A Review of the Literature of Mirtazapine in Co-Occurring Depression and an Alcohol Use Disorder.

BACKGROUND: Prior medication studies involving individuals with major depression in combination with an alcohol use disorder (MDD/AUD) have mainly focused on SSRI and tricyclic antidepressants, with generally ineffective results. Consequently, effective treatments for that common comorbid condition remain elusive. Mirtazapine is an antidepressant medicine with a unique pharmacological profile, whose effectiveness for treating non-comorbid depression reportedly may exceed that of SSRIs. OBJECTIVE/METHODS: We now review the published literature regarding the tolerability and efficacy of mirtazapine for the treatment of the depression and the pathological alcohol ingestion of individuals with co-occurring MDD/AUD, including a review of four of our own small studies and two studies conducted outside the United States. RESULTS/CONCLUSIONS: The findings of these studies suggest that mirtazapine is well tolerated among persons with comorbid MDD/AUD. Results also provide some evidence of efficacy for mirtazapine for decreasing the level of depression of persons with co-occurring MDD/AUD, and suggest that decreases in depression may occur relatively quickly after starting treatment, but provide no evidence of effectiveness for decreasing the level of alcohol ingestion. Large-scale double-blind, placebo-controlled studies are warranted to further clarify the tolerability and efficacy of mirtazapine among individuals with MDD/AUD.

Usefulness of DSM-III axis III in psychiatric inpatients: an actuarial comparison with the DSM-II period.

This study is a retrospective evaluation of the usefulness of DSM-III axis III (physical disorders) and its ability to enhance clinical case description in general psychiatric patients. The subjects of this study consisted of two samples of 75 inpatients; each was randomly selected and age-matched to represent DSM-II (1975-1979) and DSM-III (1981-1985) periods, respectively. The results indicated a substantial and statistically significant difference in the frequency of physical disorders recorded at intake before (9.3%) and after (46.7%) the implementation of DSM-III. DSM-III axis III may significantly enhance the recording of physical disorders in psychiatric inpatients.

Disproportionate lethality in psychiatric patients with concurrent alcohol and cocaine abuse.

OBJECTIVE: The aim of this study was to examine the association between active, concomitant cocaine and alcohol abuse and the prevalence and severity of current suicidal and homicidal behavior among hospitalized psychiatric patients. METHOD: Three groups of patients--with cocaine and alcohol abuse (N = 38), alcohol abuse only (N = 38), and cocaine abuse only (N = 25)--consecutively admitted to a psychiatric and substance abuse dual-diagnosis unit were comparatively examined for the presence of current suicidal and homicidal behavior. RESULTS AND CONCLUSIONS: Logistic regression analysis revealed that the alcohol and cocaine abuse group had a higher likelihood of associated current homicidal behavior than the alcohol-only and the cocaine-only groups.

Increasing treatment adherence among outpatients with depression and cocaine dependence: results of a pilot study.

OBJECTIVE: This pilot study examined the effect of a modified motivational therapy intervention on outpatient treatment adherence and completion for patients with comorbid depressive disorder and cocaine dependence. METHOD: Depressed cocaine patients, stabilized with antidepressant medications on an inpatient psychiatric unit, were consecutively assigned on discharge to motivational therapy (N = 11) or treatment-as-usual (N = 12) during the first month of outpatient care. Patients were compared on treatment adherence and completion and on 1-year rehospitalization rates. RESULTS: Motivational therapy patients attended significantly more treatment sessions during month 1, completed 30 and 90 days of outpatient care at higher rates, and experienced fewer psychiatric rehospitalizations and days in the hospital during the first year from entry into outpatient treatment. CONCLUSIONS: An outpatient program combining individual and group motivational therapy sessions holds promise for improving treatment adherence and completion among depressed patients with cocaine dependence.

Heterogeneity of adolescent alcoholism.

Adolescent alcoholics in treatment were classified into two broad clusters. The larger group consisted of youth who demonstrated behavioral dyscontrol and hypophoria, whereas the smaller group consisted of individuals with primarily negative affect. These two clusters differed with respect to age of first drug use, age of first substance abuse diagnosis, severity of substance use, behavior disturbance, and psychiatric disorder. Difficult temperament loaded on the negative affect factor. In a second study, it was observed that difficult childhood temperament led to a number of different first diagnoses in the adolescents. No specific psychiatric outcome followed a difficult temperament. These results illustrate the heterogeneity of the adolescent alcoholic population and suggest that there are many developmental pathways to this outcome where a predisposing risk factor is a difficult temperament makeup.

