Childhood neglect and parental care perception in cocaine addicts: Relation with psychiatric symptoms and biological correlates

Available online at www.sciencedirect.com

Neuroscience and Biobehavioral Reviews 33 (2009) 601–610 www.elsevier.com/locate/neubiorev

Review

Childhood neglect and parental care perception in cocaine addicts: Relation with psychiatric symptoms and biological correlates G. Gerra a,b,*, C. Leonardi c, E. Cortese c, A. Zaimovic d, G. Dell’Agnello a, M. Manfredini e, L. Somaini f, F. Petracca d, V. Caretti g, M.A. Raggi h, C. Donnini e a

UNODC, Global Challenges Section, Division for Operations, P.O. Box 500, A-1400 Vienna, Austria b Servizio Tossicodipendenze, AUSL di Parma, Italy c Dipartimento Dipendenze ASL Roma C, Italy d Consiglio Nazionale delle Ricerche (CNR), Istituto di Fisiologia Clinica, Pisa, Italy e Dipartimento di Genetica Biologia dei Microrganismi Antropologia Evoluzione, Universita` degli Studi di Parma, Italy f Servizio Tossicodipendenze, ASL di Biella, Italy g Dipartimento di Psicologia Clinica, Universita` degli Studi di Palermo, Italy h Dipartimento di Scienze Farmaceutiche, Universita` degli Studi di Bologna, Italy

Abstract Childhood neglect and poor child–parent relationships have been reported to increase substance use disorders susceptibility. Stressful environmental factors, including emotional neglect, could affect individual personality traits and mental health, possibly inducing stable changes in hypothalamic–pituitary–adrenal (HPA) axis and brain mono-amine function, in turn involved in addictive behavior vulnerability. Therefore, we decided to investigate homovanillic (HVA) and prolactin (PRL) plasma levels, as expression of possible changes in dopamine function, ACTH and cortisol plasma levels, as measures of HPA axis function, and concomitant psychiatric symptoms profile in abstinent cocaine addicts, in relationship to their childhood history of neglect and poor parental care perception. Methods: Fifty abstinent cocaine dependent patients, and 44 normal controls, matched for age and sex, were submitted to a detailed psychiatric assessment (DSM IV criteria). All patients and controls completed the Symptoms Check List-90 (SCL-90) and the Buss Durkee Hostility Inventory (BDHI), to evaluate psychiatric symptoms frequency and aggressiveness levels. The Childhood Experience of Care and Abuse-Questionnaire (CECA-Q) and Parental Bonding Instrument (PBI) have been used to retrospectively investigate parent–child relationships. Blood samples were collected to determine HVA, PRL, ACTH and cortisol basal plasma levels. Results: Cocaine addicted individuals in general showed significantly lower HVA, and higher PRL, ACTH and cortisol basal levels respect to controls. In particular, neuroendocrine changes characterized cocaine addicts with childhood history of neglect and low perception of parental care. Obsessive–compulsive, depression and aggressiveness symptoms have been found related to poor parenting, inversely associated to HVA levels and directly associated to PRL, ACTH and cortisol levels. Conclusions: These findings suggest the possibility that childhood experience of neglect and poor parent–child attachment may partially contribute to a complex neurobiological derangement including HPA axis and dopamine system dysfunctions, playing a crucial role in addictive and affective disorders susceptibility. # 2007 Elsevier Ltd. All rights reserved. Keywords: Psychiatric symptoms; Obsessive–compulsive; Depression; Aggressiveness; Homovanillic (HVA); Prolactin (PRL); Adrenocorticotropic hormone (ACTH); Cortisol; Neglect; Childhood; Parental care; Cocaine; Addiction

* Corresponding author. UNODC, Global Challenges Section, Division for Operations, PO Box 500, A-1400 Vienna, Austria. Tel.: +39 0521 393558. E-mail addresses: [email protected], [email protected] (G. Gerra). 0149-7634/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2007.08.002

602

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

Contents 1. 2.

3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Material and methods . . . . . . . . . . . . . . . . . . . . . . 2.1. Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Psychiatric assessments . . . . . . . . . . . . . . . . 2.3. Infancy parent–child retrospective evaluation . 2.4. Current psychiatric symptoms and personality 2.5. Neuroendocrine measures . . . . . . . . . . . . . . 2.6. Statistical analysis . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

........... ........... ........... ........... ........... traits measures ........... ........... ........... ........... ...........

1. Introduction A variety of evidence demonstrated that attachment between parents and child plays a crucial role in healthy development and, in contrast, impaired parental bonding seems to be a major risk factor for mental diseases, substance abuse and dependence later in life (Canetti et al., 1997; Newcomb and Felix-Ortiz, 1992; Petraitis et al., 1995; Brook et al., 1989). Negative early childhood experiences of abuse and neglect have been found also involved in the susceptibility for obesity and cardiovascular diseases, and other behavioral/health risk conditions (McEwen, 2000). Accordingly, all types of childhood maltreatment, including emotional abuse, have been reported as serious risk factors for substance use during adolescence (Moran et al., 2004) and emotional neglect was found associated with a greater severity of substance abuse, particularly among female subjects (Hyman et al., 2006). The individuals affected by substance use disorders have been previously reported to perceive high maternal and paternal control and low maternal care, a pattern characteristic of an ‘‘affectionless control’’ rearing style (Torresani et al., 2000), that was also evidenced in the history of pathological gamblers (Grant and Kim, 2002), depressed subjects (Narita et al., 2000), alcoholics (Joyce et al., 1994), young offenders (Chambers et al., 2000) and, in general, psychiatric disorders (Scinto et al., 1999a, b). At a retrospective evaluation, disturbed parenting was frequently found in the history of narcotic addicts (Bernardi et al., 1989) with the perception of parents as cold, indifferent, controlling and intrusive (Schweitzer and Lawton, 1989). To this purpose, our previous psychometric investigation, in a large sample of high school students, showed an inverse correlation between parental care and aggressiveness/social maladaptation scores, in turn related with illicit drugs experimenting (Gerra et al., 2004a, b). Similarly, the lack of adequate parental care was very recently identified as a consistent predictor of adult affective disorders (Lancaster et al., 2007) and a prospective investigation showed that child abuse and neglect were associated with an increased risk for major depression (Widom et al., 2007), again suggesting that the disruption in early rearing conditions may significantly contribute to mood problems, negative affects

