Seventy-Five Years of Comorbidity Research

Abstract

Objective:

As part of the 75th anniversary edition of the Journal of Studies on Alcohol and Drugs, this article reviews research on the relationship between mental disorders and substance use disorders (“comorbidity”) from 1940—the journal’s inception—to the present.

Method:

First, a survey of the titles and abstracts of all articles published in the journal was used to identify those articles pertaining to comorbidity. Seminal and representative works from this set of articles and a limited selection of articles from other journals were included in the review.

Results:

The early psychosocial research emphasized psychoanalytic formulations of alcohol use as a defensive symptom, which informed the early experimental research on the tension-reducing properties of alcohol. The “cognitive revolution,” occurring in the 1970s, enabled an expansion of the tension-reduction theory to include a central role for mental processes (e.g., alcohol expectancies) in promoting drinking to cope with negative affectivity. The early clinical research characterized mental conditions commonly co-occurring with alcohol disorders and considered their etiological relationship to alcohol disorders. The “neo-Kraepelinian revolution” in psychiatry, which also occurred in the 1970s, infused the clinical comorbidity research with a more rigorous diagnostic technology and a range of biomedical research methodologies to study the mechanistic linkages of co-occurring disorders.

Conclusions:

Although a substantial quantity of scientific information on comorbidity has accumulated over the past 75 years, a standard model(s) of comorbidity has yet to congeal. Barriers and opportunities related to achieving this important goal are discussed.

Bowman and jellinek (1941a) reviewed the literature though 1941 on “alcoholic mental disorders” and concluded that the work split along the lines of two core questions: “(a) Is alcohol addiction (without psychosis) itself a symptom of an underlying personality disorder; (b) in the case of alcoholic mental disorders is drinking itself etiological or symptomatic?” (p. 313). These questions, although somewhat lacking in precision, provide a surprisingly serviceable structure for distinguishing streams of research and thought on comorbidity that extend from that early period to the present day. For example, the first question can be seen to map onto psychosocially oriented work that includes the early psychoanalytic perspective of chronic alcohol use as a defensive symptom and the later tension-reduction theories that evolved from this view. The second question can be seen to map onto the clinically oriented work that includes early observations of the variety of mental and behavioral disturbances occurring in many chronic alcohol users (broadly referred to as alcoholic psychosis in the early literature) and the later taxonomic, epidemiologic, longitudinal, and family studies designed to systematically account for these associations. For convenience, the review labels these two general approaches to comorbidity research as psychosocial and biomedical, respectively.

Although these two streams of comorbidity research have run continuously since the journal’s inception in 1940, each was affected significantly by paradigm-shifting scientific revolutions that occurred over the decade of the 1970s. First, clinical psychology moved away from an operant behaviorism that discounted the scientific value of subjective mental experiences and toward a cognitive–behaviorism that placed such phenomena at the very center of its scientific models (the “cognitive revolution”). Second, psychiatry moved away from the arcane “mentalism” of psychoanalysis and toward a biomedical epistemology emphasizing the differentiation of specific clinical syndromes based on descriptive characteristics presumed to mark distinct biological etiologies (the “neo-Kraepelinian revolution”; so named because of the influence of the German psychiatrist, Emil Kraepelin, in formulating an early disease-model of psychiatry in the late 1800s). For convenience, the review labels research affected by these scientific revolutions as modern and the earlier work as pre-modern.

Method

The term comorbidity, adapted from Feinstein (1970), is used here to broadly refer to the interaction of any abnormal psychological process or psychiatric disorder with the development, maintenance, or relapse of problematic alcohol or other drug use. The author and two assistants examined the title and abstract of articles published in the journal to identify those pertaining to comorbidity. Those articles identified as relevant—approximately 8% of all articles reviewed—were next sorted by methodology (e.g., family history, laboratory-human, treatment, prospective) and further subdivided as pre-modern or modern (see above). Finally, the author selected articles from each category for inclusion in the review deemed to be either (a) seminal (i.e., both original and having the potential to affect the field significantly), (b) a high-quality representation of a number of similar contributions, or (c) especially pertinent to a particular point being made in the review. In the pre-modern literature, seminal review articles were emphasized and, where appropriate, illustrated with direct quotes. In the modern literature, empirical articles were emphasized with major findings summarized. A small number of articles not published in the journal were cited to make specific points pertaining to but not fully addressed by work published in the journal.