Association between hyperactivity and executive cognitive functioning in childhood and substance use in early adolescence.

OBJECTIVE: To determine whether deficient executive cognitive functioning (ECF) in association with high behavioral activity level comprise components of the liability to substance abuse. METHOD: A high-risk (HR) group having fathers with a lifetime DSM-III-R diagnosis of a psychoactive substance use disorder was compared with a low-average-risk (LAR) group whose fathers had neither psychoactive substance use disorder nor another adult Axis I psychiatric disorder. ECF and behavioral activity were measured using neuropsychological tests, activity monitor, diagnostic interview, and informant ratings when the subjects were 10 to 12 years of age. Alcohol, tobacco, and cannabis use were measured at 2-year follow-up. RESULTS: At baseline, the HR group had a significantly higher behavioral activity level and exhibited poorer performance on ECF tests than the LAR group. By early adolescence, HR subjects had a higher lifetime rate of tobacco and cannabis use and earlier age at onset of cannabis use. ECF capacity, but not behavioral activity level, predicted tobacco and cannabis use, total number of drugs ever tried, and severity of drug involvement. ECF accounted for additional variance beyond the effects of conduct problems on these outcomes. CONCLUSION: Whereas behavioral activity and ECF capacity in late childhood distinguishes HR from LAR youth, childhood ECF capacity is the more salient predictor of drug use in early adolescence.

Psychopathology in preadolescent sons of fathers with substance use disorders.

OBJECTIVE: While preadolescent children of parents with substance use disorders (SUDs) are known to have more behavior problems, depression, and anxiety than expected, psychiatric disorders in these children and their relationships with parental disorders have not been systematically investigated. This study compares the psychiatric disorders of preadolescent boys of fathers with and without SUDs and examines the relationships between offspring and parental psychopathology. METHOD: Fathers (i.e., probands) of boys 10 through 12 years old were recruited to represent families of boys with paternal SUD (high risk or HR: n = 113) and boys without paternal SUD (low average risk or LAR: n = 170). These boys (i.e., index cases) and their biological parents participated in structured diagnostic interviews, and diagnoses were determined by the best-estimate method. RESULTS: Disruptive behavior disorders and anxiety disorders were more prevalent in HR than in LAR index cases. Logistic regression analyses examining the relationships between parental and index case psychopathology indicated that parental childhood psychiatric disorders were more strongly predictive of index case psychiatric disorders than parental adulthood psychiatric disorders, including SUDs. CONCLUSIONS: Inasmuch as HR boys had increased rates of disruptive behavior disorders and anxiety disorders, these disorders may be important targets for early intervention to prevent the development of SUD, as well as the morbidity associated with these disorders. Prevention efforts and studies of the transmission of liability for psychiatric disorders in children should carefully consider parental childhood characteristics.

Behavioral self-regulation: correlates and 2 year follow-ups for boys at risk for substance abuse.

This investigation demonstrated the heuristic construct of behavioral self-regulation (BSR) as a salient component of the liability to substance abuse. Three dimensions of childhood behaviour were employed to create a dimensional model of BSR: inattention, impulsivity/hyperactivity and aggressivity. Multiple measures and multiple informants were employed to develop indices of the three traits in a sample of 10-12 year old sons of substance abusing fathers (high risk (HR); n = 180) and normal controls (low average risk (LAR); n = 200). Informants included mothers, boys and their teachers. The results confirmed the presence of a first-order latent trait of BSR. HR boys had significantly higher scores on BSR than LAR boys. Concurrent validity of the BSR trait scores was supported by significant associations with measures of family dysfunction, deviant peer affiliations and poor school performance. These latter problems are commonly prodromal to substance abuse. Predictive validity of the BSR trait baseline scores (age 10-12 years) was supported at 2 year follow-up by significant associations of BSR scores with magnitude of deviant peer affiliations; trends toward significance were found for family dysfunction and poor school performance. Taken together, these results confirm and extend previous findings which indicate that poor BSR is prodromal to substance abuse.

Adolescent versus adult onset and the development of substance use disorders in males.

This study examines the influence of adolescent age of onset on the development of substance use disorders (SUD) by comparing adult males (n = 181) with SUD categorized into adolescent-onset, early-adult onset and late-adult onset groups on patterns of substance use and related disorders, time course of the development of substance dependence and rates of comorbid mental disorders. A sample of male adolescents (n = 81) with SUD was also included as a comparison group. The subjects were recruited from intervention programs in the community and participated in semistructured interviews with diagnoses determined by the best estimate method. Adolescent-onset adults, compared with other adult-onset groups, had higher lifetime rates of cannabis and hallucinogen use disorders, shorter times from first exposure to dependence, shorter times between the development of their first and second dependence diagnoses and higher rates of disruptive behavior disorders and major depression. Adolescents were similar to adolescent-onset adults. While the findings must be interpreted in light of methodological limitations, these results suggest that adolescent-onset SUD is a distinct subtype involving different substances and more rapid development than adult-onset SUD.