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

602 603 603 603 603 604 604 605 605 607 609

and behavioral under-control, as possible risk factors for substance abuse susceptibility. As previously evidenced by Roy (2002) in cocaine addicts, adverse childhood experiences, and particularly poor child– parent relationships, appear to negatively influence personality development, possibly contributing to a stable dysfunction of brain monoamines, with an inverse correlation between emotional neglect during infancy and CSF metabolites of serotonin and dopamine in the adult. Nevertheless, hypothalamic–pituitary–adrenal axis and autonomic nervous system hyper-reactivity, observed in the adults affected by affective and addictive disorders (Gold et al., 1986; Holsboer et al., 1986; Krishnan et al., 1993; Holsboer et al., 1995; Sher, 2006), could be a persistent consequence of childhood abuse and neglect, that may have contributed to the diathesis for adulthood psychopathological conditions (Arborelius et al., 1999; Heim et al., 2000). A variety of clinical studies have evaluated the long-term effects of early developmental stress, such as child abuse and neglect or parental loss. Severe early stress and maltreatment have been found to induce a neurobiological cascade of events that have the potential to alter brain development and to increase the risk of developing depression, symptoms of attention-deficit/hyperactivity, borderline personality disorder, dissociative identity disorder and substance abuse (Teicher et al., 2002). In particular, compared to levels in subjects who had experienced neither loss nor a separation, parental loss by death was found associated with higher cortisol throughout the day, suggesting that affective deprivation provoked by bereavement during childhood may have lasting effects on the HPA axis, even in the absence of psychopathology (Nicolson, 2004). Accordingly, infants who experienced frequent emotional withdrawal by their mothers (either as a result of maternal depression, or mother’s strategic use of withdrawal as a control tactic) showed elevated baseline levels of cortisol, with sensitization to later stress, cognitive deficits, and social– emotional problems (Bugental et al., 2003). Taking into account these evidence, a possible neurobiological derangement, involving both dopaminergic function and hypotalamic–pituitary–adrenal (HPA) axis function may be hypothesized to underlie substance dependence and depression vulnerability in humans (Oswald et al., 2005; Duval et al.,

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

2006), possibly as a consequence of chronic stress exposure during childhood. For all these reasons, we decided to investigate homovanillic (HVA) and prolactin (PRL) plasma levels, as expression of possible changes in dopamine function, ACTH-cortisol plasma levels, as measures of HPA axis function, and concomitant psychiatric symptoms profile in cocaine addicts, in relationship to their childhood history of parent–child attachment and parental care perception. Aims of the study were to evaluate: (1) whether reduced perception of parent–child attachment and childhood neglect were associated with dopamine and HPA axis dysfunction in the adult, (2) whether adverse childhood experience were related with comorbid psychiatric disorders and personality traits among cocaine addicted individuals, (3) the possible relationship between dopamine turnover, HPA axis activity measures and psychiatric symptoms. The hypothesis of the study was that dopamine system impairment, with decreased HVA and increased PRL plasma levels, and HPA axis hyperactivity, with high basal levels of ACTH and cortisol, were partly related to a history of adverse childhood experience in addicted individuals and may contribute to a complex psychobiological derangement underlying both addictive behavior and comorbid psychiatric symptoms. Fifty abstinent cocaine dependent patients, who stopped cocaine use from at least 3 months at the time of the study, and 44 healthy controls have been included in the protocol and submitted to detailed psychiatric assessment and psychometric tests to evaluate childhood neglect and abuse, parental care perception, current psychiatric symptoms and impulsive– aggressive attitude. Blood samples have been collected for the hormonal assays. 2. Material and methods 2.1. Subjects Fifty cocaine addicted male patients (mean age: MSD=28.37.9 years) were randomly selected from among patients attending Rome (ASL C) and Parma Addiction Treatment Services programs. They were recruited during the 18 months between January 2005 and June 2006. To be eligible for the study, the patients had to fit the DSM criteria for cocaine dependence from at least 36 months (4.11.0 years). No exclusion criteria are applied to select patients in the public health system. Only three patients out of 53 refused to participate in the study. Previous long-lasting consumption of other drugs of abuse and psychotropic agents, and excessive alcohol intake, was anamnestically excluded, utilizing a structured interview and patients records. Episodic cannabis use and alcohol abuse was reported in the history many years before heroin dependence onset. The duration of the history of cocaine dependence was recorded, as a measure of drug exposure extent. The subjects underwent treatment program from at least 4 months (5.21.1) and were not submitted to any prescribed psychotropic medication. The patients were included in a long-term, inpatients psychosocial rehabilitation program that was

603

associated with cognitive-behavioral therapy. If a twice-aweek analysis for urine metabolites of the main illegal substances of abuse excluded their consumption in the previous 3 months, the patients were included in the study, after giving written informed consent. Exclusion criteria included severe chronic liver or renal diseases or other chronic physical disorders, recent weight loss (more than 10%) or obesity, endocrinopathies, immunopathies, and, in particular, HIV disease. The subjects treated with other prescribed drugs in association with psychosocial therapy were not included in the study. All the subjects reported weekly alcoholic drinking ranging from 3 to 14 per week. The subjects were smoking not more than 10 cigarettes per day and drinking not more than 2 cups of coffee daily. Forty-four healthy male volunteers who have never used illicit psychotropic drugs of misused alcohol, recruited from hospital staff workers, blood donors and university students, and matched for age (mean age: MSD=28.9+6.2 years), were used as controls, after giving informed consent (Group B). Subjects were defined healthy by physical examination and routine biochemical tests. Exclusion criteria from the study were the same as those used for the patients. Socio-economical and educational back-ground of healthy volunteers were not significantly different from patients background. Volunteers were also controlled by urinary drug screening for 4 weeks before the study. Seven subjects, among healthy controls, reported no current alcohol use, while the other subjects reported weekly alcoholic drinking ranging from 2 to 16 per week. Age and years of education were similar to those of drug dependent patients. Both drug dependent subjects and controls had no legal or economic problems, no present personal or familiar unusually stressful situations and no athletic training at the moment of the study. Urine and breath samples examined at the beginning of the study excluded illegal drugs or alcohol abuse in patients and controls immediately before the study procedure. The subjects were not allowed to smoke cigarettes 2 h before blood test. The study was approved by local review board and by the ethic’s committee. 2.2. Psychiatric assessments Addicted patients and controls were submitted to structured interviews and diagnostic evaluation by trained psychiatrists, utilizing the SCID (Structural Clinical Interview) for axis I disorders (Spitzer et al., 1990, Italian Version: Clinical Interview structured for the DSM-III-R by Fava et al., 1993) and the SIDP (Structured Interview for DSM IV Personality Disorders) for Axis II disorders (Pfohl et al., 1989: Italian Version by Maffei et al., 1997). A second clinical interview, in the presence of a family member, was performed to avoid denial of symptoms. 2.3. Infancy parent–child retrospective evaluation The possible experiences of neglect and abuse during infancy and adolescence were measured retrospectively