Results

Psychosocial research

Chronic drinking as a defensive symptom.

Lisansky (1960) asserted, “a basic question that must be posed before considering the problem of personality variables involved in alcoholism is whether alcoholism is a diagnostic entity in and of itself or only a syndrome or symptom” (p. 314). In this regard, Strecker (1941) reflected the prevailing psychoanalytic view on alcoholism of his day in saying that “true chronic alcoholism is a psychoneurosis, defensive in character, with the object of shutting out reality inimical to emotional immaturity—a mechanism which appears to be a logical aftermath of the stunting in childhood of the emotional growth” (p. 14).

This view seems to imply that treating alcoholism directly would be clinically misguided because it is understood to be a mere symptom of a primary psychiatric/psychological condition. However, Tiebout (1951) criticizes the prevailing sentiment that “anyone who stops to study a symptom is thought to be therapeutically naïve and in need of some instruction about first principals” (p. 53). While not disputing that chronic drinking leading to alcoholism could start as a defensive symptom, Tiebout (1951) argued that psychiatrists are mistaken when they conclude, “The drinking is merely a sign of depression, of withdrawal or of some neurotic complication” (p. 53). Instead, he noted that regardless of the initial causes, chronic drinking “finally assumes disease significance and we then treat it as an independent illness” (p. 54). Ten years earlier, Strecker (1941) also concluded that treating the patient’s primary underlying psychological disorder “is impossible so long as he uses alcohol” (p. 14). Notably, the disease versus symptom question raised by Lisansky above, and still with us today, has diminishing practical importance if both conditions require specific treatment regardless.

The pharmacobehavioral tension-reduction theory (PB-TRT).

While the empirical search for a particular psychoanalytic personality disturbance (e.g., “latent homosexuality”) that predisposes one toward alcoholism consistently failed (e.g., Bowman and Jellinek, 1941b), the idea that pathological drinking was used as a buffer against distressing psychological feelings continued to thrive. For example, Ullman (1952) suggested that chronic drinking can be “a tension-reducing activity with the source of tension lying in the ordinary problems of human beings” (p. 603). By evoking Thorndike’s “law of effect,” Ullman argued that when drinking relieves distress (even when that distress is caused by “ordinary” problems), it would be reinforced and thereby escalate, potentially to the level of an independent disorder. “What this danger consists of is the possibility that the response may become so exaggerated that it becomes a problem or even a disease itself” (Ullman, 1952, p. 604).

Conger (1956) continued to develop the PB-TRT by embedding it in a learning-based drive-reduction model and using a variety of experimental analog models with animal subjects to test specific hypotheses derived from the psychoanalytic view of alcoholism. For example, he cited several studies showing that experimentally induced “neurosis”—indicated when the animal decreases the frequency of making a response to receive food once that response is also paired with a shock—is reversed by alcohol (i.e., the animal increases responding for food again). “Before alcohol the avoidance is stronger than approach; after alcohol the avoidance is weaker than approach” (Conger, 1956, p. 299). However, Conger continued to understand this work as a mere analog to the real world of clinical dysfunction in which it remained important to find out “. . . what need or drive patterns are particularly important among various kinds of alcoholics. The work of the psychoanalyst in this regard is a case in point” (p. 304). Up to this time, then, the conceptual continuity between the TRT and the psychoanalytic view of alcoholism remained explicit.

However, by the early 1970s, many dozens of laboratory studies had tested the PB-TRT using various learning paradigms with little or no reference to psychoanalytic precepts; that is, the TRT had evolved from a laboratory-based psychoanalytic analog model into a distinct scientific species. Cappell and Herman (1972) reviewed this literature decomposing the PB-TRT into two hierarchal hypotheses: (a) that alcohol reduces tension and (b) that alcohol is consumed for its tension-reducing properties. Importantly, their review was concerned only with experiments testing the former hypothesis because “clearly it makes little sense to assert that tension relief motivates drinking unless it can be demonstrated that such relief is indeed a consequence of alcohol administration” (Cappell and Herman, 1972, p. 34). They concluded that the TRT (a) was not supported by studies using avoidance and escape paradigms, (b) was supported by studies using conflict and experimental neurosis paradigms, and (c) was understudied in the area of subjective effects of alcohol on negative emotions and frank psychiatric symptoms in humans. Their overall conclusion regarding the PB-TRT, however, was unmistakably pessimistic: “Much of the evidence is negative, equivocal and often contradictory” (p. 33).

