Psychopharmacotherapy in Special Populations
This chapter clarifies the clinical assessment and drug treatment issues raised by patients whose symptoms occur in the context of specialized circumstances. It specifically covers psychopharmacotherapy in medical and psychiatric conditions that can complicate psychiatric assessment and drug therapy, including
Alcoholism
Human immunodeficiency virus (HIV) infection
Eating disorders
In this chapter, we underscore how complications related to each of these specialized groups may alter the clinician’s approach to diagnosis and treatment. Such circumstances are always considered in the context of changes in the riskto-benefit ratio posed by these patients.
The Alcoholic Patient
The World Health Organization defines alcoholism as a chronic behavior disorder manifested by repeated drinking of alcoholic beverages in excess of community norms for dietary and social purposes and to an extent that it interferes with one’s health or social and economic functioning (1).
A committee composed of representatives from the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine also developed a definition that includes typical behavioral changes as well as the concept of denial (2).
They characterize alcoholism as
A primary chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations
Often progressive and fatal
Impaired control over drinking
Preoccupation with this drug
Use despite adverse consequences
Distortions in thinking, especially denial
Continuous or periodic
Alternatively, unhealthy alcohol use is categorized into risky use, problem drinking, alcohol abuse or harmful use, and alcohol dependence (3). Valid assessment instruments to screen for alcoholrelated problems include the CAGE questionnaire (CAGE is an acronym for its four questions) or the Alcohol Use Disorders Identification Test (AUDIT) (4,5).
After heart disease and cancer, alcoholrelated disorders are considered the third most important health problem in the United States, estimated to account for at least one fourth of all hospitalizations in this country. Almost 50% of those who suffer from alcohol dependence also abuse other legal, as well as illicit, drugs. Alcohol is involved in 25% to 35% of all suicides and 50% to 70% of all homicides; it also figures prominently in accidental deaths and domestic violence (6,7). Furthermore, causes of death resulting from excessive alcohol use include (8,9)
Cirrhosis
Cancers of the oropharynx
Breast cancer in women
Injuries and other external causes in men
By contrast, moderate alcohol consumption in the middle-aged and elderly slightly reduces overall mortality risk.
Of the approximately 100 million Americans who imbibe, about 10% suffer from alcoholism, drinking about 50% of all alcoholic beverages consumed in this country. There are also an estimated 10 to 12 million “problem drinkers,” with men’s risk for development of severe problems being three to four times higher than women’s. Although the heaviest drinking occurs at an earlier age for men than for women, the abstinence rate for both sexes begins to increase after age 50 years (10). The “end-stage” drinker constitutes less than 3% of the alcoholic population and describes an individual who is, generally
Unemployed
Transient
A daily drinker
Without social and economic support
In a deteriorated psychological and physical state
Adolescents abuse alcohol more often than any other drug, with an incidence ranging from 15% to 25%. Traffic accidents involving teenagers often have alcohol as a contributing factor, and the number of traffic-related deaths increases or decreases concomitantly with the lowering or raising of the legal drinking age.
The precise incidence of alcoholism in the elderly remains unknown, but retired and recently widowed men may be at higher risk (11). Physicians and family members often overlook the effects of alcohol on an elderly person’s physical and psychological health and may mistake this problem for an organic mental disorder. In the elderly, preexisting organic mental disorders, a decreased volume of distribution, and the concurrent use of other medication may potentiate the effects of alcohol on cognition, affect, and behavior (see also Chapter 15).
Strong evidence indicates at least a familial pattern and a potential hereditary basis for some types of alcoholism (12). Alcoholism can be classified as (13) type I (late onset, type A), which is associated with anxious personality traits, less severe dependence, fewer childhood risk factors, and may be more influenced by environmental stressors (e.g., combat exposure) (14). Type II (early onset, type B) typically occurs before 25 years of age, is associated with a family history of alcoholism, features more severe dependence, and has a strong biological basis. The distinction between these two types is supported in part by genetic characteristics of alcohol metabolism (15). Support comes from a genome-wide association study that identified several SNPs located on chromosome 2q35 which is also implicated in linkage studies for alcohol phenotypes (16). Further, heaviness of alcohol consumption may be genetically determined and predictive of alcohol dependence (17). Data also show that genotype accounts for approximately 33% of the overall variance in liability (18).