604

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

utilizing the Child Experience of Care and Abuse Questionnaire (CECA-Q; Bifulco et al., 2005) both in patients and controls. The self-report questionnaire was used to assess lack of parental care (neglect and antipathy), parental physical abuse, and sexual abuse from any adult before age 17. CECA-Q sub-scales include mother neglect, father neglect, mother antipathy, father antipathy, mother physical abuse, father physical abuse, and sexual abuse. The patient–therapist relationship permitted to obtain also a clinical evaluation of adverse childhood experience in the history of the patients, demonstrating CECA-Q reliability. Neglect cutoff was considered for the scores 522. The Parental Bonding Instrument (PBI; Parker et al., 1979), a measure of perceived parental care and overprotection, was administered to cocaine users and to healthy control subjects. An Italian modified version (Scinto et al., 1999a, b), with 25 items, was used in the present study. The test evaluated retrospectively the perception of child–parent attachment. Four scores were expressed, respectively maternal and paternal care perception and maternal and paternal overprotection perception. Scores<20 indicate low care and low protection perception. 2.4. Current psychiatric symptoms and personality traits measures Both cocaine addicted patients and normal subjects have been submitted to the Symptoms Check List 90 (SCL 90; Derogatis et al., 1992), that was administered after at least 12 weeks of abstinence. SCL-90 included somatization, obsessive–compulsive, interpersonal sensitivity, depression, anxiety, anger–hostility, phobic anxiety, paranoid ideation, psychoticism sub-scales. A total SCL-90 score was expression of psychiatric symptoms in general. The evidence obtained with SCL-90 about psychiatric symptoms was confirmed by trained psychiatrists clinical evaluation and collecting data from someone who knows the patient well enough to rate their current symptoms (e.g., spouse, close friend, parent, sibling). The rationale for having a collateral informant stems from concerns about the reliability of patient self-reports about their symptoms. Characters and quantification of aggressiveness (defined as direct, indirect or verbal, irritability, negativism, resentment, suspiciousness, guilt and global aggressiveness) were analyzed by the Buss-Durkee Hostility Inventory (BDHI; Buss and Durkee, 1957) in the Italian version, ‘‘Questionario per la Tipizzazione della Aggressivita`’’—QTA (Castrogiovanni et al., 1993). QTA raw scores, in accordance with Castrogiovanni, have been used for the total score and for the single subscales scores: the normal range of aggressiveness score is under 60. 2.5. Neuroendocrine measures For HVA assays, heparin-de-coagulated blood samples (3 mL each) and for PRL, ACTH and cortisol assays, EDTA-decoagulated blood samples (9 mL each) were drawn at 3.00 p.m., (time: 0) through a catheter inserted in a vein 30 min before

(time: 30) starting the test and kept patent by saline infusion. Blood samples were drawn at 3.00 p.m. (time: 0) and 3.30 p.m. (time: 30). Previous evaluations of two basal blood samples, 30 min from one another, evidenced that the second baseline hormonal value was not influenced by i.v. insertion (Kirschbaum et al., 1993; Gerra et al., 1998), suggesting that the emotional state was not significantly changed 30 min after insertion: the catheter was not perceived as a stressful stimulus at time 0. Blood samples were immediately centrifuged in the cold and the plasma frozen at 80 8C until assayed. PRL and cortisol plasma concentrations were measured utilizing a competitive enzyme immuno-assay by commercial kits (AIAPACK, Eurogenetics Italy, Torino, Italy). ACTH plasma levels were measured by commercial kits (Medical System DPC— Immulite, Los Angels, USA). The intra-assay and inter-assay coefficients of variation were 5 and 7% for PRL, 3.7% and 7.5% for cortisol and 6% and 10% for ACTH. Assay sensitivities were 0.3 ng/ml for prolactin, 0.3 nmol/l for cortisol and 15 pg/ ml for ACTH. The HPLC method for HVA assay uses a Jasco (Tokyo, Japan) PU-1580 chromatographic pump and an ESA (Milford, MA, USA) Coulochem III coulometric detector. The conditioning cell was set at +0.100 V; in the analytical cell, detector 1 was set at 0.200 V and detector 2 at +0.500 V. The chromatographic separation was achieved by isocratic elution on a Varian (Harbor City, CA, USA) Microsorb reversed phase column (C8, 250 mm4.6 mm i.d., 5 mm). The mobile phase was a mixture (10:90, v/v) of methanol and an aqueous solution of 49 mM citric acid, 110 mg/l octanesulfonic acid and 22 mg/l EDTA adjusted to pH 4.8. The flow rate was 1.2 ml/min and the samples were injected by means of a 20 ml loop. In order to avoid analyte degradation, the stock solutions of HVA were prepared by dissolving 20 mg of the substance in 20 ml of ultrapure water to which 20 mg of sodium metabisulfite, 160 mg of sodium chloride and 10 ml of concentrated hydrochloride acid (37%) were previously added. HVA standard solutions were prepared daily by diluting the stock solutions with the mobile phase. Stock solutions were stable for at least 2 months at 20 8C, standard solutions were pre-paredafresh every day and were stable for at least 8 h at room temperature. Plasma sample pre-treatment was carried out by solidphase extraction (SPE) on BondElut SAX (strong anion exchange) cartridges (100 mg, 1 ml) from Analytichem International (Harbor City, CA, USA). The cartridges were activated and conditioned with 51 ml of methanol and 51 ml of water. An aliquot of 50 ml of the IS (50 ng/ml) was added to 250 ml of plasma sample and the mixture was diluted with 500 ml of water and loaded onto the previously conditioned cartridge. Interference was washed out with 1 ml of water and 1 ml of methanol, then the cartridge was dried applying full vacuum ( 30 kPA) for 1 min. The analytes were eluted with 1.5 ml of 5% ammonia solution in methanol, applying full vacuum again for 1 min. The eluate was brought to dryness with a rotary evaporator; the residue was redissolved in 125 ml of mobile phase and injected into the HPLC (Saracino et al., 2006). The measures of plasma HVA are expressed in ng/ml.