The cognitive-behavioral tension-reduction theory (CB-TRT).

An early manifestation of the cognitive revolution described above can be seen in the “cognitive social-learning” revision to the TRT outlined by Donovan and Marlatt (1980). Whereas the PB-TRT focused on alcohol’s pharmacologically mediated tension-reducing effects, the CB-TRT focused primarily on the subjective appraisals and beliefs affecting the likelihood that alcohol would be used to cope with distress. In fact, the CB-TRT does not technically require that alcohol be tension reducing at all, only that one expects this effect in the context of other relevant conditions: “. . . an individual’s cognitive expectancies concerning the effects of alcohol may exert a greater degree of control over drinking and subsequent behavior than the pharmacological effects of the drug” (p. 1159). Conceptually, this view stands in direct contrast to Cappell and Herman’s (1972) assertion that the TRT model of drinking is viable only insofar as alcohol can reliably reduce tension.

As predicted by the CB-TRT, studies have shown that individuals consume more alcohol than usual when drinking for the purpose of coping with distress and that drinking for this purpose is most likely among those who (a) expect alcohol to be effective in reducing distress and (b) doubt their own effectiveness in managing distress without alcohol (Jung, 1977; Kassel et al., 2000; Laurent et al., 1997). (Predictions from CB-TRT studies are also supported for marijuana use; Johnson et al., 2009). Findings showing that those with alcohol problems are more likely than others to expect tension reduction from alcohol and to drink to obtain these effects add face validity to the CB-TRT as a psychosocial model for the etiology of alcohol dependence (Beckman, 1980; Carpenter and Hasin, 1999; Russell and Bond, 1980).

Status of the TRT as a comorbidity model.

These findings, although consistent with CB-TRT, do not clarify the extent to which it is a general etiological model of substance use disorders (all individuals), a general model of comorbidity (all individuals with any mental disorder), or a specific model of comorbidity (only individuals with a specific type[s] of mental disorder). In fact, since the TRT split off from its psychoanalytic progenitor, the theory has been conspicuously agnostic concerning the quality and quantity of distress most relevant to the model, with many studies purporting to test the TRT operationalizing stress without any reference to mental illness (Linsky et al., 1985). Nonetheless, numerous studies do show that mental conditions characterized by intrapsychic distress are robust correlates of drinking to cope, including trait anxiety (Brown and Munson, 1987), depression and fear (Hussong et al., 2005; Martens et al., 2008), social anxiety (Tran et al., 2004), posttraumatic stress disorder (S. E. Ullman et al., 2005), anxiety sensitivity (O’Connor et al., 2008), personality pathology (Bruce et al., 2013), and generalized anxiety (Litt et al., 2013). The breadth of these findings, along with those showing that significant negative life transitions (e.g., job loss) and chronic stress (e.g., poverty) are associated with drinking, suggest that the TRT is not specific to one type of mental disorder and may suggest, as did Ullman (1952), that various forms of mental illness are simply one possible source of chronic stress that can motivate alcohol or other drug use as a means of coping. Further, Koob (e.g., Koob, 2013) has argued persuasively that drinking itself (i.e., its effect on the brain’s stress-response systems) can become one source of negative affectivity that drives TRT processes in substance dependence.

A final issue relevant to the TRT as a comorbidity model stems from the reliable finding that drinking to cope is associated with alcohol-related problems over and above the amount of alcohol being used (Cutter and O’Farrell, 1984; Kassel, et al., 2000; Perkins, 1999). These findings seem anomalous to the supposition that escalating alcohol use via negative reinforcement is the process by which drinking to cope confers risk for the development of substance use disorders and may implicate drinking to cope as an endophenotypic marker or prodromal status related to risk for the development of substance use disorders (e.g., Kushner et al., 2011, 2012a; Menary et al., 2011).

Biomedical comorbidity research

Symptom versus disease conundrum.

