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Mood Stabilizers in the Treatment of Substance Use Disorders


Icro Maremmani, MD, Matteo Pacini, MD, Francesco Lamanna, MD, Pier Paolo Pani, MD, Giulio Perugi, MD, Joseph Deltito, MD, Ihsan M. Salloum, MD, MPH, and Hagop Akiskal, MD


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CNS Spectr. 2010;15(2)95-109

 

Contents

Abstract
Methods
Acute Intoxication
        • Amphetamines
        • Alcohol
        • Cannabinoid Drugs
 

 

Dr. Maremmani is Professor of Addiction Medicine and Chief of the Vincent P. Dole Dual Diagnosis Unit at Santa Chiara University Hospital, Department of Psychiatry, University of Pisa, Italy and Co-Director of G. de Lisio Institute of Behavioural Sciences in Pisa. Dr. Pacini is Researcher of G. De Lisio Institute of Behavioural Sciences in Pisa. Dr. Lamanna is consultant in the Vincent P. Dole Dual Diagnosis Unit at Santa Chiara University Hospital. Dr. Pani is Director at the Sardinia Regional Coordination Unit, Health District 8, in Cagliari, Italy. Dr. Perugi is Director of the Institute of Behavioural Sciences and researcher at the Department of Psychiatry at the University of Pisa. Dr. Deltito is Clinical Professor in the Department of Psychiatry and Behavioral Science at New York Medical College in Valhalla, NY. Dr. Salloum is Director, Addiction Psychiatry and Psychiatric Comorbidity Programs in the Department of Psychiatry and Behavioral Sciences at University of Miami in Florida. Dr. Akiskal is Professor of Psychiatry and Director of International Mood Center at the San Diego Veterans Administration Medical Center in California.

Faculty Disclosures: Dr. Perugi is a consultant to Boehringher Ingelheim, Eli Lilly, Janssen, and Sanofi-aventis; has received research/grant support from Boehringher-Ingelheim and Eli Lilly; he has received honoraria from AstraZeneca, Abbott, Boehringher-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Janssen, Lundbeck, and Sanofi-aventis. Dr. Deltito is on the speaker’s bureau of and received honoraria from Merck. Dr. Salloum has received grant/reseach support from AstraZeneca and Janssen. Drs. Maremmani, Pacini, Lamanna, Pani, and Akiskal report no affiliation with or financial interest in any organization that may pose a conflict of interest. 

Off-label usage: All mood stabilizers referred to in the article (lithium, topiramate, lamotrigine, carbamazepine, oxcarbazepine, gabapentin, valproic acid, nimodipine, tiagabine) are unlabelled as regards drug addiction disorders, but their use is approved in psychiatric comorbidity with drug addiction disorders.

Submitted for publication: June 23, 2009; Accepted for publication: December 22, 2009.

Please direct all correspondence to: Icro Maremmani, MD, Vincent P. Dole Dual Diagnosis Unit, Santa Chiara University Hospital, Department of Psychiatry, University of Pisa, Via Roma, 67 56100 PISA, Italy, EU; Tel: 39-0584-790073, Fax: 39-0584-72081; e-mail: maremman@med.unipi.it.


 

Abstract

Individuals suffering from drug addiction may also manifest features of bipolar spectrum disorders. Hyperthymic and cyclothymic temperaments may render individuals vulnerable to later development of substance abuse. Bipolar disorders themselves may be altered or precipitated by substance use, most notably by stimulants (amphetamines), alcohol, and cannabinoids. The clinical usefulness of mood stabilizers, particularly antiepileptics, has been established as safe and effective in substance abusers with and without comorbid mood disorders. Most studies on this issue have been of short duration and focused on the resolution of a currently manifest period of illness. Few studies have been conducted on the usefulness of these drugs on the long-term longitudinal course of these diseases, such as frequently encountered recurrent relapses into states of agitation, impulsivity, and/or dissatisfaction. As opposed to the clinical experience with traditional antidepressants and neuroleptics, antiepileptics do not induce counter-polar states (depressed patients abruptly turning manic or hypomanic; nor patients currently hypomanic or manic turning abruptly depressed). Many clinicians consider antiepileptic mood stabilizers to be the preferred category of medications for the treatment of such patients. Valproate appears to be a potentially fruitful medication to study in these dual diagnosis patients due to preliminary evidence demonstrating its anticraving efficacy.

Focus Points

• The conceptualization of the link between bipolar spectrum and addictive disorders has not only heuristic and scientific value, but also an important message for the clinician.
• Dual diagnosis does not account for transient substance-related symptoms, but instead has an autonomous course and relapse-proneness.
• It is necessary to treat mood instability and counteract impulse discontrol without using neuroleptics and/or antidepressants.

 

Introduction

Mood stabilizers are widely employed for the acute and chronic treatment of bipolar disorders presenting with varying severity and symptom profiles. Studies in clinical and general populations have shown a high degree of comorbidity beween substance-related and other mental disorders. Two large surveys have been carried out in the United States: the US Epidemiologic Catchment Area (ECA) and the US National Comorbidity Survey (NCS). The ECA study found odds ratios (OR) of 2.9 and 4.7 for comorbidity between any of the lifetime mental disorders and any alcohol use or drug use disorder, respectively.1 The NCS study identified an OR of 2.4 for comorbidity between any of the lifetime Dianostic and Statistical Manual of Mental Disorders, Third Edition-Revised, mental disorders assessed in that survey and any lifetime alcohol or drug use disorder. ECA respondents with a lifetime alcohol use or other drug disorder also met criteria for at least one lifetime mental disorder in 36.6% or 51.3% of cases, respectively. NCS respondents with a lifetime alcohol or drug use disorder also met criteria for at least one lifetime mental disorder in 51.4% of cases, while past alcohol or drug abuse or dependence was present in 50.9% of the NCS respondents with a lifetime mental disorder.2,3 Comparable results for 12 month comorbidity in the NCS were 42.7% of respondents with an alcohol or drug disorder also having a mental disorder and 14.7% of respondents with mental disorders also having an alcohol or drug disorder (OR 2.6).
 