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

605

PRL, ACTH, cortisol and HVA values presented in the study were the average of the two values obtained in the two basal measures. 2.6. Statistical analysis For the evaluation of differences between the groups of cocaine addicted patients and control subjects, or between cocaine addicts with or without a history of poor parenting and neglect, Kruskal–Wallis non-parametric test has been utilized. Spearman correlation test has been used to evaluate the possible relationships among psychometric values and hormonal values. To test the causal relationships among ACTH-Cortisol, HVA, PRL and SCL-90—BDHI scores, family-context variables (CECA-Q and PBI) and other factors we used least-square dummy-variable regression model (LSDV). This procedure is a common linear regression that uses dummy and categorical variables as explanatory variables of a continuous dependent variable. The coefficients of dummy variables express the difference in the mean values of the dependent variable in the two categories. 3. Results Among cocaine addicted patients, who were diagnosed as ‘‘cocaine dependent’’ following DSM IV criteria, 9 (18%) were dually diagnosed (life time) for major depression (MD); 4 (8%) presented bipolar disorder; 8 (16%) of the subjects were found affected by antisocial personality disorder (ASPD); 6 (12%) presented attention deficit hyperactivity disorder (ADHD). Among addicted individuals, other subjects showed psychiatric symptoms (generalized anxiety, borderline personality disorder traits), but they did not fulfil the complete DSM criteria for overt diagnoses. None of the control subjects was found affected by psychiatric disorders. When evaluated with the Symptoms Check List-90 (SCL 90) criteria, DSM diagnoses were confirmed in all the patients. In Table 1, CECA-Q scores and PBI scores (meanSE) in cocaine addicts, in comparison with healthy controls, have been reported in details. The results confirm the existence of Table 1 Child Experience of Care and Abuse—Questionnaire (CECA-Q) scores in cocaine addicts and control subjects: neglect, antipathy and care have been reported for both mother and father

Neglect mother Antipathy mother Antipathy father Neglect father Maternal care Paternal care

Cocaine patients Control group Cocaine patients Control group Cocaine patients Control group Cocaine patients Control group Cocaine patients Control group Cocaine patients Control group

N

Mean

50 44 50 44 50 44 50 44 50 44 50 44

20.96 10.79 24.11 11.47 23.54 12.47 23.04 13.81 20.79 24.96 19.78 23.30

           

1.34 0.50 1.25 0.52 1.01 0.84 1.14 0.80 0.79 0.33 0.67 0.89

x2

p

42.32

<0.001

47.19

<0.001

41.19

<0.001

35.16

<0.001

33.26

<0.001

12.6

<0.005

Fig. 1. Homovanillic acid (HVA, ng/ml), adreno-corticotrophic hormone (ACTH, pg/ml), cortisol (mcg/dl) and prolactin (ng/ml) values in cocaine addicted patients and control subjects. The difference between cocaine patients and controls was significant for all hormones ( p<0.001).

statistically significant differences between groups in the mean values of both CECA-Q and PBI sub-scales. Cocaine addicted patients showed significantly higher scores on ‘‘mother neglect’’, ‘‘father neglect’’, ‘‘mother antipathy’’ and ‘‘father antipathy’’ sub-scales at CECA-Q (x2 = 42.32, p < 0.001; x2 = 41.19, p < 0.001; x2 = 47.19, p < 0.001; x2 = 35.16, p < 0.001), and significantly lower scores on maternal and paternal care sub-scales at PBI (x2 = 33.26, p < 0.001.; x2 = 12.6, p < 0.005), in comparison with control subjects. ‘‘Mother neglect’’ and ‘‘father neglect’’ scores at CECA-Q inversely correlated respectively with maternal (r = 0.68, p < 0.01; r = 0.62, p < 0.01) and paternal care scores at PBI at Pearson test (r = 0.54, p < 0.01; r = 0.43, p < 0.01). In Fig. 1, HVA, PRL, ACTH and cortisol plasma values (meanSE) in cocaine addicted patients and controls have been presented in details. Also for hormonal measures, statistically significant differences have been evidenced between groups in the mean basal values of HVA, PRL, ACTH and cortisol. Cocaine addicted patients showed significantly lower plasma levels of HVA (x2 = 25.28, p < 0.001) and significantly higher levels of ACTH, cortisol and PRL (x2 = 33.49, p < 0.01; x2 = 13.73, p < 0.001; x2 = 14.35, p < 0.001), in comparison with control subjects. Then, cocaine addicts were divided into two groups, on the basis of their childhood experience of parental behavior: group 1 (22 patients): low maternal and paternal care scores (< 20) at PBI on at least one sub-scale; high maternal or paternal neglectantipathy scores (522) at CECA-Q on at least 2 sub-scales; clinical evaluation of poor-ineffective parenting; group 2 (28 patients): high scores (> 20) at PBI on both maternal and paternal care sub-scales; low maternal or paternal neglectantipathy scores (< 22) at CECA-Q on all sub-scales; clinical evaluation of effective parenting. When compared on the basis of their parents–child relationships history, cocaine addicted patients with neglect and poor parenting perception (group 1) showed significantly lower HVA plasma levels (x2 = 15.63, p < 0.001) and significantly higher PRL, ACTH and cortisol levels

606

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

Fig. 2. Homovanillic acid (HVA, ng/ml), adreno-corticotrophic hormone (ACTH, pg/ml), cortisol (mcg/dl) and prolactin (ng/ml) values in cocaine addicted patients with neglect and poor parenting perception (group 1) and cocaine-addicted patients with effective parenting and perception of high levels of parental care (group 2). The difference between group 1 and 2 was significant for all the hormones: p < 0.001 for HVA, p < 0.01 for ACTH, p < 0.05 for cortisol and p < 0.005 for prolactin.

(x2 = 5.64, p < 0.01; x2 = 5.12, p < 0.05; x2 = 7.16; p < 0.005), respect to group 2 cocaine addicts, with a history of effective parenting and perception of consistent parental care (Fig. 2). The neuroendocrine variables did not show any difference between cocaine-addicted patients with effective parenting and perception of high levels of parental care (group 2) and healthy controls who were never exposed to psychotropic drugs and were not neglected during infancy. SCL-90 profiles reported in Fig. 3 evidenced significant differences between group 1 and group 2, in relationship to neglect history and parents behavior perception, in three symptoms sub-scales: in particular obsessive–compulsive, depression, anger–hostility sub-scales scores have been found significantly higher in cocaine addicts of group 1, characterized by neglect and poor parenting perception (x2 = 6.3, p < 0.01; x2 = 7.47, p < 0.01; x2 = 4.47, p < 0.05), in comparison with group 2, with effective parenting history and higher perception of parental care.

