, double-blind study conducted by the drug’s manufacturer, paliperidone palmitate, 78 mg to 234 mg once monthly, and long-acting risperidone, 25 mg to 50 mg every other week with supplemental oral risperidone for 2 to 3 weeks, were reported as equivalent.¹ Both groups showed similar decrease in PANSS scores (-18.6 vs -17.9); however, reported adverse events were slightly higher in patients receiving paliperidone (57.9% vs 52.8%).¹

Adverse events

Common side effects include insomnia (15%), anxiety (10%), and headaches (9%). Dizziness, agitation, gastrointestinal upset, hypotension, and urinary tract infection have been reported. Rarely, tachycardia, clinically nonsignificant QTc prolongation, and tardive dyskinesia occur. Increased prolactin levels have been observed, particularly in females. This drug should not be prescribed to pregnant or lactating women or elderly patients with dementia-related psychosis. In the 13-week trial, patients gained up to 3.3 lbs. Other adverse effects include allergic reactions, blood dyscrasias, elevated liver enzymes, lower seizure thresholds, body temperature dysregulation, neuroleptic malignant syndrome, dysphagia, and motor impairments.¹

Clinically significant adverse effects were reported in 25% of paliperidone-treated subjects compared with 20% in the risperidone IM group. The discontinuation rate was 5% for paliperidone palmitate, compared with 3% for IM risperidone. Hyperkinesia with paliperidone (6%) was less prominent than with risperidone (10%).³

Drug brand names

• Carbamazepine • Tegretol
• Divalproex • Depakote
• Paliperidone • Invega
• Paliperidone palmitate • Invega Sustenna
• Risperidone IM • Risperdal Consta

Disclosure

Dr. Lindenmayer has received grant support from AstraZeneca, Otsuka, Pfizer Inc., Dainippon Sumitomo, Azur, Janssen, Eli Lilly and Company, and National Institute of Mental Health. He is a consultant to Eli Lilly and Company and Janssen. Drs. Sedky, Nazir, and Lippmann report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgments

The authors thank Dr. Roop Parlapalli, an observer physician at University of Louisville School of Medicine, for his editorial revision.