Findings from the ECA and NCS studies have been substantially confirmed by other major surveys, such as the National Longitudinal Alcohol Epidemiologic Survey,4 the International Consortium in Psychiatric Epidemiology,5 and the National Epidemiologic Survey on Alcohol and Related Conditions.6 These surveys and other observations in clinical populations have shown a higher degree of association with substance use in regard to anxiety, mood, and personality disorders. Moreover, the strength of the association of these disorders has been shown to be higher for drug dependence than for drug abuse.3,5,7
 

Comorbidity for substance abuse is common among bipolar subjects.1,8-15 The association between mania and substance abuse is widely documented.1,8,11,12,14,16 Abusers tend to increase their rates of consumption during manic phases,11,14 except for alcohol abusers who may increase their drinking behavior more readily while in depressed mood states.12,17-19 A general lack of agreement between studies documenting the prevalence of bipolar disorders among substance abusers may be due to different methods and sensitivities used to detect sub-manic forms of elation or irritability.20,21 There has been a trend to classify any clinical pictures featuring prominent depressive and anxious symptoms as depressive disorders.22 Part of such depressive pictures may only be the expression of severe intoxication,23 whereas another portion may represent a depressive phase in the context of a lifetime minor bipolar disorder.24
 

Among borderline patients, parasuicidal behavior and substance abuse are elicited by different cues, so that depressed-agitated moods may contribute to a higher rate of parasuicidal conduct. This is not necessarily associated with a higher risk for substance abuse through a putative mechanism of self-medicating.25 On the other hand, the role of anxiety as a major reason for substance abuse is controversial. Perugi and colleagues26 found that the awareness of a self-medicating action of alcohol upon anxiety by social phobics is not enough to discriminate consumers from abstainers. Habitual drinking in social situations is not so common; indeed, despite it seeming congruent with self-medicating it is predominantly displayed by those patients with a personal or familial lifetime history of bipolar II disorder. A dominant cyclothymic temperament discriminates heroin addicts from healthy controls, regardless of the presence of dual diagnoses.27
 

Addressing psychiatric instability is a reasonable strategy to increase retention rates in the early phases of addiction treatment. During treatment, mood elation and behavioral excitement undermine the consolidation of positive treatment outcomes. Over self-confidence, a profound need for “immediate“ change, and a lack of patience for the attainment of a gradual control of symptoms may very well be signs of the irrational escalation of mood. This can hamper adherence to a therapeutic treatment program aimed at long term wellness. Such exuberance for rapid change may erroneously be interpreted as a positive clinical outcome, when close scrutiny would see such attitudes as irrational in quantity and quality.
 

Anti-craving properties have been suggested for several antidepressants, although this has been established only over the short term. On the other hand, longer-term antidepressant exposure may favor mood swings to the manic-side, to which substance abusers may have a greater disposition.28 As a consequence, the favorable effect observed early in treatment during withdrawal would turn into an increased risk of relapse due to increased levels of impulsivity later on.15 In other words, researchers who stop their observations after witnessing a major improvement in depressed/dysphoric mood may miss a worsening of substance use that may follows in the long term. They may be truly witnessing, but not recognizing, evolving states of manic or hypomanic elation or irritability.
 

The present paper discusses the use of mood stabilizers in subjects who use various psychoactive agents to determine specific effects against craving and relapse. The discussion will be made separately for different clinical scenarios: acute intoxication, withdrawal, addiction, and dual diagnosis. The qualitative distinction between use, heavy use, and addiction is not always clear in the premises of some studies. As for dual diagnoses, data will be reported about the possible specific effectiveness of mood stabilizers in the reduction of psychiatric symptoms in cases of concurrent substance abuse or the selective impact of mood stabilizers on addictive symptoms in mentally ill patients. 

 

Methods 

The evaluation of the efficacy, effectiveness, and safety of mood stabilizers was based on a review of the literature on the subject available in MEDLINE. Although all randomized controlled trials and controlled clinical trials were considered for the article, meta-analysis or other quantitative methods for weighing the evidence were not applied. Cohort, case-control, time-series, cross-sectional, and cases studies were also included, weighing the quality of the information given and the strength of recommendation against the weaknesses of the design and increased risk of bias, but without referring to pre-defined grading criteria. Some literature not available on MEDLINE was also considered when cited in included studies. For each relevant statement, the design of studies on which it was based was specified. In the reference list, references testifying the best available evidence for each considered subject were included.