However, SCL-90 obsessive–compulsive, depression, anger–hostility sub-scales scores in group 2 patients were significantly higher than those obtained in healthy controls (x2 = 33.2, p < 0.001; x2 = 41.5, p < 0.001; x2 = 20.3, p < 0.001): independently from the history of adverse childhood experiences, abstinent cocaine addicts showed a higher frequency of psychiatric symptoms than healthy controls on these three sub-scales. Similarly, BDHI profiles (Fig. 4) showed significant differences between cocaine addicted patients of group 1 and group 2. Group 1 patients, with a history of neglect, scored higher at BDHI on direct, guilt, resentment sub-scales (x2 = 6.87, p < 0.005; x2 = 4.36, p < 0.05; x2 = 5.12, p < 0.05), in comparison with group 2 patients, with effective parenting history. BDHI scores in group 2 patients were significantly higher on direct, indirect and resentment sub-scales than those obtained in healthy controls (x2 = 36.54, p < 0.001; x2 = 38.4, p < 0.001; x2 = 27.36, p < 0.001), again indicating a proneness to aggressive behavior in cocaine addicts, in comparison with healthy controls, independently from adverse childhood experiences. Spearman correlation test showed an inverse relationship between HVA plasma levels and PRL plasma levels (r = 0.25, p < 0.05); similarly, inverse relationships have been demonstrated between HVA plasma levels and cortisol plasma levels (r = 0.32, p < 0.01) and between HVA plasma levels and ACTH plasma levels (r = 0.58, p < 0.01). The results of logistic regression model in Table 2 show that in a general context of positive association between parentallevel covariates and HVA, ACTH, cortisol and PRL levels, mother neglect resulted statistically significant in affecting HVA, ACTH and cortisol plasma levels; mother antipathy affected HVA and PRL plasma levels. The models explain about 30–50% of the total variability of HVA, ACTH and cortisol plasma levels, so that other environmental-bond issues

Fig. 3. SCL-90 symptoms sub-scales scores (obsessive–compulsive, depression, anger–hostility) in cocaine addicted patients with neglect and poor parenting perception (group 1) and cocaine-addicted patients with effective parenting and perception of high levels of parental care (group 2).

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

607

Fig. 4. BDHI sub-scales scores (direct aggressiveness, resentment, guilt) in cocaine addicted patients with neglect and poor parenting perception (group 1) and cocaine-addicted patients with effective parenting and perception of high levels of parental care (group 2). Table 2 Regressions with continuous and dummy variables Variables

Dependent variable HVA

Dependent variable PRL

Coeff.

p-Value

Age Years of dependency Antipathy mother Antipathy father Neglect mother Neglect father R2

0.234 0.181 S0.548 0.362 S0.641 0.392 0.345

0.906 0.492 0.009 0.054 0.001 0.090

Variables

Dependent variable ACTH Coeff.

Age Years of dependency Antipathy mother Antipathy father Neglect mother Neglect father R2

0.096 0.123 0.214 0.220 0.504 0.313 0.238

Coeff. 0.191 0.027 0.610 0.256 0.364 0.231 0.267

p-Value 0.622 0.891 0.001 0.034 0.052 0.123

Dependent variable cortisol p-Value

Coeff.

0.851 0.325 0.211 0.526 0.005 0.361

0.123 0.291 0.354 0.100 0.483 0.290 0.124

p-Value 0.685 0.672 0.126 0.623 0.016 0.142

Effects of HVA, ACTH, cortisol and prolactin on antipathy/neglect of the mother scores in cocaine addicted patients.

and genetic factors could be involved in the interpretation of the residual unexplained variance. The levels of HVA, ACTH and cortisol resulted to be significantly related to some features of the parents–child relationship among cocaine-addicted individuals. In particular, mother neglect was positively related to HVA, ACTH and cortisol plasma levels and father antipathy to HVA and cortisol levels. The other variables (age, cocaine dependence exposure extent) did not show any statistical significant effect on neuroendocrine measures, SCL-90 scores and BDHI scores. 4. Discussion Abstinent cocaine addicted patients included in the present study showed higher rates of depression, obsessive–compulsive

and hostility-aggressiveness symptoms, in association with lower HVA, and higher PRL, ACTH, cortisol plasma levels than healthy control subjects, who never used illicit drugs. In particular, the patients with a history of childhood neglect and reduced perception of parental care presented a more consistent reduction of the dopamine metabolite, higher basal levels of stress hormones and a significantly higher rate of psychiatric symptoms, in comparison with cocaine addicts who did not report early adverse family experiences. An impaired dopaminergic activity in the brain of cocaine addicted individuals was not unexpected, being dopamine mesolimbic system crucial both in the mechanism of action of addictive psychotropic drugs, that can have significantly influenced monoamines transmission (Di Chiara et al., 2004), and in the neurobiological changes possibly underlying

608

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

substance abuse susceptibility (Blum et al., 2000; Comings, Blum, 2000). Like our abstinent drug addict patients, alcoholic patients (Fulton et al., 1995; Kohnke et al., 2003), individuals with a family history positive for paternal alcoholism with violence (Virkkunen et al., 1996) and heroin users at post mortem evaluation (Kish et al., 2001) have been previously reported to present significantly lower levels of HVA, compared to healthy controls. Furthermore, in agreement with our results, HVA concentrations in CSF were found markedly lower in nicotine smokers, in comparison with abstinent controls (Geracioti et al., 1999). In particular, depressed subjects with a history of alcoholism were reported to present lower CSF HVA levels, higher suicide ideation scale scores and proneness to tobacco smoke, compared with depressed subjects without a history of substance use disorders (Sher et al., 2003). Our previous findings repeatedly evidenced increased ACTH and cortisol values at baseline, and blunted responses to stressful stimuli, in drug-free addicted individuals (Gerra et al., 2004a, b, 2003a), suggesting that a persistent basal overdrive of HPA axis may underlie substance use disorders susceptibility, without reference to specific drug of choice or substance abuse clinical history. Accordingly, in depressed adolescents at risk for substance abuse, HPA-axis was found hyperactive when the system is normally quiescent and unable to express any response during coping processes with stressful conditions (Rao et al., 1999). In addition, the relationship between depression and HPA axis hyperactivity, evidenced in the present study, seems to be in agreement with the large body of evidence concerning the biological correlates of affective disorders (Parker et al., 2003; Appelhof et al., 2006). In specific, HPA hyper-responsivity to removal of glucocorticoid negative feedback with metyrapone was found associated with cocaine addiction, even in the setting of methadone maintenance for heroin addiction, which previously has been shown to be associated with normalization of HPA axis function (Schluger et al., 2001). Although not completely confirmed in humans, a large body of evidence indicate the involvement of HPA axis dysregulation in cocaine addiction (Goeders, 2002) and cocaine reward (Sarnyai, 1998). Alterations in the mechanisms that regulate HPA axis activity have been hypothesized to predate the development of addiction, being part of inherited traits (Sher, 2006). A complex neuroendocrine dysfunction could be associated with addictive/ affective disorders, including a derangement of both dopamine system and HPA axis, underlying risk behaviors and temperament in vulnerable individuals, and not simply acquired as a consequence of the exposure to psychotropic drugs. To this purpose, a correlation between reduced dopamine receptor sensitivity and HPA basal hyperactivity was evidenced in our previous studies in abstinent ecstasy users (Gerra et al., 2003b), and our findings were unable to exclude that the neurobiological changes were preexisting to ecstasy use. HPA overdrive and impaired dopamine system may be associated with negative affects, mood problems and behavioral under-control, all risk conditions, evidenced in depressed individuals, increasing cocaine dependence susceptibility.