Substance use and risky sexual behavior in female adolescents.

The purpose of this study was to elucidate the etiological pathways towards substance use and risky sexual behavior in female adolescent substance abusers. The study had three aims: (1) to determine the relations between behavioral dysregulation, negative affectivity, and childhood victimization with substance use and risky sexual behavior, (2) to determine whether these relations are mediated by internalizing symptomatology, antisocial behavior, and affiliating with an adult boyfriend; and (3) to determine whether age of menarche moderates the relation between the mediating variables and substance use and risky sexual behavior. Multiple behavioral, psychiatric interview, and self-report measures were used to index behavioral dysregulation, negative affectivity, childhood victimization, internalizing symptomatology, antisocial behavior, affiliation with adult boyfriends, substance use, and risky sexual behavior in 125 substance abusing female adolescents and 78 controls between the ages of 14-18 years. Structural equation modeling was used to determine the etiological pathways. Results indicated that behavioral dysregulation, negative affectivity, and childhood victimization were related to substance use and risky sexual behavior. Age of menarche was significantly correlated with affiliation with an older boyfriend and risky sexual behavior. Antisocial behavior mediated the associations between behavioral dysregulation, negative affectivity and childhood victimization with substance use and risky sexual behavior. Affiliation with an adult boyfriend was directly associated with substance use involvement and accounted for the relationship between chronological age and risky sexual behavior. Finally, late menarche enhanced the association between internalizing symptomatology and substance use involvement. The results highlight the importance of behavioral dysregulation, negative affectivity, and childhood victimization in predicting substance use and risky sexual behavior, as well as the finding that antisocial behavior and affiliation with an adult boyfriend may be etiologically important in predicting these outcomes. Therefore, from a prevention and treatment standpoint, behavioral and affective dysregulation, childhood victimization as well as antisocial behavior may serve as clinical 'gateways' for altering the developmental trajectory toward substance use and risky sexual behavior in high risk and substance abusing youth. For example, reducing dysregulation through behavior modification procedures that have been developed for conduct disordered children would appear to be a heuristic avenue of investigation emanating from the results obtained in this study.

Substance abuse and associated psychosocial problems among Argentina adolescents: sex heterogeneity and familial transmission.

OBJECTIVE: The goal of this investigation was to clarify the effects of sex and familial transmission in the psychosocial concomitants of substance abuse problems among adolescents. METHOD: Male (n = 956) and female (n = 303) adolescents in school, and male adolescents in a drug treatment program (n = 51) in Buenos Aires Province, Argentina were administered a translated version of the Drug Use Screening Inventory. Use of substances, familial substance abuse and associations between psychosocial problem domains and substance abuse problems were examined. RESULTS: Sex heterogeneity was broadly observed in terms of both substance abuse and psychosocial problems. Female adolescents in the school-based sample were found to generally report higher levels of psychosocial problems and greater use of minor tranquillizers than school boys or boys in treatment for substance abuse. Conduct deviancy was associated with substance abuse problems only in males, while health problems were associated only in females. However, among all youth, substance abuse problems were found to be associated with older age, greater social competency, problems in school performance, and involvement with deviant peers. Familial substance abuse was associated with substance abuse problems among all adolescents, however, the pattern of associations with other psychosocial problems differed between males and females. CONCLUSIONS: Sex heterogeneity was found in the associations between psychosocial problems, adolescent substance abuse, and familial substance abuse. Furthermore, the results are consistent with a syndrome of problem behaviors.

Hormonal and behavioral homeostasis in boys at risk for substance abuse.