 

Acute Intoxication

Short-term exposure to certain drugs produces a pleasurable effect referred to as euphoria. Although generally pleasurable, euphoria itself may imply altered mental functions that pose risk to an individual, as it represents an inherently unstable state. There are different types of intoxication, such as stimulation (eg, cocaine, amphetamines), sedation, and narcosis (eg, opiates, benzodiazepines), or states of primarily altered perceptions (eg, hallucinogenic drugs, cannabinoids). The same substances can produce intoxications of different types. For example, alcohol or benzodiazepines may present with the loss of inhibition and euphoria at lower doses and with sedation at higher levels. Others can be mildly sedating at lower doses and produce agitation at higher levels (cannabis). As a rule, effects are dose-dependent. But certain individuals, both on somatic and psychological grounds, are particularly vulnerable to a given psychopathic presentation, whereas others may react in a paradoxical manner (eg, agitation with benzodiazepines or behavioral inhibition from cocaine). Regular exposure to the same class of substances, or cross-reacting substances, often desensitizes an individual to its effects; this is called tolerance. Conversely, certain substances, such as cocaine, can increase their toxic potential through repeated exposure by a neurochemical mechanism called kindling.

 

Amphetamines

The use of lithium is not a highly safe option during stimulant intoxication because of lower lithium clearance due to dehydration and sodium re-absorption, and an increased risk of ventricular arrhythmias. Moreover, lysergic acid diethylamide psycho-toxic effects were enhanced in subjects with stable lithium blood levels with respect to what they had previously experienced.29
 

Antiepileptics prevent seizures and decrease the intensity of glutamate-mediated neurotoxic effects, which can lead to permanent damage. In acute methylenedioxymethamphetamine (MDMA) intoxication, a protective effect may also be exerted by previous exposure to selective serotonin reuptake inhibitors, which fight the uptake of cytotoxic MDMA metabolites.30 Unfortunately, acute behavioral effects as well as neuromuscular effects may be dangerously amplified by such a combination. Antipsychotics may be prescribed in the case of psychotic symptoms, although they lower the brain’s epileptic threshold and may also increase the risk of arrhythmias. Additionally, it has also been noted that chronic cocaine consumers have a higher rate of neuroleptic-induced dystonia.31 Therefore, antiepileptics and benzodiazepines may achieve sedation more safely.
 

Topiramate (TPM) is safe in combination with intravenous methamphetamine. Curiously, methamphetamine’s euphorizing effects, but not those of reinforcement and craving, are enhanced by concurrent TPM administration in recently detoxified subjects. TPM alone is free of euphorizing effects in these subjects (placebo controlled, cross-over study).32
 

Lamotrigine (LTG) was proved not to have significant interactions either with cocaine’s psychic nor somatic effects (double-blind, placebo controlled study).33
 

Alcohol

Alcohol intoxication should be first treated by support-measures, toxicological examinations, and possibly physical containment in cases of psychomotor excitement. When excitement does not dwindle through time, anti-withdrawal and antimanic treatment should be considered. Hirschowitz and colleagues34 reported that lithium was effective in fighting alcohol intoxication, dependent upon its intracellular concentration. However, other evidence indicates that lithium may attenuate alcohol-induced cognitive deficits, without effecting alcohol-induced euphoria.35 Valproate 3,000 mg/day proved effective against acute alcohol hallucinosis in a double-blind trial. Pre-treatment with the calcium-channel-blocker nimodipine (but not verapamil) decreases expected alcohol levels (placebo controlled study).36 Nevertheless, pre-treatment with isradipine does not attenuate expected ethanol effects (placebo controlled study).37
 

Cannabinoid Drugs

In a double case-report, carbamazepine (CBZ) was effective as an add-on resource to antipsychotic drugs in the treatment of cannabis-related (ie, tetrahydrocannabinol-positive) acute psychoses.38
 

The possible use of mood stabilizers in abusers during acute intoxication is summarized in Table 1.

 

Withdrawal Syndrome

In tolerant individuals, the abrupt interruption of drug exposure or a markedly steep reduction in exposure levels can result in a series of phenomena which counteract the substance’s particular effects. Withdrawal of sedatives is manifested by anxiety, insomnia, and agitation, whereas withdrawal of stimulants is manifested by sleepiness, low energy, and depression. Withdrawal is a transient biphasic course of variable length usually proportional to the half-life of the substance to which the individual has become tolerant. The mechanism of withdrawal corresponds to a metabolic impairment, and may imply elastic changes in receptor availability and response, or the temporary scarcity of neurotransmitters due to previous hyperstimulation. Addicted individuals often show withdrawal symptoms as a consequence of regular exposure to drugs and poor control in the handling of drug supplies. Non-addicted on-going consumers are theoretically as prone to withdrawal, but in fact seldom happen to go through it, and if so, usually it is by accident.
 

Cannabinoid Withdrawal

A group of chronic marijuana users was observed for 58 days under valproate treatment during withdrawal in a placebo controlled design. The authors found that craving was decreased, despite a worsening of mood and cognitive performance.39

 

Alcohol and Benzodiazepines Withdrawal

CBZ was used to counter alcohol withdrawal in different studies.40-45 CBZ proved as effective as tiapride in alcohol withdrawal and had a quicker effect upon fear and hallucinations.46 It is as effective as valproic acid (VPA)47 and barbiturates as a means of seizure prophylaxis.48 While CBZ alone is equivalent to standard benzodiazepine treatment,49,50 the combination with tiapride proved superior.51-54 A series of studies55-60 agree on CBZ as being effective against benzodiazepine withdrawal. The advantage of CBZ seems to be more distinct in cases of highly tolerant individuals (20 mg of diazepam or more).
 

