Psychopharmacology of substance misuseand comorbid psychiatric disorders

Abou-Saleh MT. Psychopharmacology of substance misuse andcomorbid psychiatric disorders.Acta Neuropsychiatrica 2004: 16:19–25. # Blackwell Munksgaard 2004

The common occurrence of comorbid substance misuse and otherpsychiatric disorders has challenged the diagnostic and therapeutic skills ofprofessionals concerned with the care of patients with these dual disorders.Combined pharmacological and psychological treatment approaches haveevolved empirically drawing upon standard treatments with emphasis onpsychosocial approaches to substance misuse for psychotic disorders andpharmacological approaches for mood disorders. Advances in the biology ofboth disorders have started to inform their psychopharmacology. Thespecific role of atypical antipscychotics is highlighted. Further studies of thebiology of comorbidity will impact the use of effective pharmaceuticals suchas clozapine with dual effects on schizophrenia and substance misuse.

M. T. Abou-Saleh

South-West London and St George’s NHS Trust, London, UK

Keywords: comorbid; psychopharmacology substance misuse;

psychiatric

Correspondence: Dr Mohammed T. Abou-Saleh, MPhil, PhD,

FRCPsych, South West London And St George’s NHS Trust,

Glenburnie Road, London, SW17 7DJ, UK. Tel: þ44 (0)20 8725–

0368; Fax: þ44 (0)20 8725–2914; E-mail: mabousal@sghms.ac.uk

Introduction

There is strong evidence for the occurrence ofsubstance misuse and comorbid psychiatric disor-ders in community and clinical settings. The pat-tern of this comorbidity varies between comorbidmood, anxiety and personality disorders inpatients accessing addiction specialist services andcomorbid alcohol, cannabis and cocaine misusein patients accessing general psychiatric services.Comorbidity is associated with increased risk forviolence, suicide and worse clinical and socialoutcome.

Community-based surveys have reported highprevalence of comorbidity of substance misuseand other psychiatric disorders (1,2). The Epide-miological Catchment Area study reported aprevalence rate of 30% for substance misuse inindividuals with other mental disorders, and a life-time prevalence of other mental disorders of 45%and 72% in those with alcohol and drug use dis-orders, respectively (3). The National ComorbidityStudy (1) reported that between 41% to 66% ofthose with addictive disorder have at least oneother psychiatric disorder while 51% of thosewith mental disorder have at least one addictivedisorder. The recent study by Farrell et al. (2) wasa national household survey, which reported aprevalence rate of psychiatric disorder of 22% innicotine-dependent, 30% in alcohol-dependent

and 45% in drug-dependent populations com-pared with 12% prevalence in the non-dependentpopulation.

While the diagnosis of comorbidity remainschallenging, DSM-IV diagnostic guidelines pro-vide a major advance in offering criteria fordistinguishing substance-induced (organic) andindependent (primary) psychiatric comorbidity. Itis important to differentiate between symptomsand syndromes of substance misuse and distin-guish between substance-induced and independentpsychiatric disorders. Moreover DSM IV offers athird category of comorbidity: expected symptomsof substance use or withdrawal. The diagnosis ofindependent psychiatric disorder is supported byits onset before that of substance misuse, theoccurrence of psychiatric disorder during periodsof abstinence, and previous episodes of psychiatricdisorder. To establish the diagnosis of primarycomorbidity it is crucial to continue to assess thepatient’s mental condition for at least 4 weeks afteruse or withdrawal; a timeframe within whichsubstance-induced comorbidity would resolve whileprimary comorbidity would persist. The scope ofthis review is to consider briefly the aeologicalmodels of comorbidity and its underpinning bio-logical mechanisms. Moreover, the evidence basefor the efficacy of treatment of common comorbidpsychiatric disorders will also be reviewed.

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# Blackwell Munksgaard, Acta Neuropsychiatrica, 16, 19–25 19

Biological considerations

The biology of comorbidity is considered from thevantage points of aetiopathogenesis as well as thevantage point of the biology of addiction andaddictive behaviour vis-a-vis the biology of thecomorbid psychiatric disorders.