Bowman and Jellinek (1941a) observed the “modern standpoint” to be “that the connection between heavy drinking and many of the so-called alcoholic mental disorders is not causative but that the drinking itself is the symptom of a psychosis” (p. 312). (Again, psychosis at the time of their writing referred to mental and behavioral disturbances that did not necessarily include formal thought disorders.) However, they were at pains to add, “The term ‘modern standpoint’ is not intended to imply that this is a discovery of recent date, but to denote the contemporaneous adoption of this viewpoint by a majority” (pp. 312–313). They concluded that “To venture on distinguishing between drinking merely incidental to the psychosis and drinking as a precipitating factor of the nonalcoholic psychosis, although desirable, is not altogether feasible at the present stage of knowledge” (p. 316). Lewis (1941) also struck a skeptical position regarding the assertion by prominent investigators of his day that the general problem of “alcoholic psychosis” is a result of years of heavy drinking: “I can place very little confidence in the statistics on alcoholic psychosis as at best these statistics are recording the fact, and only the fact, that an excessive use of alcohol was somewhere in the picture. However, in many instances, it may have had nothing to do with the etiology or even with the hospitalization of the patient” (p. 295).

Efforts at overcoming taxonomic and methodological chaos in the pre-modern comorbidity research.

It was clear in the pre-modern era that research was needed to quantify comorbidity and discover the etiological relations among comorbid disorders. However, without the methods for making reproducible diagnostic decisions concerning the presence or absence of specific mental syndromes, this agenda was severely restricted. May and Ebaugh (1953), for example, concluded that terms such as alcoholic hallucinosis and psychosis are “obsolete and inadequate” (p. 226). Because these diagnostic categories were defined idiosyncratically by different investigators, the scientific value of knowing how many cases of “alcoholic psychosis” occurred in New York State in 1940 (Malzberg, 1944) or in Massachusetts between 1917 and 1933 (Dayton et al., 1942) was very low indeed.

Recognizing these problems, Freed (1970) laid out a well-developed and ambitious agenda for the study of comorbidity that anticipated the neo-Kraepelinian zeitgeist that was soon to overtake psychiatry. He called for establishing reliable diagnostic criteria as a prerequisite to the serious study of comorbidity and recommended (a) epidemiological studies to quantify the actual rate at which well-defined psychiatric disorders co-occur with alcoholism, (b) longitudinal studies to determine the temporal order of onset and also the symptom covariations of comorbid disorders, and (c) family transmission studies to evaluate the possible shared neurobiological, genetic, or psychiatric “kinship” of comorbid disorders. Notably, these suggestions closely parallel those made independently by Feinstein (1970) in his seminal paper on the conceptual and practical implications of medical comorbidities. With the introduction of the Research Diagnostic Criteria (RDC) and the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III; American Psychiatric Association, 1980), both based to a large extent on the earlier Feighner criteria (Feighner et al., 1972), the neo-Kraepelinian research program finally had the tools necessary for its implementation.

Modern epidemiological studies of comorbidity

Weissman and colleagues (1980) were among the first to produce scientifically valid psychiatric epidemiological data concerning comorbidity using (a) a well-specified and agreed upon set of diagnostic criteria, (b) a structured diagnostic interview delivered by trained interviewers, (c) tests of inter-rater reliability among interviewers, and (d) established protocols for settling diagnostic disagreements. Their results showed that an astounding 70% of individuals who were diagnosed as having a lifetime diagnosis of an RDC alcohol use disorder were also diagnosed as having had at least one other lifetime RDC psychiatric disorder, the most common of which was major depression (44%) followed by “minor depressive disorders” and generalized anxiety disorder.

While the methods and findings of the Weissman study were groundbreaking, it was regionally restricted. Helzer and Pryzbeck (1988) used the Epidemiological Catchment Area survey, including about 20,000 individuals sampled from five widely distributed urban centers and their associated rural areas in the United States, to provide the first unbiased estimates of how the odds of being diagnosed with several common DSM-III mental disorders were modified when an alcohol disorder was present. Their results showed that having a lifetime history of alcohol disorder increased the odds of having a lifetime history of antisocial personality disorder by 21-fold; mania by 6-fold; schizophrenia by 4-fold; panic disorder by 2-fold; obsessive–compulsive disorder, major depression, or dysthymia by 2-fold; and any one of the common phobic disorders by 1.4-fold.