Oxcarbazepine (OXC) was equivalent to placebo in a pilot, double-blind, randomized controlled trial.49 A different study proved it equivalent to CBZ and superior against craving in the short-term.61 An open-label comparison study proved the OXC-tiapride combination to be equivalent to clomethiazole.62
 

TPM was found effective in the prophylaxis of alcohol-withdrawal-related seizures at a 100 mg/day dose in an open, non-controlled pilot study of 12 patients.63 It also proved equivalent to standard diazepam in a single-blind, randomized study comparing different anti-glutamatergic compounds to diazepam.64
 

A series of works have suggested gabapentin’s (GBP) effectiveness against alcohol withdrawal.65-67 Two controlled studies found it equivalent to phenobarbital68 or clomethiazole after lead-in domethiazole treatment of acute withdrawal on the first alcohol-free day.69 One advantage of GBP may be a more satisfactory effect on insomnia, when compared in a randomized, double-blind fashion to lorazepam in patients who underwent several episodes of withdrawal.70
 

GBP (900 mg on average) was superior to trazodone (100 mg on average) in the open-label treatment of persistent refractory insomnia during a 4–6 week period.71 A double-blind, randomized, placebo-controlled trial confirmed this finding.72 GBP’s impact upon the mood of alcoholics during the first two days of withdrawal seems to be at least partially independent of baseline withdrawal severity, but rather relates to comorbidity with mild depression (randomized controlled trial).73
 

Several studies,47,74-78 three of which were conducted in a randomized controlled or randomized, double-blind, controlled fashion,47,75,77 were carried out to investigate the therapeutic potential of VPA against alcohol withdrawal. Results indicate the equivalence of VPA to standard gaba-ergic agents such as barbiturates and benzodiazepines. In one case VPA was more rapid in the buffering of withdrawal symptoms.77 A comparison with CBZ and placebo showed a favorable profile of side effects for VPA.47 In a comparison between VPA, trazodone, and placebo to ameliorate benzodiazepine withdrawal in 78 subjects who had been tolerant to benzodiazepines for at least one year,79 VPA and trazodone were similarly effective and allowed a more rapid tapering of benzodiazepines than placebo.
 

Nimodipine (60 mg on four separate occasions) failed to prove superior to placebo in reducing the need for clomethiazole in 32 subjects undergoing alcohol withdrawal in a placebo-controlled manner.80 Thus, previous positive open-label results81,82 were not confirmed. However, a double-blind study indicated nimodipine’s efficacy in reducing depressive symptoms in short-term abstinent alcoholics.83
 

LTG may be an alternative to classic diazepam (ie, with no need of further diazepam vs. diazepam itself), as one randomized, single-blind work indicated.64
 

A Cochrane systematic review, including 48 studies (3,610 people) evaluated the efficacy of CBZ, valproate, GPB, vigabatrin, diphenylhydantoin, barbital, chlormethiazole, phenytoin, and other classic anticonvulsants on the severity of overall alcohol withdrawal, withdrawal seizures, and withdrawal delirium as primary outcomes. It showed a tendency for therapeutic success [relative risk (RR) 1.32; 95% CI 0.92–1.91] and protection against seizures [RR 0.57; 95% CI 0.27–1.19] among the anticonvulsant-treated patients in comparison with placebo, but no effect reached formal statistical significance. Moreover, comparing CBZ versus benzodiazepine, a statistically significant protective effect on withdrawal severity was found for the anticonvulsant [WMD -1.04; 95% CI -1.89 to -0.20), P=.02], but this was based on only 260 randomized participants. The conclusion of the authors was that it is not possible to draw definite conclusions about the effectiveness and safety of anticonvulsants in alcohol withdrawal because of the heterogeneity of the trials in both interventions and the assessment of outcomes.
 

Opiates Withdrawal

Lithium treatment of detoxified heroin addicts may be effective in preventing mood elevation, but is not effective in blocking morphine-elicited euphoria.85 A combination of mianserin-CBZ proved superior to traditional clonidine against morphine/heroin withdrawal.86 The introduction of CBZ during gradual methadone withdrawal was shown to possibly exacerbate withdrawal symptoms due to a steeper reduction of methadone blood levels caused by an increase in the metabolism of methadone.87
 

GBP 1,200 mg/day was successfully employed in pentazocine withdrawal added on to clonidine and following naltrexone. Muscular pain, craving, and psychic discomfort were buffered to a greater extent (non-controlled study).88 The addition of GBP 1,800 mg/day to standard treatment for heroin-withdrawal also proved to be a significant advantage.89 The antinociceptive effect in a condition of altered opioid metabolism was also suggested by a later non-controlled study of opiate-addicts rapidly detoxified following a naltrexone-based regimen.90 One double-blind, randomized controlled study has been performed in methadone-detoxified addicts, only showing the absence of further advantage of GBP 900 mg add-on.91
 

In animal models, VPA is characterized by a dual action with respect to analgesia and withdrawal. If administered shortly before naloxone, it attenuates withdrawal signs, whereas it has a worsening impact if administered one hour before a naloxone challenge, suggesting some VPA metabolite may act as an opiate antagonist. Similarly, morphine-analgesia was found to be reduced in animals chronically exposed to VPA.92,93 Unlike CBZ, VPA seems to have no effect on methadone metabolism.94
 

The calcium-channel blocker nimodipine demonstrates a significant advantage when added to the dextropropoxiphen-benzodiazepine combination for opioid withdrawal95 and favors the cessation of morphine in tolerant individuals who need to be detoxified (randomized, double-blind, controlled study).96
 

Contrary to the study hypothesis, LTG failed to attenuate naloxone-induced withdrawal (vs. placebo).97
 

The possible use of mood stabilizers in abusers during withdrawal syndrome is summarized in Table 2.
 