Accordingly, plasma cortisol levels were found significantly increased and plasma HVA, the dopamine metabolite, significantly decreased in the depressed patients, in comparison with controls (Mitani et al., 2006). The difference evidenced in HVA, PRL, ACTH and cortisol plasma levels and in the rates of concomitant psychiatric symptoms and aggressiveness between our cocaine addicts with or without a history of parental neglect and low perception of parental care, appear to confirm the hypothesis that a preexisting psychobiological dysfunction, possibly resulting from both inherited and environmental factors, may take part in the vulnerability for cocaine addiction and concomitant affective disorders. Our recent findings obtained with the evaluation of cocaine addicts genotype, personality traits and retrospective analysis of parent–child relationships suggested that a very large part of the change in the risk for cocaine dependence, associated to gene variants, was actually due to the low perception of parental bonding of the individuals bearing a specific genotype, rather than to the genotype itself (Gerra et al., 2007). Environmental factors, such as early adverse experiences during infancy, could have contributed to stable changes in dopamine function and HPA axis reactivity in the adult, possibly playing a permissive role in the expression of behavioral and psychological phenotypes. In agreement with our results, intermittent maternal separation during the early infancy in experimental animals was found to influence both ACTH/cortisol responsiveness to stress (Huot et al., 2004) and dopamine release in response to cocaine in the nucleus accumbens (Brake et al., 2004), in association respectively with alcohol preference and cocaine psycho-motor sensitivity. Similarly, in humans, early stressors such as maternal separation have been previously reported to result in lasting effects on stress-responsive neurobiological systems, including persistent changes in the function of HPA axis and brain monoamines system (Bremne and Vermetten, 2001). The lack of significant difference in the neurobiological measures between cocaine addicts with a history of effective parenting/high perception of parental care and control subjects in the present study seems to indicate that dopamine system and HPA axis changes were related more to childhood neglect and poor parental care, rather than to addiction to cocaine per se. Similarly, neuroendocrine measures showed a greater association with concomitant psychiatric symptoms than with addictive behavior without depressive–aggressive pattern. Although prolonged cocaine exposure could have been primarily responsible of consistent changes in dopamine system and HPA axis function (Goeders, 1997), we were unable to demonstrate a relationship between the extent of drug dependence and neuroendocrine data, that, vice versa, correlated with adverse childhood experiences and psychiatric symptoms scores. The strength of our findings is reduced by many limitations. On one side, we cannot exclude that cocaine addicted individuals, and particularly those with psychiatric symptoms, may have over-reported mother–father neglect and antipathy, and under-reported parental care, because of their mispercep-

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

tion of parental support. The higher ‘‘scores’’ of parental neglect and related deficiency could perhaps be ascribed to the recent history of cocaine abuse, being the scores themselves the result of chronic psychopharmacological after-effects of cocaine. On the other hand, parent neglectful child-rearing style might have been induced by the difficult temperament (and related at risk neurobiological changes) of problematic children (Maccoby, 2000). Moreover, many other confounders, associated with humans variability that could have been underestimated by our protocol might have influenced the results. In conclusion, a psychobiological dysfunction including both dopamine reduced turnover and stress hormones overdrive seems to be associated with lack of parent–child bonding and parental neglect in abstinent cocaine addicts, possibly underlying comorbid affective disorders and individual attitude to aggressive–impulsive behavior. References Appelhof, B.C., Huyser, J., Verweij, M., Brouwer, J.P., van Dyck, R., Fliers, E., Hoogendijk, W.J., Tijssen, J.G., Wiersinga, W.M., Schene, A.H., 2006. Glucocorticoids and relapse of major depression (dexamethasone/corticotropin-releasing hormone test in relation to relapse of major depression). Biological Psychiatry 59 (8), 696–701. Arborelius, L., Owens, M.J., Plotsky, P.M., Nemeroff, C.B., 1999. The role of corticotropin-releasing factor in depression and anxiety disorders. Journal of Endocrinology 160 (1), 1–12. Bernardi, E., Jones, M., Tennant, C., 1989. Quality of parenting in alcoholics and narcotic addicts. British Journal of Psychiatry 154, 677–682. Bifulco, A., Bernazzani, O., Moran, P.M., Jacobs, C., 2005. The childhood experience of care and abuse questionnaire (CECA.Q): validation in a community series. British Journal of Clinical Psychology 44 (Pt. 4), 563– 581. Blum, K., Braverman, E.R., Holder, J.M., Lubar, J.F., Monastra, V.J., Miller, D., Lubar, J.O., Chen, T.J., Comings, D.E., 2000. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. Journal of Psychoactive Drugs 32 (Suppl: i–iv), 1–112. Brake, W.G., Zhang, T.Y., Diorio, J., Meaney, M.J., Gratton, A., 2004. Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioural responses to psychostimulants and stressors in adult rats. European Journal of Neuroscience 19 (7), 1863–1874. Bremne, J.D., Vermetten, E., 2001. Stress and development: behavioral and biological consequences. Development and Psychopathology 13 (3), 473– 489. Brook, J.S., Nomura, C., Cohen, P., 1989. Prenatal, perinatal, and early childhood risk factors and drug involvement in adolescence. Genetic Social and General Psychology Monographs 115 (2), 221–241. Bugental, D.B., Martorell, G.A., Barraza, V., 2003. The hormonal costs of subtle forms of infant maltreatment. Hormones and Behavior 43 (1), 237–244. Buss, A.H., Durkee, A., 1957. An inventory for assessing different kinds of hostility. Journal of Consulting Psychology 21, 343–349. Canetti, L., Bachar, E., Galili-Weisstub, E., De-Nour, A.K., Shalev, A.Y., 1997. Parental bonding and mental health in adolescence. Adolescence 32 (126), 381–394. Castrogiovanni, P., Maremmani, I., Di Muro, A., 1993. Aggressive behaviour and hostility in depression: clinical aspects. In: Placidi, G.F., Dell’Osso, L., Nistico`, G., Akiskal, H.S. (Eds.), Recurrent Mood Disorders. Springer, Berlin, Heidelberg, pp. 51–65. Chambers, J.A., Power, K.G., Loucks, N., Swanson, V., 2000. Psychometric properties of the Parental Bonding Instrument and its association with psychological distress in a group of incarcerated young offenders in