In addition, specific neurocircuitry and neurochemical systems appear to be important in the etiology of alcoholism (19). Thus, positive reinforcement may be mediated by activation of γ-aminobutyric acid (GABA)-A receptors, release of opioid peptides and dopamine, inhibition of glutamate receptors, and interactions with the 5-HT system (20,21). In particular, the dopamine mesolimbic system (i.e., ventral tegmentum, nucleus accumbens, prefrontal cortex) and the ventral striatum are implicated in reinforcing both natural and pharmacological rewards (22,23). In this context, decreased volumes in related structures (e.g., amygdala) may predict increased risk of alcohol craving, intake, and relapse (24). Neurobehavioral effects of alcohol and their association with these various neurocircuits serve as potential targets for novel drug therapies.
In summary, alcohol dependence requires intervention aimed at medical, psychological, and social complications. The goal is to reduce or eliminate the desire to drink, produce a reduction or cessation in alcohol consumption, and minimize its harmful consequences. Treatment involves detoxification, rehabilitation, and prevention of relapse (25). Unfortunately, recent surveys indicate that most patients with an alcohol use disorder do not perceive a need for treatment, further complicating adequate interventions (26).
ALCOHOL-RELATED PSYCHIATRIC COMPLICATIONS
Alcohol abuse is associated with many psychiatric complications, starting with those involving acute consumption or withdrawal:
Intoxication and its complications (e.g., disinhibition, aggressiveness, depression, and suicide)
Idiosyncratic (or pathological) intoxication
Withdrawal syndrome, which may include tremors, hallucinosis, seizures, and delirium (e.g., delirium tremens)
A patient who is intoxicated or undergoing alcohol withdrawal should be hospitalized for management if any of the following are present (27):
History of severe withdrawal symptoms
Recent seizure or history of withdrawal seizures
Recent head trauma
Serious medical complications (e.g., pancreatitis, gastrointestinal bleeding, hepatitis, cirrhosis, or pneumonia)
Delirium or hallucinosis
Body temperature greater than 101°F
Significant malnutrition or dehydration
The Wernicke-Korsakoff syndrome
Severe depression or suicide risk
Comorbid depression associated with alcohol dependence can represent a difficult clinical challenge (28). Although antidepressants may be appropriate and useful, premature intervention may be unnecessary. For example, Dackis et al. (29) found that 80% of 49 severely depressed alcoholics remitted after 2 weeks of unmedicated sobriety. They concluded that many severe depressions are alcohol-induced organic mood syndromes and improve spontaneously with abstinence.
Most intoxicated individuals do not need hospitalization, display none of the previous medical problems, and experience minimal withdrawal symptoms. Thus, observing and treating them in the emergency room or a nonmedical detoxification center for 6 to 12 hours may be sufficient.
Acute Alcohol Intoxication
Alcohol is similar to other general anesthetics in that it depresses the central nervous system (CNS). Clinically, however, it may appear to be a stimulant because it first suppresses inhibitory control mechanisms, resulting in early disinhibition. In general, the effect of alcohol on the CNS is proportionate to its blood concentration, but the effects are more marked when the concentration is increasing.
In the alert intoxicated patient, general management is primarily supportive and protective. Thiamine (100 mg intramuscularly) is given initially and repeated three times a day orally for the next several weeks. A multivitamin preparation should also be given orally each day. If the patient is restless, a short-acting benzodiazepine (BZD) such as lorazepam (1 to 2 mg intravenously, intramuscularly, or orally) may be given and repeated as often as needed. If the patient is violent or severely agitated, an antipsychotic may be necessary with low-dose, highpotency agents, such as haloperidol (HPDL; 2 to 5 mg intramuscularly or intravenously as needed). If larger doses are necessary, the clinician should reconsider the diagnosis.
Alcohol Idiosyncratic Intoxication
This syndrome has similarities to the paradoxical reaction seen with barbiturates or BZDs, as well as epileptoid syndromes, including temporal lobe seizures and intermittent explosive disorder. Brain injury from trauma or encephalitis may also predispose some to an abnormally excessive response to even small amounts of alcohol.
Clinical signs and symptoms include sudden onset of irrational, combative, or destructive behavior after ingesting relatively small amounts of alcohol. The behavior is atypical of the individual when not drinking, and it usually begins within minutes to hours. After the acute outburst, the patient usually lapses into deep sleep and upon awakening, has only fragmentary memory or total amnesia for the episode. Treatment should attempt to diminish stimulation as much as possible, and antipsychotics, such as HPDL (2 to 5 mg orally or intramuscularly), may reduce combative or destructive behavior.
Alcohol Withdrawal or Abstinence Syndrome
Alcohol withdrawal or abstinence syndrome may emerge after a period of relative or absolute abstinence, with the cause unknown. The duration of drinking and quantity of alcohol required to produce noticeable symptoms vary widely. Abstinence may also result from intercurrent illness, hospitalization for an unrelated illness, or lack of money to buy alcohol. The full spectrum of this syndrome, which ranges from an early, mild withdrawal picture to delirium, is commonly seen in large urban hospital emergency rooms.