 

Dependence/Addiction

Addiction is the continuous use of certain drugs (usually against an individual’s desire), manifesting a rapid-cycling series of failed attempts to control one’s drug-using behavior. The uncontrollable urge and desire to consume drugs is called craving and is self-maintaining even in the prolonged absence of reward. We may say addiction is a possible persistent consequence of habitual drug use, consisting in the impossibility to grant oneself self-controlled intoxication. The term dependence has become popular to refer to a state where addictive substance use is self-maintained to a personal detriment of general functioning—either by the need to avoid withdrawal or the need to keep certain discomfort under control. However, when the role of primary loss of behavioral control is not focused upon in dependence, the consequence is oftentimes mistaken for the cause. There appears to persist an erroneous idea that addicts would spontaneously tend to reach an equilibrium, except for substance kinetics, which ties them to a vicious cycle of intoxication and withdrawal. We will refer to addiction as a brain disorder corresponding to the stable loss of the capacity to control one’s way to individual reward by the fixation of behavioral reinforcement to a certain addictive stimulus. 
 

Opiates Dependence/Addiction

The clinical experience with mood stabilizers in heroin addicts has been limited by the existence of a broad-spectrum, highly effective treatment regimens, such as methadone or buprenorphine maintenance, and by the lack of major opioidergic properties in mood stabilizers, which would have been an obstacle to their liberal clinical use. The same obstacle may be a limit to the employment of opiate agonist drugs, such as methadone98,99 for primary mood-stabilizing properties in non-addicted individuals.
 

A 1970’s open, observational study evaluating lithium in the post-detoxification course of heroin addicts showed poorer retention rates regardless of the treatment arm on which they were maintained. Although lithium-treated subjects tended to be retained more readily in the short-term, the dropout rate was similar for all groups in the medium-term.100
 

Alcohol Dependence/Addiction

In general, alcohol abuse/addiction comorbidity is a negative predictor of lithium’s effectiveness upon bipolar disorder. Other predictors of lithium-resistance, such as mixed states and rapid-cycling presentations, are quite common in affective disorder complicated by substance abuse. A discriminant feature may be the alcohol use of lithium-treated subjects. Detoxified alcoholics, who spontaneously achieve abstinence or are treated in an in-patient setting, may relapse later and avoid further hospitalization in double-blind settings.101-104 Fawcett and colleagues103,104 identified compliance and lithium blood levels over .4 mEq/l as major predictive factors for a good outcome in a double-blind setting, but also stated that lithium responsiveness of alcoholics is independent of compliance. In fact, placebo-compliant subjects are more likely to relapse; nor do lower lithium blood levels (active arm, partial compliance) correspond to any relapse-prevention effect. Moreover, there are no clear indications that the impact of lithium upon alcoholism is a collateral aspect of its antidepressant properties. On the other hand, active drinkers do not benefit from lithium treatment, either in terms of the amount of their alcohol consumption nor the likelihood of their relapse.105-109
 

Little data are available on the relapse-preventing effectiveness of VPA treatment in alcoholics. Longo and colleagues77 compared a group of alcoholics observed on a drug-free regimen after detoxification by benzodiazepine or VPA to a third arm which maintained valproate for a further 6 weeks. Relapse was less likely in the VPA-maintenance group. Brady and colleagues110 compared VPA to placebo over 12 weeks after the completion of detoxification and reported that VPA did not influence the likelihood of maintaining abstinence, but did reduce the likelihood of relapse into heavy drinking.
 

Salloum and colleagues111 performed a double-blind, randomized controlled trial comparing standard lithium treatment with the combination lithium-VPA in detoxified alcoholics suffering from bipolar I disorders. Results indicate a significant effect of VPA upon alcohol consumption, which is independent of mood, since lithium treatment alone results in equivalent mood outcomes. Time to sustained relapse (3 days) is longer in the lithium-VPA group, as it is in all other parameters of consumption. Higher valproate serum concentration significantly correlated with improved alcohol use outcomes.
 

In a double-blind, randomized trial of 371 alcoholics, TPM treated patients (up to 300 mg/day) showed greater improvement of somatic, behavioral, and psychological alcohol-related symptoms at 14 weeks.32,112 Another non-controlled, observational study evaluating the effect of TPM 200 mg/day on 64 treatment-resistant alcoholics indicated a significant advantage at 1 year.113
 

OXC is comparable to acamprosate in a randomized controlled 3 month open trial on a group of detoxified alcoholics.114 Drinkers using OXC do not experience adverse effects due to the combination. A higher dose of OXC (1,500–1,800 mg/day) showed a higher retention rate at 3 months within a randomized controlled trial versus naltrexone 50 mg/day, with a more robust effect in dual diagnosis patients, along with a reduction of aggressiveness (according to the Symptom Checklist-90 [SCL-90] Anger-Hostility subscore). Otherwise, patients treated with a lower dose OXC (600–900 mg) are equivalent to naltrexone, despite a smaller decrease in craving, as measured by the Obsessive Compulsive Drinking Scale.115
 

GBP up to 1,200 mg/day proved safe versus placebo in double-blind trials on currently drinking alcoholics21,65,116 or upon those during withdrawal.68,69,73 No adverse reactions emerged from a study on healthy volunteers at doses of 1,000 or 2,000 mg 4 hours before a session of repeated alcohol consumption.21
 

Indirect evidence on the utility of GBP in alcohol-abusing subjects is offered by the study of Perugi and colleagues.26 They administered GBP (1,300 mg on average) to a group of treatment-resistant bipolars, and established a correlation between concurrent alcohol abuse and a favorable clinical response. A single open label 3 month study with pregabalin on detoxified patients does not allow any sound conclusions to be drawn beyond its presumable safety.117
 

 

Cocaine Dependence/Addiction

Lithium does not seem to be a potential agent against addictive cocaine use.118-120 Although it may ameliorate the affective status of cocaine-abusers to some extent, the correction of dysphoria may not be the key factor. In fact, the antidepressant desimipramine proved superior, although no long-term comparison is available119-121 and available evidence does not support its use.
 