The Helzer and Pryzbeck (1988) data also highlighted complexities in interpreting epidemiological data that are affected by how the comorbid associations are characterized and by moderating variables such as gender. For example, although phobias had the least increase in the odds of being diagnosed when an alcohol disorder is present and mania had one of the highest, these positions were reversed when cast in terms of the absolute number of comorbid cases (i.e., phobia was the most common psychiatric disorder co-occurring with alcohol disorder, whereas mania was the least common). Also, the increase in risk for antisocial personality disorder when alcohol disorder was present was four times greater among women compared with men; however, once again, the absolute number of cases of antisocial personality disorder was substantially higher in men.

Modern longitudinal studies of comorbidity

Study of the temporal patterns of comorbid disorder— what Feinstein (1970) referred to as chronometry—is an intuitively appealing method for inferring causal relationships based on the simple logical proposition that only an earlier event can cause a later event. (However, post hoc ergo propter hoc—assuming that an earlier event must have caused a later event simply because it came first—is a logical error that is common in interpreting longitudinal data.) While longitudinal studies are typically focused on the temporal priority of comorbid disorder onsets, additional parameters of interest are the comorbid disorders’ temporal (a) proximity of symptoms, (b) priority of offsets/remissions, and (c) relationship of relapses.

Temporal priority.

Respondents in the Weissman et al. (1980) study reported that their depression began before their alcohol disorder in 60% of the cases in which both conditions were present. Notwithstanding caveats related to the retrospective method used, these findings do imply that the alcohol disorder did not cause comorbid depression in a majority of cases; however, this does not demonstrate that either disorder caused the other. A study by Sexton et al. (1999) also suggested that gender is an important moderator in these temporal associations. Over the 7-year interval in which they followed 8,000 individuals, earlier drinking tended to predict later worsening of depression in men but predicted improvement of depression in women. By contrast, Repetto et al. (2004) reported that higher depression in high school predicted greater future alcohol use in boys but not girls. Reminding us again that amount of substance use is not synonymous with problems caused by the use, Mason et al. (2008) reported that after controlling for gender and depressed mood, alcohol problems but not amount of alcohol use predicted later major depressive episodes in adolescents. Also reminding us that stressful experiences are not synonymous with stressful reactions to those situations, Wu et al. (2010) reported that alcohol use initiation was more common within 2 years of a trauma in 10- to 13-year-olds, but only among those who developed significant symptoms of posttraumatic stress disorder. Although these data seem to confuse more than clarify the causality question, they do suggest that the likelihood of finding a single unidirectional causal pattern in comorbid disorder onset—something of an idée fixe among many comorbidity-focused clinicians and researchers—is rather low.

Temporal proximity.

Schuckit and colleagues (2013) considered the temporal proximity of the manifestations of comorbid disorders by prospectively evaluating “depressive episodes” that either occurred during episodes of heavy drinking (“substance-induced”) or outside of periods of heavy drinking (“independent”). They found that approximately 15% of the sample had developed an independent depressive episode by the conclusion of the 30-year follow-up. They also found that about 30% of the depressive episodes experienced by those who developed an alcohol use disorder diagnosis occurred in the context of periods of heavy drinking. This is fairly consistent with the finding by Weissman et al. (1980) that alcoholism began before depression for about 40% of those with both disorders. Of particular importance was their finding that those with independent depressive episodes had “no increased rate of AUDs [alcohol use disorders] and evidenced no higher rate of use or abuse/ dependence on illicit substances” (Schuckit et al., 2013, p. 271). These findings provide compelling support for the importance of distinguishing subgroups of individuals with depression (and likely other psychiatric disorders) whose symptoms do versus do not become intermingled with substance use.

Disorder remissions (“offsets “).

Another common logical error is to assume that removal of the initial cause of a disorder would necessarily resolve that disorder; that is, initiating and maintaining causes can be distinct. For example, in a 40-year follow-up study of more than 200 males at high risk for alcoholism, Penick et al. (2010) observed that there is “a striking disconnect between measures that predicted alcohol dependence and measures that predicted remission from alcohol dependence” (p. 215). This suggests that successfully treating the causal disorder in a comorbid pair would not necessarily resolve the other condition. With that said, it does appear that the elevated levels of anxiety and depression symptoms that are evident in many individuals at the beginning of an inpatient alcoholism treatment decline as they accommodate to their new environment, emerge from acute withdrawal, and otherwise respond to medical and psychosocial treatments while remaining abstinent (Brown and Schuckit, 1988; Schuckit et al., 1990). However, this does not clarify whether individuals meeting diagnostic criteria for specific psychiatric disorders while actively misusing drugs or alcohol would continue to meet these criteria after a period of abstinence.