Early withdrawal peaks at about 24 hours and rarely can emerge several days after cessation.
Symptoms can clear in a few hours or last up to 2 weeks and include
Symptoms can clear in a few hours or last up to 2 weeks and include
Tremulousness, which is the earliest and most common sign. Associated symptoms may last for 10 to 14 days and include nausea, vomiting, tension, and insomnia.
Alcoholic hallucinosis, which usually consists of auditory hallucinations (but may also be visual) in the presence of a clear sensorium. They usually emerge within the first few days and may persist after other withdrawal symptoms have resolved.
Seizures (rum fits), which are generalized motor events that usually peak 12 to 48 hours after cessation of alcohol consumption. Partial seizures suggest a focal lesion and require careful neurological evaluation.
Withdrawal delirium (delirium tremens), which usually appears 1 to 4 days after abstinence and peaks at about 72 to 96 hours. The mortality rate may be as high as 15% if serious complicating medical problems are also present. Clinical signs and symptoms include profound confusion, illusions, delusions, vivid hallucinations, agitation, insomnia, and autonomic hyperactivity. Death results from infection, cardiac arrhythmias, fluid and electrolyte abnormalities, or suicide (e.g., in response to hallucinations, illusions, or delusions).
Treatment. The treatment of alcohol withdrawal incorporates general supportive, nonjudgmental, but assertive measures, as well as management of specific symptoms (30). Supportive measures include abstinence from alcohol, ample rest, adequate general nutrition, and reality orientation. It is important to treat the syndrome vigorously and, when appropriate, to prevent it by using sufficient doses of medication.
One meta-analysis of 11 trials found that over 48 hours, BZDs reduced withdrawal symptoms to a significantly greater degree than placebo (31). Typically, these agents are used on an as-needed basis to treat objective signs of withdrawal, such as tremor, tachycardia, or hypertension. The longer-acting BZDs, such as chlordiazepoxide and diazepam, have the advantage of less frequent dosing but the risk of drug accumulation. The intermediate-acting agents, such as lorazepam, are less likely to accumulate but need to be administered more frequently to prevent reemergence of signs and symptoms. One approach might be lorazepam, 2 mg orally every 2 hours as needed, for as long as needed. The acute dose is then tapered over a 1- to 2-week period, using a two- or three-times-daily regimen. Total daily doses of more than 10 to 12 mg are rarely required. A fixed-dose regimen may not work because of the variability in duration and severity of symptoms. In the severely agitated patient, lorazepam (intramuscularly 2 mg/hr) or diazepam (intravenously 5 to 10 mg slowly) may be necessary
Treatment of withdrawal seizures depends on whether there is a prior history. For example, in one study of patients who had experienced a withdrawal seizure, lorazepam (2 mg intravenous) was significantly more effective than normal saline placebo in reducing the risk of a recurrent seizure (32). If there is no history, prophylactic anticonvulsants will probably not help. Furthermore, BZDs used for sedation also have anticonvulsant properties, so adequate doses should minimize the risk of seizures. However, anticonvulsants such as carbamazepine (CBZ) and valproate (VPA) demonstrated benefit for alcohol withdrawal symptoms in controlled trials (33,34). One controlled pilot study also found CBZ to benefit alcohol dependence (35).
In addition, patients with a more complicated history of withdrawal or other seizure disorders are at greater risk and should receive an anticonvulsant. If the patient is currently receiving a maintenance dose, it should be continued. If the patient is not receiving medication or if it was discontinued 5 or more days previously, a loading dose of phenytoin (15 mg/kg intravenously in saline) could be given at a rate not to exceed 50 mg/min. Maintenance doses are started 24 hours later. Some withdrawal seizures can be prevented by restoring serum magnesium levels with magnesium sulfate (2 mL of a 50% solution, up to three doses), given with intravenous fluids over 8 hours.
Occasionally, antipsychotics such as HPDL (2 to 10 mg intramuscularly or orally) may be needed. Antipsychotics that lower the seizure threshold, cause extrapyramidal symptoms (EPSs) or hypotension should be avoided.