Two studies examined the effect of VPA upon cocaine abuse. Halikas and colleagues122 found it useful in reducing the number of days of cocaine use among 55 patients, while favoring their psychosocial rehabilitation. In this open pilot study, efficacy was found to be dose-dependent, so that serum VPA levels over 50 mcg/ml rendered better results. Myrick and colleagues123 administered a load of 20 mg/kg/day of VPA to 17 patients in an open-label model. The retention rate was as high as 50% at 8 weeks, with significant improvement in drug using parameters. The multiple comparison trial performed by Reid and colleagues124 (olanzapine 10 mg/day, VPA 1,500 mg/day, coenzyme Q10/L-carnitine 500 mg/day) found all active treatment options equivalent to placebo.
 

LTG at dosages up to 300 mg/day can be safely administered to cocaine abusing bipolar patients improved in general affective stability and affective modulation of craving (less urgency and dysphoria associated during craving) both in the short and long term (36 weeks). However, in two open studies, objective improvement in additive behaviors was not clearly proven when the main parameter was self-report of money spent on cocaine.125,126 A controlled trial comparing LTG 150 mg/day to GBP 1,600 mg/day and reserpine found the former two to be inferior to reserpine at 10 weeks.127
 

A positive finding with LTG up to 300 mg/day in a group of HIV-positive cocaine abusers was not easily interpretable,128 since bipolar spectrum disorders were likely to be frequent in such a sample.129 The supposed anticraving effect of LTG may thus be nonspecific and may actually be a consequence of mood stabilization. However, due to the need for a slow upwards titration (12.5 mg/week), longer terms of observation are required to obtain sound conclusions.
 

Some authors indicated GBP as useful for cocaine abuse on the basis of open case observations130,131 and one placebo-controlled discrimination study proved that GBP does reduce cocaine’s discriminative stimulus in cocaine-dependent volunteers.132 Cocaine preference to $5 reward is not altered by GBP pre-treatment in hospitalized street addicts, which does not allow to draw any conclusion given the presumably low  impact of such a reward on cocaine craving.133
 

However, positive results of this kind are difficult to translate into a generalized judgement of effectiveness. Studies were performed in an inpatient setting on small samples of subjects who had been spontaneously in touch with psychiatric facilities, which suggests less involvement in addictive cocaine use. Controlled studies, however, agree on the equivalence of GBP to placebo (3,200 mg/day at 12 weeks,21 1,800 mg/day at 10 weeks,127 2,400 mg/day at 10 weeks,134 2,400/3,200 mg/day at 48 days135).
 

Tiagabine was reported as superior to placebo in a group of methadone maintained cocaine abusers, who showed clinical improvement and a higher retention rate at 10 weeks.134
 

In animal models, CBZ failed to reduce cocaine self-administration,136,137 although it did decrease dopamine release in the nucleus accumbens in vivo.138 A partial effect emerging at higher dosages is non-specific, since it also affects food intake and is accompanied by a general decrease of almost any activity. Indeed, such an effect can only be observed for heavier cocaine intake.137 Lastly, no antagonist effect (vs. placebo) is reported in human subjects.139 A metanalysis of controlled studies140-143 concludes that CBZ is not useful either in terms of effectiveness or having subjects retained in treatment.144
 

If some groups appear to benefit to some extent, this may merely correspond to better compliance, reflecting their initial lower level of cocaine addiction severity. Halikas and colleagues have provided a number of positive reports140,141,145,146 which have some major flaws. In one case, observations only lasted 3 weeks, which is not enough time to come to any definite conclusions; in another case, the impossibility of ruling out a difference in compliance makes it impossible to interpret their results; another study was an open-label observation based on self-report. The fourth study was a randomized, double-blind one (placebo, CBZ 400 mg, and CBZ 800 mg), but the finding of better results of the low-dose group versus placebo (with a blood CBZ-response correlation) is not clearly understandable.144
 

The issue of compliance again limits the interpretation of data from cocaine abusing methadone maintained subjects, so that compliant patients may show some response merely because they are less severely ill. Moreover, a reduction of 60% of methadone blood levels will worsen the quality of the stimulating properties of cocaine (because of a lower opioid buffering of unpleasant side effects), with hypothetical consequences on the amount and frequency of consumption.145 A single non-controlled 3 month observation with OXC does not allow to draw any sound conclusions.147
 

A Cochrane systematic review, including 15 studies (1,066 participants) evaluated anticonvulsants drugs efficacy (CBZ, GBP, LTG, phenytoin, tiagabine, topiramate, valproate) on primary outcomes such as retention in treatment, side effects, and use of cocaine. No significant differences were found for any of the efficacy measures comparing any anticonvulsants with placebo. Placebo was found to be superior to GBP in diminishing the number of dropouts [two studies, 81 participants, RR 3.56 (95% CI 1.07-11.82)] and superior to phenythoin for side effects [two studies, 56 participants RR 2.12 (95% CI 1.08-4.17)]. All the other single comparisons were not statistically significant. The authors concluded for the absence at present of evidence supporting the clinical use of anticonvulsants medications in the treatment of cocaine dependence.148
 

The possible use of mood stabilizers in dependent/addicted patients is summarized in Table 3.
 