609

Scotland. Social Psychiatry and Psychiatric Epidemiology 35 (7), 318– 325. Comings, D.E., Blum, K., 2000. Reward deficiency syndrome: genetic aspects of behavioral disorders. Progress in Brain Research 126, 325–341. Derogatis, L.R., 1992. SCL-90-R: Administration, Scoring and Procedure Manual—II. Clinical Psychometric Research, Baltimore, MD. Di Chiara, G., Bassareo, V., Fenu, S., De Luca, M.A., Spina, L., Cadoni, C., Acquas, E., Carboni, E., Valentini, V., Lecca, D., 2004. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47 (Suppl. 1), 227–241. Duval, F., Mokrani, M.C., Monreal-Ortiz, J.A., Fattah, S., Champeval, C., Schulz, P., Macher, J.P., 2006. Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: dopaminergic, noradrenergic and thyroid correlates. Psychoneuroendocrinology 31 (7), 876– 888. Fava, M., Guaraldi, G.B., Mazzi, F., Rigatelli, M., 1993. Intervista Clinica Strutturata per il DSM-III-R. Organizzazioni Speciali, Florence. Fulton, M.K., Kramer, G., Moeller, F.G., Chae, Y., Isbell, P.G., Petty, F., 1995. Low plasma homovanillic acid levels in recently abstinent alcoholic men. American Journal of Psychiatry 152 (12), 1819–1820. Geracioti Jr., T.D., West, S.A., Baker, D.G., Hill, K.K., Ekhator, N.N., Wortman, M.D., Keck Jr., P.E., Norman, A.B., 1999. Low CSF concentration of a dopamine metabolite in tobacco smokers. American Journal of Psychiatry 156 (1), 130–132. Gerra, G., Zaimovic, A., Giucastro, G., Folli, F., Maestri, D., Tessoni, A., Avanzini, P., Caccavari, R., Bernasconi, S., Brambilla, F., 1998. Neurotransmitter-hormonal responses to psychological stress in peripubertal subjects: relationship to aggressive behavior. Life Science 62 (7), 617– 625. Gerra, G., Baldaro, B., Zaimovic, A., Moi, G., Bussandri, M., Raggi, M.A., Brambilla, F., 2003a. Neuroendocrine responses to experimentally induced emotions among abstinent opioid-dependent subjects. Drug and Alcohol Dependence 71 (1), 25–35. Gerra, G., Bassignana, S., Zaimovic, A., Moi, G., Bussandri, M., Caccavari, R., Brambilla, F., Molina, E., 2003b. Hypothalamic–pituitary–adrenal axis responses to stress in subjects with 3,4-methylenedioxy-methamphetamine (‘ecstasy’) use history: correlation with dopamine receptor sensitivity. Psychiatry Research 120 (2), 115–124. Gerra, G., Angioni, L., Zaimovic, A., Moi, G., Bussandri, M., Bertacca, S., Santoro, G., Gardini, S., Caccavari, R., Vicoli, M.A., 2004a. Substance use among high-school students: relationships with temperament, personality traits, and parental care perception. Substance Use & Misuse 39 (2), 345– 367. Gerra, G., Zaimovic, A., Moi, G., Bussandri, M., Bubici, C., Mossini, M., Raggi, M.A., Brambilla, F., 2004b. Aggressive responding in abstinent heroin addicts: neuroendocrine and personality correlates. Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (1), 129–139. Gerra, G., Zaimovic, A., Garofano, L., Ciusa, F., Moi, G., Avanzini, P., Talarico, E., Gardini, F., Brambilla, F., Manfredini, M., Donnini, C., 2007. Perceived parenting behavior in the childhood of cocaine users: relationship with genotype and personality traits. American Journal of Medical Genetics B: Neuropsychiatric Genetics 144 (1), 52–57. Goeders, N.E., 1997. A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology 22 (4), 237–259. Goeders, N.E., 2002. Stress and cocaine addiction. Journal of Pharmacology and Experimental Therapeutics 301 (3), 785–789. Gold, P.W., Loriaux, D.L., Roy, A., Kling, M.A., Calabrese, J.R., Kellner, C.H., Nieman, L.K., Post, R.M., Pickar, D., Gallucci, W., Avgerinos, P., Paul, S., Oldfield, E.H., Cutler, G.B., Chrousos, G.P., 1986. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease: pathophysiologic and diagnostic implications. New England Journal of Medicine 314, 1329–1335. Grant, J.E., Kim, S.W., 2002. Parental bonding in pathological gambling disorder. Psychiatric Quarterly 73 (3), 239–247. Heim, C., Newport, D.J., Heit, S., Graham, Y.P., Wilcox, M., Bonsall, R., Miller, A.H., Nemeroff, C.B., 2000. Pituitary—adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284 (5), 592–597.