In treating delirium
Reduce environmental stimulation
Monitor vital signs frequently
Restrain combative or agitated patients
Monitor fluid and electrolyte balance, correcting any imbalance
Maintain blood pressure with intravenous saline and glucose
Give thiamine, 100 mg intramuscularly initially, then 100 mg orally three times a day
Replenish other vitamin stores with folate, B-complex, and multivitamin supplements
Give a BZD, such as diazepam, 5 to 10 mg orally every 1 to 2 hours as needed for sedation, with a maximum of 80 to 100 mg/day; if the patient is severely agitated, give 5 to 10 mg diazepam intravenously slowly every 20 minutes, until the patient is sedated
If necessary, a low-dose, high-potency antipsychotic, such as HPDL (2 to 5 mg intramuscularly every 2 to 4 hours) can control acute symptoms
Search for and treat complicating illnesses such as pneumonia, gastrointestinal bleeding, hepatic decompensation, pancreatitis, subdural hematoma, and fractures
Alternative adjunctive strategies with some evidence for efficacy include
Clonidine (an α-agonist), which may attenuate withdrawal symptoms
β-Adrenergic blockers, such as atenolol (e.g., 100 mg orally daily for moderate-to-severe tachycardia) used as adjuncts can treat autonomic hyperactivity
Calcium antagonists (36)
COMPLICATING MEDICAL CONDITIONS
Because several major diseases are commonly associated with alcoholism, treatment may need to be modified if one of these conditions is present.
Cirrhosis
Ninety-five percent of alcohol is metabolized in the liver; the remaining 5% is excreted via the kidneys and the lungs (see also Chapter 2). The rate of metabolism increases with fasting and after protracted periods of drinking. Although alcohol has a direct toxic effect on the liver, significant hepatic damage develops in only 10% to 20% of long-term heavy drinkers. In this context, BZDs must be used cautiously because they are primarily metabolized by this organ. If there is evidence of disease, oxazepam and lorazepam are preferred because they are not metabolized by the liver. When oral drugs cannot be used, lorazepam (2 to 8 mg intramuscularly daily) is preferred.
As discussed in Chapter 2, the phases of alcohol consumption can have varying effects on the metabolism of concomitantly administered psychotropics. Thus, acute alcohol ingestion generally interferes with the metabolism of drugs, increasing plasma concentration. Ingestion over several weeks stimulates hepatic enzymes, accelerating the metabolism of many drugs. Finally, cirrhosis induced by long-term alcohol consumption diminishes enzyme concentration and liver mass, again increasing plasma levels of concurrently administered drugs metabolized by this system. Fluid and electrolyte therapy must take into account the development of ascites and the possibility of right-sided heart failure. Salt restriction (i.e., 500 mg/day) and bed rest are the initial conservative treatments, with medical consultation usually required (9).
Other Medical Conditions
Because heavy cigarette smoking is typically associated with alcohol dependence and may lead to impaired pulmonary function, BZDs are used more cautiously to reduce the risk of oversedation and respiratory depression. Hypoxia can cause agitation and is exacerbated by treatment with sedative drugs. Again, shorter half-life agents and those with fewer active metabolites are preferred (e.g., oxazepam or lorazepam). Alcoholic patients also have an increased risk of aspiration of gastric contents or infected oropharyngeal material, with resulting aspiration pneumonia.
Erosive gastritis caused by recent excessive ingestion of alcohol is the most common cause of gastrointestinal bleeding in alcoholics. Bleeding usually subsides with cessation of drinking and administration of antacids. If the patient has cirrhosis, bleeding from esophageal varices should be considered.
ALCOHOL-RELATED NEUROLOGICAL DISORDERS
The following chronic neuropsychiatric disorders may arise from nutritional deficiencies, gastric malabsorption, and hepatic dysfunction (37):
The Wernicke-Korsakoff syndrome
Cerebral cortical atrophy (alcohol-associated dementia)
Cerebellar degeneration
Polyneuropathy
Alcohol myopathy
Pellagra
Deficiencies of thiamine and other B vitamins arising from poor nutrition and malabsorption are usually the basis for these neurological sequelae.
The Wernicke-Korsakoff syndrome consists of both an acute phase (i.e., Wernicke’s encephalopathy) and a chronic phase (i.e., Korsakoff’s psychosis). The acute encephalopathy may be precipitated or worsened by carbohydrates (including intravenous glucose) unless thiamine is also replenished before or during administration. Wernicke’s encephalopathy may first be manifested by
Mental status abnormalities, especially global confusion, inattentiveness, and a hypokinetic delirium
Ataxia
Ocular findings, including nystagmus (horizontal or vertical), weakness or paralysis of the lateral recti muscles, and weakness or paralysis of conjugate gaze
Korsakoff’s psychosis is characterized by
Anterograde and retrograde amnesia
Decreased insight
Apathy
Inability to learn
Although confabulation (unconscious fabrication of facts because of memory impairment) is often considered a key symptom, it is not always present. Thiamine, initially 100 mg given intramuscularly and then 100 to 300 mg/day orally, can improve many of these symptoms, assuming irreversible changes have not occurred.