 

Substance Use In Dual Diagnosis

Dual diagnosis is defined as the longitudinal combination of two mental diseases, one represented by an addictive disease. Unlike comorbidity, dual diagnosis does not account for transient substance-related symptoms, but comprises affect with an autonomous course and relapse-proneness. The expression “mentally ill substance abusers,” which is currently employed in substance abuse literature, is probably closer to the concept of dual diagnosis, although it includes non-addictive substance abuse patterns. It fails to specify that all drug-addicts are mentally ill by definition and that ones with dual diagnoses are those with a further source of mental disturbance. In most studies evaluating the effectiveness of putative antimanic agents, substance abuse and addiction have been used as exclusion criteria. Several studies on putative anticraving agents focusing on dual diagnosis have held psychotic disorders as exclusion criteria.
 

Lithium

Merry and colleagues101 suggested a selective responsiveness of depressed alcoholics versus non-depressed peers in a double-blind trial lasting over 1 year, although placebo-treated depressed patients were more severely ill as regards to their alcoholism. Later evidence did not confirm such a link between comorbid depression and lithium effectiveness.103,108 A double blind work by Nagel and colleagues149 indicates a possible favorable preventive effect upon mood elevation, which is also exerted upon detoxified alcoholic bipolars.104
 

The original observation by Gawin and Kleber120 (on mood related outcomes) about the utility of lithium in cocaine abusing cyclothymics was not confirmed by later studies. A small, open label trial on subjects with bipolar spectrum disorders failed to prove any effectiveness118; likewise, no effectiveness emerged from studies on generic groups of cocaine abusers, among whom bipolar spectrum disorders are known to be quite frequent.15,150
 

Albanese and colleagues151 described a favorable outcome of 20 patients with mood disorders and mixed substance abuse, currently abstinent for 45 days on average, under VPA treatment lasting 5 weeks on average. Almost all subjects were retained without relapse into substance use. VPA at 1,500 mg/day was effective in a small group of bipolar subjects currently using a variety of substances, as it is typical of abusing bipolars. Both depressive and manic symptoms decreased by the first month of treatment and stably throughout the follow up, lasting on average 4 months.152 Substance use is maintained at irregular and at lower doses, and it does not tend to be eradicated.
 

At present, the prevalent opinion among experts in the field is that VPA seems effective in bipolar disorders with comorbid substance abuse.153 Both VPA and its combination with lithium are preferable to lithium alone in manic pictures complicated by substance use in the extinction of mania.15 In a 16 week pilot observation, the administration of VPA to abusing bipolars was effective in decreasing Young Mania Rating Scale manic symptoms and Hamilton Rating Scale for Depression-rated depressive ones.152 Moreover, compliance tends to be better under VPA treatment than under lithium in similar populations of bipolar abusers.14
 

Salloum and colleagues111 enrolled bipolar I patients with comorbid alcoholism in a double-blind, randomized controlled trial adding VPA to standard lithium treatment and reported a stronger effect on alcohol-related outcome measures, despite an equivalent impact on affective symptoms. Hence, the action of VPA in this category of patients is to target addictive symptoms aside from the influence of mood swings and can lead to an improvement of both mood and substance abuse, either of which is usually expected to be quite refractory to treatment.
 

VPA was employed in 19 methadone maintained heroin addicts with a dual diagnosis of bipolar I disorder, with the surprising finding of a similar retention rate as that of single-diagnosis controls (Figure).99 It should be noted that methadone dosages on average were 30 mg/day higher than the average effective range for heroin addiction (80–120 mg/day), so it cannot be excluded that the surprisingly high retention rate may also be a consequence of methadone’s primary mood-stabilizing action, especially at these dosages.98,99
 

 

Among other antiepileptics, OXC was found effective at higher dosages (1,500–1,800 mg/day) in a 3 month randomized, open-label study on alcoholics. In fact, beyond a general superiority to naltrexone, OXC proved particularly effective in patients with generic dual diagnoses whose anger-hostility SCL-90 subscore was reduced to a greater extent than in naltrexone-treated subjects.115 As for anxiety disorders, VPA proved effective in the treatment of panic disorder with comorbid substance abuse.154
 

Carbamazepine

Brady and colleagues110 noted a longer time to relapse in cocaine abusers suffering from affective disorders in a 12 week double-blind trial. In this population, CBZ improved compliance, whereas subjects without an affective disorder failed to show any improvement with regard to either cravings or compliance. In a comparison between desimipramine, CBZ, and placebo, both psychotropics improved symptoms of affective discomfort but neither succeeded in reducing cocaine-seeking behaviors.155
 

CBZ may be helpful in reducing impulsiveness in the short term, thus enhancing compliance due to a non-specific anti-manic potential, which may explain the positive substance-related outcome of some works.145,146,155 On the other hand, depressive symptoms of unselected cocaine abusers did improve under placebo treatment as well.142 However, they were mostly transient, so it would not be reasonable to employ CBZ for such a purpose.
 

The addition of CBZ to antipsychotic treatments in alcohol abusing schizophrenics was effective in decreasing symptoms of psychopathology and of alcohol withdrawal.156 CBZ was also tried upon 40 subjects with a diagnosis of inhalant-induced psychosis, proving as effective as haloperidol in terms of Brief Psychiatric Rating Scale ratings.157
 

The possible use of mood stabilizers in dual diagnosed patients is summarized in Table 4.
 