Penick et al. (1988), for example, provided data showing that the absolute number and relative risk of psychiatric syndromes identified in substance use disorder treatment patients were stable up to 1 year following treatment; however, it is not clear how continued sobriety versus relapse figured into these outcomes. Verheul et al. (2000) found that recovery of substance use covaries with recovery from some but not other types of psychiatric problems. Ramsey et al. (2004) found that up to one third of patients deemed to have “secondary” depression continued to be clinically depressed up to 1 year after successful alcoholism treatment. These findings are consistent with other epidemiological data from the National Epidemiologic Survey on Alcohol and Related Conditions showing that “only a few individuals” had anxiety or mood disorders that both began after the onset of an alcohol disorder and ceased being symptomatic during periods of prolonged abstinence (Grant et al., 2004, p. 107). Similarly, it appears that successful treatment of an anxiety disorder does not appreciably affect comorbid hazardous drinking and AUDs (Thomas et al., 2008). These data would appear to suggest that even if a psychiatric disorder or substance use disorder is caused (“induced”) by the other, it would not necessarily resolve once the primary condition was successfully treated. This conclusion is also consistent with the observations and intuitions of several pre-modern researchers that secondary comorbid conditions can evolve into independent disorders (e.g., Ullman, 1952).

Relapse.

A final issue to consider in distinguishing initiating from maintaining causal influences in comorbid disorders is the relative “no man’s land” of relapses to substance use in this formulation. Perhaps causal influences related to initiating disorder onsets, but not their offsets, regain causal potency in terms of relapse. For example, relapses to alcohol and drug use following treatment are commonly associated with exacerbations in psychiatric symptoms, and patients often attribute their relapses to worsening affect and anxiety (Kranzler et al., 1996; Najavits et al., 2007); however, disentangling the cause-and-effect relationships between comorbid conditions and relapse remains notoriously difficult (Booth et al., 1991). For example, both affective disorders and substance use disorders are characterized by cycles of remission and relapse even when no comorbidity is present.

Modern family studies of comorbidity

Family studies probe the possibility of a shared heritable etiology of comorbid disorders by evaluating their direct (“true”) transmission (e.g., depression in proband to depression in offspring) versus their cross-transmission (e.g., depression alone in proband to alcoholism alone in offspring). Merikangas et al. (1985) used this approach in comparing rates of depression and alcoholism in the offspring of probands with either depression and “secondary” alcoholism or depression alone. The general conclusion reached by the authors was “that depression and alcoholism are not alternate forms of expression of the same underlying illness” (p. 199). However, they also noted, “some evidence suggested that specificity of transmission existed for the combination and the order of presentation of the two disorders among the adult first-degree relatives” (p. 202). These findings and conclusions are also largely consistent with those reported by Dawson and Grant (1998). This is quite provocative in suggesting that the combination of alcoholism and depression (and perhaps other mental disorders) may constitute a genetically distinct disorder subtype.

At least two family studies have failed to find evidence of cross-transmission as an explanation for comorbidity between anxiety disorder and alcohol use disorder. Schuckit et al. (1995) reported that after controlling for substance-induced “organic” anxiety syndromes and controlling for assortative mating in the parents of probands, there was no evidence of an exceptionally high rate of anxiety disorders in the close relatives of alcoholic men and women. Similarly, Blonigen et al. (2013) found that the within-twin-pair differences in lifetime internalizing disorders (comprised of common affective and anxiety disorders) were significantly related to the within-twin-pair differences in the development of alcohol problems 10 years later (i.e., the twin with the earlier internalizing disorder had more risk for the development of later alcohol problems). They concluded that a history of such psychiatric problems “appears to be linked to problem drinking in midlife above and beyond the confounding influence of genetic effects” (p. 136).

In a small family history study, Winokur et al. (1993) found that, among individuals with bipolar disorder, the rate of alcoholism in their family members was not statistically different between the individuals who did (21%) versus did not (35%) have a co-occurring alcohol disorder. Given the low number of participants and the absence of control groups, it is hard to interpret these findings, but they are consistent with a cross-transmission pattern indicating a shared genetic liability to both disorders. This is consistent with other findings pointing to the possibility of a specific genetic parallel across mania and alcohol use disorders (Schuckit et al., 2003).