Pellagra is often characterized by mental abnormalities such as anxiety, irritability, and depression. The classic symptoms of pellagra are known as the “four Ds”: dementia, diarrhea, dermatitis, and death. Inflammation of mucosal surfaces, weakness, anorexia, and other gastrointestinal disturbances are also seen. Niacin (300 to 500 mg/day) is the appropriate therapy.
Other neurological syndromes (e.g., cerebral cortical atrophy, myopathy, cerebellar degeneration) are also associated with alcoholism, but their pathogenesis is less certain than that of nutritional deficiency disorders. Abstinence from alcohol plus vitamin replacement and physical therapy comprise the standard treatment approach for these conditions.
ALCOHOLISM IN CHRONIC MENTAL ILLNESS
Proper diagnosis, important with any illness, is even more crucial in treatment planning for patients with a dual diagnosis. Because psychoactive substance use can obfuscate the diagnosis, special care must be taken to preclude organically based syndromes. Thus, adequate periods of abstinence must first be achieved, and then the patient must be reexamined for residual symptoms compatible with a nonaddictive, nonsubstance-induced psychiatric disorder (38).
Important demographic information relevant to the pharmacotherapy of patients with a dual diagnosis can be gleaned from several studies. For example, in their report of chronic mentally ill patients, with or without addictions, Drake and Wallach (39) found that the dually diagnosed were
Generally young
Usually male
More commonly hostile, suicidal, and disordered in their speech
Less compliant with medication
Less able to manage their lives in the community in terms of maintaining regular meals, adequate finances, stable housing, and regular activities
Smith and Hucker (40) note the following characteristics in the population of schizophrenic addicts included in their review of the literature:
More violence
More suicidality
More nonadherence
Earlier psychotic breakdown
Exacerbations of psychosis
Relative antipsychotic refractoriness
Increased rates of hospitalization
Increased tardive dyskinesia
Poor prognosis overall
Additionally, Noordsy et al. (41) indicated that a family history of alcoholism in alcoholic schizophrenics is associated with a more severe course
of illness, greater resistance to treatment, and more frequent abuse of other drugs.
of illness, greater resistance to treatment, and more frequent abuse of other drugs.
DRUG THERAPY DURING REHABILITATION
Treatment is best approached by using a disease model in which alcoholism is considered a chronic medical disorder and not simply a psychological or social problem. As with any other chronic illness, relapse is a normal part of the recovery process. Because the etiology of alcoholism is unknown and it afflicts a heterogeneous population, treatment strategies must keep in mind that some will not respond to more accepted forms of psychotherapeutic management such as cognitive behavioral, motivation enhancement, and others (42). In this context, agents that reduce a person’s desire to drink may be important adjuncts (43,44 and 45).
Disulfiram
Disulfiram (Antabuse) is an aversive drug that can be prescribed in conjunction with other forms of therapy such as Alcoholics Anonymous (AA) and individual counseling. Although controlled trials have not consistently demonstrated benefit with this agent in comparison with placebo, many clinicians believe it has a psychological effect that may attenuate impulsive drinking in selected patients (46,47).
This agent works by blocking the conversion of acetaldehyde to acetate by aldehyde dehydrogenase. This strategy is recommended only for those with good compliance and no serious physical condition (e.g., cardiovascular disease). A patient who drinks alcohol while taking this agent may experience facial flushing, sweating, headaches, nausea, vomiting, chest pain, dyspnea, weakness, dizziness, blurred vision, and confusion within minutes. Respiratory depression, shock, arrhythmias, seizures, and death are rare. Therefore, before disulfiram is prescribed, patients must be informed about these adverse effects and about the possibility of a serious disulfiram-ethanol reaction. Also, patients must be aware that many foods and aftershave lotion contain alcohol, as well as some over-thecounter (OTC) mouthwashes and cough syrups. Written informed consent should be obtained. Disulfiram may also interfere with the action of other commonly coprescribed drugs such as anticoagulants, phenytoin, and isoniazid. After 6 to 12 months, disulfiram may be stopped if a patient has been able to remain sober; however, some patients may require the drug indefinitely to ensure sobriety. The usual loading dose is 250 to 500 mg/day for 3 to 5 days, although adverse effects may require a lower dose. Most patients are adequately maintained on 125 to 200 mg/day.
Although disulfiram is sometimes helpful as an adjunct to nonpharmacological treatments for alcoholism, it has the potential to worsen psychosis. Kofoed (48) notes, however, that these findings are based on untreated chronically affected patients given high doses. He and his colleagues used disulfiram with a small number of dually diagnosed psychotic and alcohol-dependent patients after they were stabilized on appropriate antipsychotic medications. They found that compliance with disulfiram therapy in their dualdiagnosis group was as good as in primary alcoholic outpatients. They also reported no particular problems, concluding that disulfiram seemed less of a risk than continued alcohol misuse (49).