This study modeled the influences of cortisol reactivity, androgens, age-corrected pubertal status, parental personality, family and peer dysfunction on behavioral self-regulation (BSR), in boys at high (HAR) and low average risk (LAR) for substance abuse. Differences between risk groups in cortisol and androgen concentrations, and cortisol reactivity were also examined. Subjects were 10- through 12-year-old sons of substance abusing fathers (HAR; n = 150) and normal controls (LAR; n = 147). A multidimensional construct of BSR was developed which utilized multiple measures and multiple informants. Boys reported on family dysfunction and deviant behavior among their peers. Parents reported on their propensity to physically abuse their sons, and their own number of DSM-III-R Antisocial Personality Disorder symptoms. Endocrine measures included plasma testosterone, dihydrotestosterone, and salivary cortisol. HAR boys, compared to LAR boys, had lower mean concentrations for testosterone, dihydrotestosterone, salivary cortisol prior to evoked related potential testing, and lower cortisol reactivity. The number of maternal Antisocial Personality Disorder symptoms, parental potential for physical abuse, degree of family dysfunction, and peer delinquency were significantly associated with BSR. Parental aggression antisocial personality symptoms and parental physical abuse potential are likely to influence sons' behavioral dysregulation and homeostatic stress reactivity. These key components of liability are posited to increase the likelihood of developing suprathreshold Psychoactive Substance Use Disorder (PSUD).

Phosphorus-31 magnetic resonance brain spectroscopy of children at risk for a substance use disorder: preliminary results.

The purpose of this exploratory investigation was to evaluate the heuristic potential of 31P magnetic resonance spectroscopy (MRS) in elucidating a neurobiologic component of the liability for a substance use disorder (SUD). We investigated 31P MRS spectra employing chemical shift imaging (CSI) derived from four distinct anatomic brain locations (i.e. frontal, occipital, right parietal, left parietal) in three groups of peripubertal children who are hypothesized to be at increasing levels of familial SUD risk. Specifically, we studied children with a positive paternal family history of SUD and a disruptive behavior disorder (DBD) diagnosis (SUD+/DBD+; n = 10), in contrast, to those with a positive paternal SUD history in the absence of other psychopathology (SUD+/DBD-; n = 13) and matched control children from normal families (SUD-/DBD-; n = 13). In addition, we examined neurocognitive tests of our subjects to determine any associations between cognitive capacities with regional 31P MRS spectra. The highest-risk sample (SUD+/DBD+) demonstrated a diminished proportion of phosphodiesters confined to the right parietal voxel. This right parietal phosphodiester proportion correlated only with the Information Scale score on a standard intelligence test for children. This suggested a relationship between general learning ability and motivation for academic achievement and right parietal physiology in the highest-risk sample. Variations in synaptic pruning could account for this observation.

Event-related potential negative shift in sons of polysubstance- and alcohol-use disorder fathers.

Previous research has considered event-related potentials (ERPs) in relation to liability for alcohol and other substance use. This study explored ERPs in preadolescent boys at elevated risk for substance use due to paternal history of substance abuse or dependence. Sons (age 10-12) of fathers with an alcohol-use disorder (ALC, n = 29) were matched by age, IQ, education and parental alcohol use with sons of fathers with a polysubstance abuse or dependence diagnosis (POLY, n = 37). These two groups were matched with a low-risk comparison group (LOW, n = 29) of boys whose fathers had no substance-use disorder diagnosis. No boy in the study met criteria for a substance-use disorder. ERPs were collected from midline (Fz, Cz, Pz) and parietal (P3, P4) electrode leads during an auditory oddball task. ERPs of boys from the ALC and POLY groups showed a slow negative shift prominent at Cz and Pz. This negative shift, evident by 100 ms post-stimulus and lasting for the duration of the 1000-ms recording period, overlapped temporally with N1, N2 and P3 amplitude differences distinguishing the ALC and POLY groups from the LOW group. The ALC and POLY groups differed from each other in N2 amplitude at Cz, which was larger for ALC subjects. These findings offer a possible alternative explanation for previously observed amplitude anomalies noted in children at risk for substance-use disorders and suggest new avenues of inquiry.

Norms and sensitivity of the adolescent version of the drug use screening inventory.

The distribution and the statistical accuracy of scores on the Drug Use Screening Inventory (DUSI) and the discriminative power of the DUSI for identifying individuals who qualify for a DSM-III-R diagnosis of Psychoactive Substance Use Disorder (PSUD) were examined in 846 adolescents. The subjects with PSUD had higher mean scores, and the distribution of their scores approximated a normal distribution in each of the 10 domains measured by the DUSI. All of the DUSI domains yielded more precise trait estimates for the subjects who had more severe PSUD. Within the normal sample, using a score of 30 on the overall problem density index as the cutoff score, the DUSI correctly classified 95% of the normal sample and 81% of the PSUD cases.

Early adolescent gateway drug use in sons of fathers with substance use disorders.