 

Discussion And Clinical Implications

Some antiepileptic mood stabilizers may be a safe and effective alternative in the treatment of acute intoxication and withdrawal states of substance abuse disorders. Although effective treatments are already available in most cases, mood stabilizers may be preferable in poly-abuse pictures to avoid the risk of synergistic interaction with unreported substances (eg, if someone was treating with benzodiazepines for cocaine intoxication while hiding concurrent benzodiazepine abuse) or before exam results showing benzodiazapines in urine or blood are available to clinical personnel.
 

On the whole, a body of double-blind, controlled studies with long-term follow-up data demonstrate lithium as a reasonable option in the treatment of alcoholism combined with mood disorders. The notion that bipolar disorders’ responsiveness to lithium is hampered by comorbid alcohol abuse does not justify neglecting lithium itself as a means of relapse-prevention in detoxified alcoholics. Favorable results for an anticraving action are present for valproate, too, although only one study (on a combined lithium-valproate regimen) shows a reasonably long (6 months) follow-up evaluation.111
 

Although lithium may result in longer time to relapses, it does not show increased alcohol use control once an individual is in a state of relapse. Therefore, relapse is a turning point towards the loss of effectiveness of lithium in such treatments. Given the relapsing-course of alcoholism, lithium may favorably interact with a common factor accompanying or underlying alcoholism, but probably fails to provide stable control of alcohol craving. Valproate does maintain a favorable impact (lower severity of drinking) in case of relapse into drinking,111 a reason it looms as more suitable in overall relapse-control.
 

Topiramate is promising, although the only study providing a long-term relapse-prevention perspective was performed on treatment-resistant subjects and in an open study design.113 CBZ, lithium, GBP, and LTG seem ineffective upon cocaine addiction in the light of double-blind and/or placebo-controlled studies. Tiagabine seems to be effective only in a special population and VPA needs controlled evaluations.
 

Apart from actual Axis I dual diagnosis, the rationale for using mood stabilizers in substance abusers is that there exists a higher prevalence of “less than manic” bipolar pictures in all types of substance abusers. A clinical model of a substance abuse-bipolar spectrum emerges,158 manifested by proneness to excitement (from full mania to milder temperamental profiles, and/or in having a family history for pathological excitement). This may be the node between substance use and the bipolar spectrum.
 

Such a mutual interaction is found at the beginning of substance abuse histories and throughout the development of full-blown addiction. Earlier in the history of addicts-to-be, the prevention of recurrent and persistent pathological excitement may be crucial in avoiding habitual drug-taking and multiple self-stimulating practices. Later on, mood swings become an obstacle outcome, although it ceases to directly influence the likelihood of drug-taking behaviors. The prevention of mood elation seems to be what is missing in the interval between the recruitment into standardized programs and the consolidation of anticraving responses. It is also true that substances may worsen the emergence and course of mood swings in drug addicts, but at this stage the control of drug-seeking by all available means is the priority in breaking this vicious cycle. In other words, no major effect upon drug-seeking is expected simply as a consequence of mood stabilization.
 

Therefore, especially in the absence of using rapidly acting anticraving instruments against early attrition, antimanic drugs may be the most effective means to have patients retained long enough to meet some clinical response as regards their addictive symptoms.159,160
 

Limits

The validity of the present review should be weighted against some important limitation. We did not follow a systematic approach. Among bibliographic databases, we checked only MEDLINE for studies on efficacy and safety of anticonvulsants in intoxication, withdrawal, dependence/addiction, and dual diagnosis, without applying a formal strategy for search and selection of studies (ie, pre-defined search terms), collection of data, and assessment of the risk of bias in included studies. Moreover, we did not apply a quantitative analysis for summary statistics.
 

Given the vastness of the subject, the multiplicity of populations (ie, alcohol, cocaine, opioid, dual diagnosed, addicted persons), health condition of interest (intoxication, dependence, etc.), interventions (different anticonvulsants alone or in combination), study design (randomized, open, etc.), and outcome (on both addiction and other mental disorders side), we considered a narrative approach more appropriate. In doing this, we gave account of the type of included studies, and graded our observations and recommendation on the bases of their quality (for design, sources of bias, number of patients, chosen outcomes, etc.), giving particular relevance to those based on the best available evidence, as in the case of Cochrane systematic reviews. Nevertheless, when the subject of the evaluation was not covered by more valid studies, we referred to less valid information. In this case we tried to give to the reader the information needed to weigh their validity.
 

As a general limitation to the research in the field, we have also to note that, in spite of the existence of a large amount of literature on the use of mood stabilizers in the treatment of substance use disorders, the relative lack of best quality research (especially randomized controlled trials), and the heterogeneity in outcomes and their definition constitute a big limitation to the evaluation of their efficacy. As signalled in the few Cochrane reviews carried out on this subject, larger randomized investigations achieving greater consistency in outcomes and the means of assessing and reporting those outcomes to enable meaningful cumulative analysis should be considered.
 

Conclusion

Some mood stabilizers loom as safe and effective for the treatment of abnormal mood in drug abusers, possibly reversing the often encountered trend towards development into dual diagnosis patients with poorer retention and outcomes. Although little data from well controlled clinical trials are available to date, mood stabilizers as a category deserve close scrutiny in properly powered, controlled clinical trials in order to ascertain possible anticraving properties, independent of mood-regulation.  CNS
 

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