Opioid Antagonists
Several studies indicate that the opioid system is involved in the regulation of alcohol intake in various animals. Naltrexone, an opiate antagonist, can reduce alcohol consumption in alcoholcraving animals (50). In this context, a within-subject, double-blind, placebo-controlled clinical trial implicated the A1186 SNP of the OPRMI gene as a moderator of naltrexone’s ability to blunt the alcohol-induced high (51). Further, the OPRMI Asp 40 allele may predict response to naltrexone in alcoholic patients (52).
Two well-controlled studies using naltrexone in humans produced dramatically effective results (53,54). The results of these trials led to US Food and Drug Administration (FDA) approval of this agent (under the trade name Revia) as an adjunct to a comprehensive treatment plan (55). A placebo-controlled trial also found that the combination of naltrexone plus cognitive behavioral therapy (CBT) decreased relapse rates or increased time between relapses (56). Not all trials have been positive, however. For example, subsequent to FDA approval, a 12-month, multicenter, placebo-controlled trial in 627 male veterans with chronic, severe alcohol dependence did not demonstrate a benefit for naltrexone over placebo (57).
Given the problem with adherence to the oral formulations in this population, a 6-month, randomized, placebo-controlled trial assessed the benefit of long-acting injectable naltrexone (380 mg, n = 205; 190 mg, n = 210) in comparison with placebo (n = 209) (58). Monthly intramuscular injections of active drug combined with 12 low-intensity psychosocial intervention sessions were superior to placebo in terms of number of heavy drinking days (380 mg, 25% decrease, p = 0.03; 190 mg, 17% decrease, p = 0.07). Further, a post hoc analysis indicated a rapid rate onset of therapeutic effect in the first 2 days (59). There is also evidence that in early problem drinkers, naltrexone dosing targeted to high-risk situations may be an alternate strategy to daily oral dosing (60).
Typical starting doses are 25 to 50 mg/day orally. A large multicenter usage study reported that in 570 patients on naltrexone, the most common adverse effects were nausea (9.8%) and headache (6.6%), with 15% of patients dropping out because of nausea (61). Although no deaths occurred, a single case report has raised the question of a possible association between naltrexone and rhabdomyolysis (62).
One double-blind, placebo-controlled trial with another opioid antagonist, nalmefene (20 or 80 mg/day), found that this agent had a significant benefit over placebo in preventing relapse to heavy drinking (63). A second controlled trial, however, did not demonstrate superiority over placebo (64).
The possible benefits of opiate antagonists in treating symptoms of schizophrenia or bipolar disorder without alcohol dependence or comorbid alcohol and cocaine dependence may warrant studies in these difficult-to-treat populations (65,66,67 and 68). Furthermore, some data support a synergistic therapeutic effect when naltrexone is combined with CBT (69).
In summary, naltrexone and perhaps other opioid antagonists are promising agents in the pharmacotherapy of alcohol dependence with or without coexisting psychiatric and addictive disorders (63). However, the duration and severity of illness, adequacy of support systems, and patient adherence may be important modifiers of efficacy.
Acamprosate
Acamprosate (calcium acetylhomotaurine) has a chemical structure similar to the endogenous amino acid homotaurine and GABA. It appears to normalize N-methyl-D-aspartate (NMDA) receptor tone in the glutamate system, possibly restoring GABA/glutamate balance. It is a recipient of FDA approval for maintenance of abstinence in alcohol dependence.
Results from animal studies indicating a decrease in voluntary alcohol intake led to a number of double-blind, placebo-controlled trials involving more than 4,500 patients with alcohol dependence (70). In a review of these data, Mason and Ownby (70) found that 13 of 16 studies demonstrated a significant benefit from acamprosate versus placebo in terms of
Rate of treatment completion
Time to first drink
Abstinence rate
Cumulative abstinence duration
One randomized trial in 160 subjects indicated that the combination of acamprosate plus naltrexone was superior to placebo (p = 0.008) and acamprosate monotherapy (p = 0.04) but not to naltrexone monotherapy. Subjects also received group psychotherapy (71).
The Combining Medications and Behavioral Interventions (COMBINE) Study is an NIAAAsponsored controlled trial of pharmacotherapy for alcoholism (43). In the largest trial of its kind to date (n = 1,383), patients were randomized to a variety of medication treatment groups or behavioral counseling only for 16 weeks with up to 16 months of follow-up (72). Those who received naltrexone with medical follow-up were the least likely to relapse to a heavy drinking day. In contrast to earlier results, however, there appeared to be no advantage in adding acamprosate. Differences in patient populations and the higher dropout rates in this trial are possible explanations for the different outcome from previous studies.