Substance-induced psychiatric disorder

This is a well-established model based on thedevelopment of psychiatric symptoms/disorderfollowing exposure/intoxication with substancessuch as amphetamine-induced psychosis and post-cocaine withdrawal depression. This is related tothe pivotal role of dopamine in both addictionand comorbid psychiatric disorder: all substancesenhance dopaminergic effects and could aggravateor precipitate schizophrenic or manic psychosiswhile withdrawal from substances may be con-ducive to the development of depression in associ-ation with low dopamine (4).

Substance misuse complicating otherpsychiatric disorders

This is based on the common occurrence of sub-stance misuse in patients with schizophrenia andbipolar disorder whereby substance misuse com-plicates the anteceding psychiatric disorder termedthe ‘self-medication’ hypothesis. Alcohol andother substances may decrease negative symptomsin schizophrenic individuals through the releaseof dopamine in the prefrontal cortex, a key com-ponent of the brain reward circuit which maybe dysfunctional in patients with schizophrenia.Moreover, it is conceivable that the use of substancesto ‘self medicate’ the unwanted effects of treatmentwith antipsychotic medication overrides these sideaffects including extra pyramidal symptoms (5).McEvoy et al. (6) reported that the use of clozapineseemed to lead to a decrease in smoking. Anotherexample is the abuse of anticholinergics byschizophrenic patients, probably because of theirstimulant effects (7).

The self-medication hypothesis has a number oflimitations (8). First, substance misuse rates inschizophrenia are substantially higher when com-pared with other psychiatric populations thatwould be as likely to self medicate, e.g. depressionand anxiety disorders. Second, the symptom reliefreported by patients is inconsistent with the wor-sening in symptoms, non-compliance with treat-ment, and increased relapse and rehospitalization.Third, drug and alcohol misuse antedates the onsetof schizophrenia in 14–69% of cases.

Supersensitivity model

The supersensitivity model stems from the observ-ation that patients with schizophrenia are moresusceptible than normal to non-dependent use ofsubstances. This model could also be conceptual-ized in terms of the primary addiction hypothesis,which views addictions as an independent processstemming directly from a common neuropatho-logical process (8). Abnormalities in the hippocam-pal formation and frontal cortex, in schizophrenia,facilitate the positive reinforcing effects of drugreward and reduce inhibitory control over drug-seeking behaviour. Disturbances in drug rewardare mediated in part by dysregulated neural inte-gration of dopamine and glutamate signalling inthe nucleus accumbens resulting from frontal cor-tical and hippocampal dysfunction, which produceneural and motivational changes similar to long-term substance misuse but without the necessity ofprior drug exposure.

Treatment considerations

Treatment of comorbidity is fraught with a num-ber of difficulties which are related to diagnosticassumptions and to the setting in which the comor-bidity is encountered. One consideration is a ten-dency for the comorbid condition to be consideredof secondary importance and hence it could beignored or insufficiently treated.

This is based on the assumption that the comor-bid disorder is secondary to the primary disorder,be it substance misuse or other psychiatric disor-ders, and that treatment of the primary disordermay resolve the secondary disorder, which is notconsidered to require specific treatment. Also thereis general reluctance to treat psychiatric patientswho misuse substances. Reasons for this are multi-ple and include concern about possible toxic inter-action between the prescribed medication and thesubstances that are misused; the assumption thatactive substance misuse will cause worsening ofcomorbid psychiatric symptoms, impair responseto treatment and cause a fear of ‘enabling’ thepatient by treating the psychiatric illness, whichwould demotivate the patient to deal with thesubstance misuse problem (9).