This study determined the relevance of preadolescent psychopathology and substance use for predicting early adolescent alcohol and cannabis involvement in boys of fathers with and without substance use disorders (SUD). Fathers of preadolescent boys (ages 10 through 12 years) were recruited to represent families of boys with paternal SUD (High Risk or HR: N = 102) and boys without paternal SUD (Low Average Risk or LAR: n = 166). These boys and a parental informant participated in semistructured diagnostic interviews at baseline and 2-year follow-up assessments (ages 12 through 14 years). Preadolescent tobacco experimentation and early adolescent regular alcohol use were more prevalent in HR than in LAR subjects. Logistic regression analyses were utilized to develop prediction equations. The presence of oppositional defiant disorder and the absence of anxiety disorders predicted preadolescent tobacco use. Preadolescent conduct disorder predicted early adolescent regular alcohol use. Preadolescent tobacco use and conduct disorder were highly predictive of early adolescent cannabis use, achieving 100% sensitivity with 76% specificity. Children with tobacco use prior to adolescence, as well as those with disruptive behavior disorders, may be important to target for interventions to prevent cannabis use.

Psychometric evaluation of the Situational Confidence Questionnaire in adolescents: fitting a graded item response model.

Self-efficacy theory has been extensively applied to alcoholism treatment, theories of relapse, and relapse prevention. Most empirical studies of perceived self-efficacy to resist heavy drinking have used the Situational Confidence Questionnaire (SCQ). Among adults, this instrument has been shown to be psychometrically sound. Little is known, however, about the psychometric properties of the SCQ in the adolescent population. We administered the SCQ to a sample of 662 adolescents to evaluate its psychometric properties. Each of the eight subscales was found to be unidimensional. Invariance of the item parameters across different groups was also examined. The reliability coefficients, based on item response theory (marginal reliability) and classical measurement theory (Cronbach alpha), were found to be high. These results demonstrate that the SCQ is appropriate for use among adolescents.

Concordance between verbal report and urine screen of recent marijuana use in adolescents.

This study compared the concordance of self-report for recent marijuana use with results obtained from urine drug screen. The sample consisted of adolescent sons of fathers with DSM-III-R lifetime substance use disorder (SUD) [high average risk (HAR); N= 75] and sons of fathers with no Axis 1 psychiatric or SUD [low average risk (LAR); N= 125]. To avoid recall bias, and to ensure that the timeframe for accurate detection was restricted to promote accuracy, urine drug screen results were compared to self-reported marijuana use during the prior 48 h using an interview format. The HAR group of adolescents reported a higher rate of recent cannabis use and also had a higher rate of cannabis detection as measured in urine. The two groups did not differ with respect to either over or under-reporting marijuana use. Overall, of 19 participants who obtained positive urine cannabis results, six (31.5%) verbally denied that they used marijuana within the previous 2 days. Among the 181 participants who obtained a negative urine drug screen, 20 subjects (11.5%) inaccurately asserted that they had used marijuana within the prior 2 days. In total, 13% of the participants (26/200) inaccurately reported recent cannabis use. These results underscore the need for caution in interpreting the results of self-report methods documenting the prevalence of drug use among youth.

Coping capacity in female adolescent substance abusers.

Female adolescents who qualified for a DSM-III-R diagnosis of Psychoactive Substance Use Disorder were not distinguishable from depressed and conduct disorder subjects on measures of coping but were differentiable from normal controls. Age of onset of substance use, interval between age of first use and age of diagnosis of abuse, and severity of substance use involvement did not correlate with coping capacity. These findings indicate that deficient coping is not specifically related to drug abuse but rather, where present, is concomitant to comorbid psychopathology among females who have a substance abuse disorder.

Correlates of mental health service utilization and unmet need among a sample of male adolescents.

The authors sought to identify the correlates of mental health services utilization and unmet need for these services among a sample of adolescent males. We hypothesized that our findings would replicate and extend those of the recent Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) study, which found that parental factors play a major role in their children's unmet mental health care needs. Our study involved an evaluation of mental health service utilization and unmet need during the prior 2 years, as reported by the subjects at a follow-up assessment at age 16. Four factors were found to predict increased mental health services utilization, including attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) among the adolescent males, the father's alcohol use disorder, and the mother's amphetamine use disorder. One factor was found to predict decreased utilization, the father's cannabis use disorder. Four factors significantly predicted unmet treatment need, including conduct disorder, the mother's amphetamine use disorder, a higher number of siblings, and a parental history of having had a childhood anxiety disorder. The results of this study suggest that parental psychopathology, parental substance abuse, the presence of conduct disorder, and an increased number of siblings act as barriers to adequate mental health treatment among adolescents. These findings confirm the crucial role that parental factors play in the treatment utilization and the unmet treatment need of their children, and also suggest that an increased number of siblings can also be associated with unmet treatment need.