610

G. Gerra et al. / Neuroscience and Biobehavioral Reviews 33 (2009) 601–610

Holsboer, F., Gerken, A., von Bardeleben, U., Grimm, W., Beyer, H., Muller, O.A., Stella, G.K., 1986. Human corticotropin-releasing hormone in depression. Biological Psychiatry 21, 601–611. Holsboer, F., Lauer, C.J., Schreiber, W., Krieg, J.C., 1995. Altered hypothalamic–pituitary–adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology 62, 340–347. Huot, R.L., Gonzalez, M.E., Ladd, C.O., Thrivikraman, K.V., Plotsky, P.M., 2004. Foster litters prevent hypothalamic–pituitary–adrenal axis sensitization mediated by neonatal maternal separation. Psychoneuroendocrinology 29 (2), 279–289. Hyman, S.M., Garcia, M., Sinha, R., 2006. Gender specific associations between types of childhood maltreatment and the onset, escalation and severity of substance use in cocaine dependent adults. Am J Drug Alcohol Abuse 32 (4), 655–664. Joyce, P.R., Sellman, D., Wells, E., Frampton, C.M., Bushnell, J.A., OakleyBrowne, M., Hornblow, A.R., 1994. Parental bonding in men with alcohol disorders: a relationship with conduct disorder. Australian and New Zealand Journal of Psychiatry 28 (3), 405–411. Kirschbaum, C., Pirke, K.M., Hellhammer, D.H., 1993. The Trier Social Stress Test—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 28, 76–81. Kish, S.J., Kalasinsky, K.S., Derkach, P., Schmunk, G.A., Guttman, M., Ang, L., Adams, V., Furukawa, Y., Haycock, J.W., 2001. Striatal dopaminergic and serotonergic markers in human heroin users. Neuropsychopharmacology 24 (5), 561–567. Kohnke, M.D., Wiatr, G., Kolb, W., Kohnke, A.M., Schick, S., Lutz, U., Vonthein, R., Gaertner, I., 2003. Plasma homovanillic acid: a significant association with alcoholism is independent of a functional polymorphism of the human catechol-O-methyltransferase gene. Neuropsychopharmacology 28 (5), 1004–1010. Krishnan, K.R.R., Rayasam, K., Reed, D.R., Smith, M., Chappell, P., Saunders, W.B., Ritchie, J.C., Carroll, B.J., Nemeroff, C.B., 1993. The corticotropinreleasing factor stimulation test in patients with major depression: relationship to dexamethasone suppression test results. Depression 1, 133–136. Lancaster, G., Rollinson, L., Hill, J., 2007. The measurement of a major childhood risk for depression: Comparison of the Parental Bonding Instrument (PBI) ‘Parental Care’ and the Childhood Experience of Care and Abuse (CECA) ‘Parental Neglect’ Journal of Affective Disorder (Epub ahead of print). Maccoby, E.E., 2000. Parenting and its effects on children: on reading and misreading behavior genetics. Annual Review of Psychology 51, 1–27. Maffei, C., Fossati, A., Agostoni, I., Barraco, A., Bagnato, M., Deborah, D., Namia, C., Novella, L., Petrachi, M., 1997. Interrater reliability and internal consistency of the structured clinical interview for DSM-IV axis II personality disorders (SCID-II), version 2.0. Journal of Personality Disorder Fall 11 (3), 279–284. McEwen, B.S., 2000. Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 22 (2), 108–124. Mitani, H., Shirayama, Y., Yamada, T., Kawahara, R., 2006. Plasma levels of homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed patients. Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (3), 531–534. Moran, P.B., Vuchinich, S., Hall, N.K., 2004. Associations between types of maltreatment and substance use during adolescence. Child Abuse & Neglect 28 (5), 565–574. Narita, T., Sato, T., Hirano, S., Gota, M., Sakado, K., Uehara, T., 2000. Parental child-rearing behavior as measured by the Parental Bonding Instrument in a Japanese population: factor structure and relationship to a lifetime history of depression. Journal of Affective Disorders 57 (1–3), 229–234. Newcomb, M.D., Felix-Ortiz, M., 1992. Multiple protective and risk factors for drug use and abuse: cross-sectional and prospective findings. Journal of Personality and Social Psychology 63 (2), 280–296. Nicolson, N.A., 2004. Childhood parental loss and cortisol levels in adult men. Psychoneuroendocrinology 29 (8), 1012–1018.

Oswald, L.M., Wong, D.F., McCaul, M., Zhou, Y., Kuwabara, H., Choi, L., Brasic, J., Wand, G.S., 2005. Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine. Neuropsychopharmacology 30 (4), 821–832. Parker, G., Tupling, H., Brown, L.B., 1979. A parental bonding instrument. British Journal of Medical Psychology 52, 1–10. Parker, K.J., Schatzberg, A.F., Lyons, D.M., 2003. Neuroendocrine aspects of hypercortisolism in major depression. Hormones and Behavior 43 (1), 60–66. Petraitis, J., Flay, B.R., Miller, T.Q., 1995. Reviewing theories of adolescent substance use: organizing pieces in the puzzle. Psychological Bulletin 117 (1), 67–86. Pfohl, B., Blum, N., Zimmerman, M., Stangl, D., 1989. Structured Interview for Personality Disorders, revised version. University of Iowa, Iowa City, IA. Rao, U., Ryan, N.D., Dahl, R.E., Birmaher, B., Rao, R., Williamson, D.E., Perel, J.M., 1999. Factors associated with the development of substance use disorder in depressed adolescents. Journal of the American Academy of Child and Adolescent Psychiatry 38 (9), 1109–1117. Roy, A., 2002. Self-rated childhood emotional neglect and CSF monoamine indices in abstinent cocaine-abusing adults: possible implications for suicidal behavior. Psychiatry Research 112 (1), 69–75. Saracino, M.A., Mandrioli, R., Mercolini, L., Ferranti, A., Zaimovic, A., Leonardi, C., Raggi, M.A., 2006. Determination of homovanillic acid (HVA) in human plasma by HPLC with coulometric detection and a new SPE procedure. Journal of Pharmaceutical and Biomedical Analysis 42 (1), 107–112. Sarnyai, Z., 1998. Neurobiology of stress and cocaine addiction. Studies on corticotropin-releasing factor in rats, monkeys, and humans. Annals of the New York Academy of Sciences 851, 371–387. Schluger, J.H., Borg, L., Ho, A., Kreek, M.J., 2001. Altered HPA axis responsivity to metyrapone testing in methadone maintained former heroin addicts with ongoing cocaine addiction. Neuropsychopharmacology 24 (5), 568–575. Schweitzer, R.D., Lawton, P.A., 1989. Drug abusers’ perceptions of their parents. British Journal of Addiction 84 (3), 309–314. Scinto, A., Marinangeli, M.G., Kalyvoka, A., Daneluzzo, E., Rossi, A., 1999a. The use of the Italian version of the Parental Bonding Instrument (PBI) in a clinical sample and in a student group: an exploratory and confirmatory factor analysis study. Epidemiologia e Psichiatria Sociale 8 (4), 276–283. Scinto, A., Marinangeli, M.G., Kalyvoka, A., Daneluzzo, E., Rossi, A., 1999b. The use of the Italian version of the Parental Bonding Instrument (PBI) in a clinical sample and in a student group: an exploratory and confirmatory factor analysis study. Epidemiologia e Psichiatria Sociale 8 (4), 276–283. Sher, L., 2006. Combined dexamethasone suppression-corticotropin-releasing hormone stimulation test in studies of depression, alcoholism, and suicidal behavior. Scientific World Journal 6, 1398–1404. Sher, L., Oquendo, M.A., Li, S., Huang, Y.Y., Grunebaum, M.F., Burke, A.K., Malone, K.M., Mann, J.J., 2003. Lower CSF homovanillic acid levels in depressed patients with a history of alcoholism. Neuropsychopharmacology 28 (9), 1712–1719. Spitzer, R.L., Williams, J.B.W., Gibbon, M., First, M.B., 1990. Structured Clinical Interview according to DSM-III-R. American Psychiatric Press, Washington, DC and London, England. Teicher, M.H., Andersen, S.L., Polcari, A., Anderson, C.M., Navata, C.P., 2002. Developmental neurobiology of childhood stress and trauma. Psychiatric Clinics of North America 25 (2), 397–426. Torresani, S., Favaretto, E., Zimmermann, C., 2000. Parental representations in drug-dependent patients and their parents. Comprehensive Psychiatry 41 (2), 123–129. Virkkunen, M., Eggert, M., Rawlings, R., Linnoila, M., 1996. A prospective follow-up study of alcoholic violent offenders and fire setters. Archives of General Psychiatry 53 (6), 523–529. Widom, C.S., DuMont, K., Czaja, S.J., 2007. A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up. Archives of General Psychiatry 64 (1), 49–56.