While it is prudent for optimum assessmentof comorbidity that this is carried out followingwithdrawal of the substance, this is rarely obtainedin the out-patient setting and treatment of thepsychiatric disorder is often initiated with activesubstance misuse. There is evidence that treatmentof the psychiatric disorder with active substancemisuse is effective and occasionally it also impacts

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positively on substance misuse itself. Saxon andCalsyn (10) showed that outcome at the end of1 year’s treatment in the substance misuse pro-gramme was as favourable for dually diagnosedpatients as those with substance misuse alone.Controlled trials of antidepressants in depressedpatients with alcohol misuse have demonstratedefficacy in treatment of depressive disorder withmodest effect on substance misuse (11,12). Thesefindings counter the assumption that treatment ofthe comorbid psychiatric disorder in active substancemisusers represents a form of ‘enabling’ when themedication may improve substance misuse (13), andat least will not worsen substance misuse (9).

Pharmacotherapy of comorbidity

The decision to use pharmacotherapy for comor-bidity is optimally based on sound clinical diag-nosis and the nature and extent of the comorbidpsychiatric disorder or substance misuse. It is amatter of clinical judgement to decide whethersubstance misuse or a psychiatric disorder haspassed the threshold to warrant specific treatmentvs. treatment of the predominant disorder thatmight impact favourably on the comorbid disor-der. For instance if serious addiction is established,i.e. substance dependence, then it would be appro-priate to treat this condition first while monitoringthe comorbid psychiatric disorder, e.g. depression,to ascertain the degree of its improvement follow-ing detoxification from substance dependence.Similarly if the predominant disorder is schizo-phrenia with concurrent non-dependent substanceuse then treatment could be targeted and combinedwith psychological treatment of substance misuse.

Schizophrenia

Common use of alcohol and drugs in patients withschizophrenia has been attributed to the notionof ‘self medication’ proposed by Khantzian (14).The hypothesis suggests that the use of substancescorrects an underlying ‘deficit’ which is related tonegative symptoms of schizophrenia. Studies havereported that 50% of patients with schizophreniaexperience a decrease in social anxiety, dysphoriaand sleep problems and nearly 40% experienceimprovement in interpersonal relationships whenthey use alcohol (15,16). However, this is count-ered by the finding that schizophrenic patients withsubstance misuse have lower levels of negativesymptoms than those without comorbid alcoholor drug misuse (17). Biological studies have sug-gested that in patients with schizophrenia, alcohol

or drug use may decrease negative symptomsby increasing dopamine activity in the prefrontalcortex and thus enhancing the functioning of thedysfunctional brain reward system by an increasein the dopamine-based ‘signal detection’ capabilityof these systems (18,19).

In parallel to the dopamine-mediated aetio-pathogenesis, there is emergent evidence forcannabis-induced psychosis (20), probably mediatedby the anandamide/cannabinoid system (21).Endogenous cannabinoids levels (anandamideand palmitylethanolamide) are elevated in thecerebrorospinal fluid of schizophrenic patients,which may reflect an imbalance in the endog-enous cannabinoid system in schizophrenia (22).

The third mechanism for drug-induced psychosisinvolves the serotonin (5-HT) system underlyingLSD/ecstasy-induced psychosis (23). Ecstasy(3,4-methylene-dioxymethamphetamine: MDMA)stimulates the release and inhibits the uptake of5-HT and repeated doses of MDMA causes 5-HTneurotoxicity with evidence for long-term neuro-pharmacological damage (5-HT axonal loss) in thefrontal and temporal lobes and the hippocamus ofhumans. Ecstasy-induced psychosis remits within3 months with olanzapine (24).

It has been widely recognized that in schizo-phrenic patients, the use of conventional antipsychoticdrugs has little impact on comorbid substancemisuse. Indeed it has been proposed that theirside-effects contribute to the occurrence of theuse of substances in an attempt to ‘self medicate’these side-effects (5). These observations promptedthe use of atypical antipsychotics in schizophrenicpatients with substance misuse. Clozapine hasbeen specifically indicated for its unique effect ofreleasing dopamine in the prefrontal cortex (25).Clozapine has similar effects to alcohol and drugson the dopamine system in the prefrontal cortexlinked to its ability to improve negative symptomsin schizophrenia. However, unlike alcohol, whichalso releases DA in the mesolimbic system (26),clozapine facilitates the physiologic modulationof the mesolimbic DA system by the prefrontalcortex.