Dose-response data indicate that 2 g daily (666 mg three times a day) is optimal. Of note, this agent is not metabolized by the liver but is excreted via the kidneys. In addition, it demonstrates an excellent safety profile, with loose stools or diarrhea being the only adverse effects reported more often than with placebo. Acamprosate does not inhibit or induce cytochrome P450 (CYP) isoenzymes. Other data indicate that this agent can be safely administered concurrently with disulfiram or naltrexone.
Ondansetron
Antidepressants
When considering the role of antidepressants in the treatment of alcohol dependence, ample evidence shows that alcoholism and depression are often associated, but they may also present as distinct entities (76). In this context, Schuckit et al. (77) addressed the issue of induced versus independent major depressive disorder (MDD) in 2,945 alcoholics. These authors concluded that it was possible to distinguish between substance-induced and -independent episodes. Symptoms often overlap, however, at times making proper diagnosis difficult.
Clinical studies of depressed alcoholics give some suggestions of the course of treatments. Brown et al. (78) demonstrated that those male patients in their sample with dual diagnoses of alcohol dependence and a mood disorder did not demonstrate more severe depressive symptoms or a slower recovery than their counterparts with either diagnosis alone. Evidence from another study shows that depression in schizophrenic alcoholics on acute inpatient admission resolves within the same time frame as does depression in nondually diagnosed alcoholics (79). If supported and broadened by further investigation, this finding would simplify treatment strategies by including patients with a dual diagnosis in mainstream addiction programs.
Tricyclic Antidepressants. The role of tricyclic antidepressants (TCAs) for depressed alcoholics has usually been limited to the period of acute withdrawal and not for longer-term maintenance. Methodological problems with studies in this area include (80)
Relative inattention to different subtypes of depression
Inadequate use of therapeutic drug monitoring (TDM)
Failure to monitor both mood and drinking behavior in response to treatment
Despite these design flaws, many of the studies support the beneficial effects of TCAs in the treatment of depression associated with alcohol withdrawal. These benefits, however, do not exceed those of placebo after 3 weeks and thus may have only limited application in clinical practice.
Of the available antidepressants, imipramine is the most extensively studied. A trial assessing the effectiveness of this agent for alcoholism with comorbid depression had certain advantages over its predecessors, including (81)
Lifetime histories to establish diagnoses of depression (thus avoiding transient depressive effects of alcohol)
A double-blind design during the second phase of the study
Adequacy of dosing as monitored by plasma levels
Although criteria for response are incomplete, the investigators reported that of 60 alcoholics who had major depression and who completed an initial 12-week open-label trial of imipramine, 27 (45%) responded, showing improvement in both mood (posttreatment Hamilton Depression Rating Scale [HDRS] score, 3; SD±3) and drinking behavior (30% achieving abstinence and another 15% a “much reduced level”). These response rates were further enhanced after dose increases or treatment with disulfiram. Patients who improved with imipramine in the initial open trial were then randomized into a subsequent 6-month, double-blind maintenance phase. During this phase, 7 of 10 (70%) suffered a relapse on placebo, in contrast to only 4 of 13 (31%) on imipramine. Although the sample sizes were small, the investigators believed that this represented a significant improvement for those on medication in a common dual-diagnosis scenario.
Selective Serotonin Reuptake Inhibitors. New possibilities emerged with the introduction of the selective serotonin reuptake inhibitors (SSRIs). Basic studies using these agents in animals demonstrated a decrease in alcohol preference and consumption, whereas nonspecific monoamine uptake blockers (e.g., amitriptyline, doxepin) did not (82). Using animal models of spontaneous alcohol consumption, Gorelick (82) reported evidence that increased brain serotonin activity tended to decrease alcohol preference and consumption. Extrapolating these results from the laboratory to the clinical arena, Gorelick and
Paredes (83) then studied the effect of fluoxetine (up to 80 mg/day) on alcohol consumption in 20 men with chronic dependence. After a 28-day, double-blind, placebo-controlled period, these investigators found that the fluoxetine group had a 14% lower alcohol intake, primarily during the first week. The beneficial effect was associated with a lower proportion of requests as well as less craving for alcohol. As in the imipramine outcomes, however, these investigators did not find a significant effect in later weeks (i.e., virtually no differences in scores on the Hamilton Depression and Anxiety Scales or the abridged Hopkins Symptom Checklist). A second 12-week, placebocontrolled trial of fluoxetine (up to 60 mg/day) did not find this SSRI different from placebo (84). A subsequent 14-week, placebo-controlled trial in 100 patients with alcohol dependence found that sertraline (maximum dose, 200 mg/day) was superior to placebo but only in type A alcoholics (i.e., 53.3% on sertraline abstained vs. 16.0% on placebo; p < 0.04) (85).