Discussion

In contemplating the challenge of understanding comorbidity, Edith Lisansky (1960) observed: “While each profession labors in the vineyard of its own research interests, each contributes a partial explanation, a piece of the puzzle which will eventually have to be integrated with the other pieces if understanding, explanation and prediction are to emerge” (pp. 318–319). After 75 years of research devoted to understanding comorbidity, we have collected an impressive quantity of the empirical puzzle pieces to which Lisansky referred. However, the 75th anniversary review also provides a unique vantage point from which to observe that the assembly of these many pieces into a coherent picture (model) of comorbidity has yet to occur. The remainder of the review considers barriers and opportunities to reaching this important goal.

Prioritizing integration

Puzzles do not assemble themselves; therefore, we must do it for them. For example, we have learned that those at genetic risk for alcohol use disorders experience a greater degree of physiological tension reduction from a fixed dose of alcohol (Schuckit et al., 1981), and, more generally, that many subjective and objective responses to alcohol are transmitted within families (Schuckit et al., 2005). Perhaps these heritable differences in response to alcohol translate into differences in drinking expectancies, motivations, and behaviors that ultimately affect the likelihood of drinking to cope with distress from various mental disorders or other sources. Schuckit and Smith (2006) present data supporting this conclusion by showing that the risk for alcoholism associated with genetically transmitted phenotypes such as internalizing and externalizing symptoms and low level of response to alcohol may be mediated through individual differences in alcohol outcome expectancies and drinking to cope. By merging psychosocial and biological/genetic processes into a general model of comorbidity, this decades-long research program provides an example of how the puzzle (model) assembly prescribed by Lisansky might proceed.

How many comorbidity models do we need?

It is worthwhile keeping in mind that comorbidity is an artificial construct that takes its meaning and form from the taxonomic system within which it is embedded. For example, Bowman and Jellinek’s (1941b) review of historical alcoholism taxonomies provided no definitional space for comorbid disorders because various psychological traits and pathologies were directly incorporated into particular alcoholism subtypes (also see Babor, 1996). Lest this seem anachronistic to the modern reader, consider that the recent family studies reviewed above suggest that there may be a specific comorbidity syndrome that is genetically distinct from both of its constituent disorders (Dawson and Grant, 1998; Merikangas et al., 1985). However, a completely different understanding comes from the neo-Kraepelinian approach in which each psychiatric diagnosis and substance use disorder is presumed to be biologically unique. It follows from this view that each possible disorder pairing is also unique, requiring its own comorbidity model. It is left to future research to determine whether a separate research program is needed for each type of mental disorder as it co-occurs with each type of substance use disorder or whether one or a few meta-models could render comorbidity tractable.

The potential for integrating comorbidity research with stress research

Kushner et al. (2012b) used a latent variable modeling approach to show that it is the shared rather than unique variance among common internalizing disorders that relates to risk for alcohol dependence. Also, Kushner et al. (2011) and Kushner et al. (2012a) support the hypothesis that the same sensitivity to allostatic dysregulation in the brain’s stress and affect response systems (e.g., sympathoadrenal-medullary complex) could render individuals vulnerable to both the development of internalizing disorders and the development of dependence on multiple substances of abuse. Along these same lines, several recent articles find overlapping neurobiological structures and processes underlying a variety of psychiatric disturbances and substance dependence (McElligott et al., 2013; Moonat et al., 2013; Saal et al., 2003). In fact, an entire recent issue of the National Institute on Alcohol Abuse and Alcoholism’s journal Alcohol Research: Current Reviews (34[4], 2012) was devoted to the association of neurobiological stress systems to the use of alcohol and development of dependence. Integrating these emerging neurobiological approaches with the already well-developed epidemiological, genetic, and cognitive approaches and findings reviewed here could constitute a new era of comorbidity research with the potential to achieve the elusive goal of developing a general working model of comorbidity that is both intellectually satisfying and clinically productive.

Concluding remarks

As described by Thomas Kuhn (1962), science normally moves forward slowly and steadily but is occasionally punctuated by rapid revolutionary changes in how problems are understood and studied. We have seen both aspects of science in the comorbidity research published over the past 75 years. The successes of the past 75 years generate much excitement and optimism to see what the future holds as we progress toward the journal’s 100th anniversary and beyond.