A number of uncontrolled trials have supportedthe therapeutic effects of clozapine in improvingsubstance misuse in patients with schizophrenia(15). In a prospective study of patients with schizo-phrenia and alcohol misuse, clozapine treatmentwas associated with an overall improvement rateof 85% with respect to alcohol use (27). Anaturalistic study of 136 patients with schizophreniawith combined alcohol misuse showed that thosewho received clozapine achieved 79% abstinencefrom alcohol while only 34% of patients who

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remained on typical antipsychotics achieved abstin-ence (28). There have been few observations ofthe effects of clozapine in comorbid drug misuse;however, it has been observed that the use of cloza-pine in patients with resistant schizophrenia is asso-ciated with a significant decrease in smoking inthese patients (29).

Open studies of other atypical antipsychoticsalso reported favourable results. Littrell et al.(30), in an open-label trial of olanzapine over12 months in patients with schizophrenia and schizo-affective disorder with comorbid substance mis-use, reported improved psychopathology. Casaset al. (31) similarly reported favourable resultswith risperidone in psychotic patients with opiateabuse and dependence. In schizophrenic patientswith comorbid alcohol and cannabis misuse,clozapine treatment over 12 months was associatedwith significantly higher abstinence rates (54%)than treatment with risperidone (13%) (32).

In summary, open and retrospective studies ofthe use of clozapine in patients with schizophreniawith comorbid substance misuse have been mostpromising and there are on-going controlled trialsto establish its efficacy in this population. It is alsocrucial to evaluate the efficacy of other atypicalantipsychotics to establish whether these effects ofclozapine are unique to clozapine and not relatedto its more favourable side-effects profile on parwith other atypical antipsychotic drugs.

Mood disorder

In clinical populations, the prevalence of mooddisorders varies between 12 and 88% in patientswith alcohol misuse and between 24 and 56% inpatients with drug misuse. Moreover, the relation-ship of mood disorders and substance misuse incommunity studies, expressed as odd ratios, showedodd ratios of 2.6–3.7 for concurrent alcohol misuseand of 3–7.2 for concurrent drug misuse (29).

A recent study of the effects of major depressionon the course of substance dependence showedthat patients with current substance-inducedmajor depression were less likely to remit fromdependence than patients with no baseline majordepression (33); moreover, a history of majordepression before lifetime onset of substancedependence also reduced the likelihood of remis-sion relative to the absence of such a history, andmajor depressive disorder during sustained abstin-ence predicted dependence relapse and substanceuse after hospital discharge compared with thosewithout abstinence major depression.

The validity of this comorbidity has been exam-ined, against an established biological marker for

depression such as the dexamethasone suppressiontest (DST) (29). This proved unrewarding in viewof the DST’s low specificity for depression includ-ing high rates of non-suppression in alcohol mis-use (34). Similar considerations apply in evaluatingneuroendocine and neuroimaging markers, whichdepicted the pivotal role of dopamine in substancemisuse in relation to mood disorder (4).

Bipolar disorder

The aetiology of bipolar disorder and comorbidsubstance misuse has not been sufficiently investi-gated (35). Post and Silberstein (36) proposed thatthe aetiology of bipolar disorder is mediated by akindling mechanism, based on its tendency tohave increasingly shorter periods of remissionin-between episodes of illness and increasing auto-maticity with less dependence on psychosocialstresses. Interestingly this hypothesis has beenbased on the animal desensitization model ofrepeated exposure to cocaine. Cocaine and otherpsychostimulants have strong effects on the dopa-mine system (37), which is central to the chemicalpathology of mania. A brain (SPECT: singlephoton emission computerized tomography) imag-ing study of amphetamine-induced dopaminerelease reported greater sensitivity (behaviouralresponse) in euthymic bipolar disorder patientsthan normal controls (38). Clinically, alcoholicswith more previous episodes of alcohol withdrawalare more likely to have seizures during subsequentalcohol withdrawal probably related to greaterbrain sensitivity, and lowering of threshold andcarbamazapine was shown to be as effective asoxazepam in the treatment of alcohol withdrawal (39).