Paredes (83) then studied the effect of fluoxetine (up to 80 mg/day) on alcohol consumption in 20 men with chronic dependence. After a 28-day, double-blind, placebo-controlled period, these investigators found that the fluoxetine group had a 14% lower alcohol intake, primarily during the first week. The beneficial effect was associated with a lower proportion of requests as well as less craving for alcohol. As in the imipramine outcomes, however, these investigators did not find a significant effect in later weeks (i.e., virtually no differences in scores on the Hamilton Depression and Anxiety Scales or the abridged Hopkins Symptom Checklist). A second 12-week, placebocontrolled trial of fluoxetine (up to 60 mg/day) did not find this SSRI different from placebo (84). A subsequent 14-week, placebo-controlled trial in 100 patients with alcohol dependence found that sertraline (maximum dose, 200 mg/day) was superior to placebo but only in type A alcoholics (i.e., 53.3% on sertraline abstained vs. 16.0% on placebo; p < 0.04) (85).
Although the mechanism of action of SSRIs in treating alcohol dependence remains unclear, Gorelick and Paredes (83) postulate that it is not due to motor inhibition or general sedation. Rather, they believe that it may be “related to decreased appetite and food intake or a conditioned taste aversion mediated by increased brain serotonin activity.” Other competing theories summarized by Thomas (86) include
Antidepressant and anxiolytic effects
Decrease in impulsivity
Extinction of reward contingencies
Garbutt et al. (46) reviewed the existing evidence for the usefulness of SSRIs in the management of alcoholic patients with and without significant depression or anxiety. The studies varied in design and outcome, but overall, these investigators believed the data were limited and not promising (87,88,89,90 and 91). The results of some trials, however, may be confounded by high rates of comorbid mood and anxiety symptoms.
Mood Stabilizers
In general, all mood-stabilizing agents used for the dually diagnosed population can at least facilitate treatment of the psychiatric and the addictive disorder by stabilizing patients, thus promoting more appropriate participation in treatment.
Lithium, however, has not fulfilled its initial promise for the treatment of primary alcoholism with and without a concurrent affective disorder. Dorus et al. (92) studied 457 male alcoholics in a Veterans Administration collaborative study and found that lithium did not alter the use of alcohol in either depressed or nondepressed alcoholics. Specifically, they reported abstinence in 38% of lithium-treated nondepressed alcoholics (compared with 28% of placebocontrolled subjects) and 32% of lithium-treated depressed alcoholics (compared with 37% of their placebo-controlled subjects). Fawcett et al. (93) reported beneficial effects of lithium in 104 alcoholics studied in a double-blind, placebocontrolled design. They found, however, that 19 of 51 patients (37%) given lithium and 22 of 53 patients (42%) given placebo were abstinent at the 6-month follow-up, with the numbers even more similar at 12-month follow-up.
Although lithium no longer appears promising to treat alcohol dependence itself, it may have a place in pharmacotherapy of the overall syndrome. A small pilot study (n = 12) by Nagel et al. (94) assessed lithium in a double-blind, placebo-controlled design focusing on recently (3 to 7 days before entry into study) detoxified alcoholics who manifested a syndrome resembling hypomania. Symptoms consisted of elevated psychomotor activity, grandiosity, irritability, a heightened desire for social contact, loquaciousness, and sexual preoccupation. The severity of symptoms was significantly decreased by treatment with low-dose lithium carbonate (serum levels 0.3 to 0.5 mEq/L) but was not affected by placebo treatment.
As noted earlier, anticonvulsants such as VPA and CBZ may be useful in withdrawal states from alcohol and for relapse prevention (32,95,96,97 and 98). Topiramate appears to indirectly decrease mesocortical dopamine by facilitating GABAergic activity on a non-BZD receptor and by antagonizing amino-5-methyl-3-hydroxy-4-isoxazolepropionic acid and kainate glutamatergic receptors (99). Two placebo-controlled trials demonstrated benefit with topiramate for alcohol dependence (100,101).
![](https://freepngimg.com/download/social_media/63059-media-icons-telegram-twitter-blog-computer-social.png)
Stay updated, free articles. Join our Telegram channel
![](https://clinicalpub.com/wp-content/uploads/2023/09/256.png)
Full access? Get Clinical Tree
![](https://videdental.com/wp-content/uploads/2023/09/appstore.png)
![](https://videdental.com/wp-content/uploads/2023/09/google-play.png)
![](https://clinicalpub.com/wp-content/uploads/2023/09/banner1.png)