The use of other mood stabilizers in the treat-ment of comorbidity has not been satisfactorilyinvestigated. Valproate, an established first-linetreatment for bipolar disorder (40), was shown tobe effective in the maintenance of abstinence inpatients with mania and alcohol misuse (41). Con-trolled trials of valproate are urgently required.The use of an atypical antipsychotic with theirestablished efficacy in mania (42) remains to beevaluated. This is all the more important in view ofthe very encouraging findings of the studies of theefficacy of clozapine (28) and of risperidone (31) inthe treatment of schizophrenia with comorbid sub-stance misuse.

Major depression

The aetiology of comorbid major depression andsubstance misuse is complex and multifactorial.

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Depressive symptoms or disorder may predisposeto substance misuse or be the result of psycho-social stresses secondary to substance misuse or theresult of neurochemical changes associated withchronic intoxication and withdrawal (43). Neuro-chemical changes including low serotonin (5-HT)have been reported in depression and alcohol usedisorder. Moreover it has been suggested that inalcoholic patients, alcohol-induced 5-HT releasemay ‘normalize’ low brain 5-HT (44). In cocainemisuse, depressive symptoms occur as part of thewithdrawal syndrome or ‘crash’, including dys-phoria, fatigue, excessive sleep with appetite andpsychomotor changes. The ‘crash’ depression syn-drome may be mediated by low noradrenalinewhile the withdrawal-induced depression is relatedto the low dopamine levels associated with chroniccocaine misuse (45). The decision to use anti-depressants is determined by the severity ofsymptoms and attendant suicidal risk. Moreoverit is prudent to start treatment 1–2 weeks after with-drawal (46).

Clinical trials of antidepressants have reportedconflicting results. This has been related todiagnostic difficulties, the high placebo responseand failure to measure plasma levels to ensureadequate dosage and ascertain compliance withmedication. Alcohol induces rapid metabolism oftricyclics (47).

Studies have supported the efficacy of imipra-mine in reducing depressive symptoms and alcoholuse in patients with a history of primary depres-sion (48). However, the positive effect of imipra-mine in alcohol use was not replicated byMcGrath et al. (11). In depression that is second-ary to alcohol misuse, desipramine with placebocontrol was effective for both depression and alco-hol use and patients who received placebo showeda higher rate of relapse to alcohol use (46). The useof selective serotonin reuptake inhibitors (SSRIs)has been particularly advocated. Fluoxetine com-pared with placebo over 12 weeks reduced depres-sion and alcohol use (13). Kranzler et al. (49) in aplacebo-controlled trial of fluoxetine as adjunct tocognitive behavioural therapy reported good effi-cacy for fluoxetine in depressive symptoms but notfor alcohol consumption. In patients with cocainedependence and major depression, fluoxetine(40 mg per day) compared with placebo over 12 weeksshowed no advantage for fluoxetine in patientswho received cognitive–behavioural psycho-therapy (50). In heroin addicts, the addition offluoxetine to naltrexone was associated withgreater retention in treatment (51).

Desipramine compared with lithium and pla-cebo was reported to reduce cocaine withdrawal

symptoms and relapse (52) and tricyclic anti-depressants were shown to be effective in depressionwith comorbid cocaine misuse (53,54). The useof SSRIs and their efficacy in this settingremains to be evaluated.

Conclusions

There is growing evidence for the efficacy of stan-dard pharmacological treatment of psychotic dis-orders co-occurring with substance misuse. Theconflicting findings of earlier studies may beattributed in part to the conceptual and diagnosticdifficulties and advances in diagnosis, e.g. DSM-IV, have informed therapeutic practice. Moreadvances in the biology of comorbidity may pavethe way for the development pharmaceuticals withmore specific/and dual therapeutic benefits.

Clozapine notwithstanding its efficacy in resist-ant schizophrenia has been reported to have dualeffects, including antiaddictive effects which maybe related to its neuropharmacology.

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