Dual diagnosis: A treatment model for substance abuse and major mental illness

The treatment of dual diagnosis, co-occurring substance abuse and mental illness, calls for addressing two serious and often confounding problems. The authors introduce an expanded version of the transtheoretical model of change as formulated by J.O. Prochaska and C.C. DiClemente, and suggest that this new version offers a pragmatic approach to the conceptualization and treatment of dual diagnosis. The potential utility of the treatment model is presented through the authors' experiences in working with inner-city, chronic mentally ill individuals with substance abuse problems. Practical guidelines for dual diagnosis group therapy are discussed.Dr. Brady is an assistant research professor at the Boston University School of Medicine and the deputy superintendent for research and training at the Dr. Solomon Carter Fuller Mental Health Center. Drs. Hiam, Saemann, Humbert, Fleming and Brickhouse were senior members of the clinical/administrative staff at the Fuller MHC.     

Cocaine's effects on speech sound identification and reaction times in baboons

The effects of cocaine on speech sound discriminations was examined to determine whether cocaine's previously demonstrated effect in reducing speech sound discriminability was dependent upon either the type of stimuli employed (simple tones versus complex speech) or the procedure (stimulus detection versus stimulus discrimination). Because of demonstrated similarities in the way that baboons and humans discriminate speech, and in the way the CNS is thought to encode and process speech sounds in these two species, baboons were trained to perform a choice procedure to identify the occurrence of different synthetic vowel sounds (/a/, /æ/, //, /U/, and /љ/). Animals held down a lever and released the lever only when one of four target vowels sounded, and not when a fifth, standard vowel sounded. Acute IM administration of cocaine (0.0032–1.0 mg/kg) produced dose-dependent decreases in vowel discriminability that were mostly due to elevations in false alarms (i.e., releases to the standard vowel) following cocaine. Cocaine also shortened reaction times to the stimuli in two of three baboons, but to a much lesser extent than observed previously. These results suggest that cocaine may interfere with the ability of the CNS to process the acoustic cues in speech sounds, and that the effects of cocaine on reaction times may depend upon the complexity of the reaction time procedure employed.     

Progressive-ratio performance maintained by drug infusions: Comparison of cocaine,diethylpropion, chlorphentermine,and fenfluramine

Cocaine, diethylpropion, chlorphentermine, and fenfluramine were compared on a drug-maintained progressive-ratio procedure in baboons. Intravenous infusions of drug were contingent on completion of a fixed-ratio response requirement (fixed number of lever-press responses) with a 3-h time-out period following each infusion. Prior to testing each dose of drug, stable self-infusion performance was first established with 0.4 mg/kg cocaine when the fixed-ratio requirement was 160. Subsequently, a test dose of drug was substituted for the standard dose of cocaine. If the dose of drug maintained a criterion level of self-infusion performance (six or more infusions per day for 2 days), the ratio requirement was systematically increased every day until the breaking point at which the self-infusion performance fell below a criterion level (one or zero infusionsper day). Fenfluramine did not maintain criterion self-infusion performance at any dose tested (0.02–5.0 mg/kg). The dose ranges of the other drugs that maintained maximum breaking points were 1.0–5.6 mg/kg for chlorphentermine, 1.0–3.0 mg/kg for diethylpropion, and 0.1–0.4 mg/kg for cocaine. Within-animal comparison of the maximum breaking points indicated that cocaine maintained the highest breaking points, followed in order by diethylpropion, chlorphentermine, and fenfluramine. The rank ordering of these drugs with the breaking point measure corresponds well with both the results of other animal experiments on measurement of reinforcing efficacy of these drugs and with the clinical information about the human subjective effects and abuse of these drugs.     

The effects of Δ9-tetrahydrocannabinol alone and in combination with cannabidiol on fixed-interval performance in rhesus monkeys

It has been reported that cannabidiol (CBD) antagonizes the effects of ⁹-tetrahydrocannabinol (THC) on operant behavior in rats and pigeons. We have replicated this finding with rhesus monkeys. Four rhesus monkeys were trained to lever press on a fixedinterval 5-min schedule of food presentation with a 1-min limited hold and 1-min time out between successive intervals. The effects of 0.3 and 1.0 mg/kg THC alone were determined three times during the experiment; before the CBD-THC interaction, after the CBD-THC interaction and once with the CBD vehicle. A dose of 30 mg/kg CBD, which alone resulted in a 24% reduction in responding, completely antagonized the response rate reduction produced by 0.3 mg/kg THC. The effects of THC revealed a rate-dependent effect that did not conform to the log-linear rate-dependency plots described for most other drugs.This research was reported at the FASEB Meeting in Atlantic City, NJ in 1978 [Fed. Proc. 37: 739 (Abs.) 1978]     

Inhibition of ferrochelatase and accumulation of porphyrins in mouse hepatocyte cultures exposed to porphyrinogenic chemicals

The ability of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), 3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (EDDC) and griseofulvin to induce porphyria in primary cultures of mouse hepatocytes has been examined. Exposure of cultured mouse hepatocytes to DDC, EDDC or griseofulvin resulted in a marked inhibition of ferrochelatase which was sustained over the 4-day exposure period. Maximal concentrations of DDC (25 M), EDDC (25 M) and griseofulvin (25 M) resulted in 14-fold, 30-fold and 9-fold increases, respectively, in total porphyrin in the culture medium. Analysis of the porphyrins accumulating indicated a predominance of protoporphyrin with all three xenobiotics. Addition of 5-aminolaevulinic acid (ALA) to mouse hepatocyte cultures (10–1000 M) resulted in much larger increases (up to 164-fold) in porphyrin accumulation in the medium and the porphyrin accumulating was predominantly uroporphyrin. These studies have demonstrated that primary cultures of mouse hepatocytes provide a valid mechanism-based in vitro model of the hepatic porphyrias produced by the dihydropyridines and griseofulvin in mice.     

Limited capacity for the removal of O6-methylguanine and its regeneration in a human lymphoma line

The Raji human lymphoma line is able to remove O⁶-methylguanine(O⁶MeG) lesions introduced by treatment of cells with N-methyl-N'-nitro-N-nitroso-guanidine(MNNG). The reaction has a rapid phase in which 40% of theO⁶MeG is removed in the first 10 min. The capacity of cellsfor rapid O⁶MeG removal is limited and is saturated at concentrationsof MNNG which do not saturate the systems removing 3-methyladenine.Pretreatment of cells with MNNG inhibits their ability to removeO⁶MeG produced by a subsequent dose given after 2 h. Treatmentwith N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) is effectivein diminishing cellular capacity for O⁶MeG removal, and cellsunable to remove O⁶MeG and sensitive to the cytotoxic effectsof MNNG are also more sensitive to ENNG than their removal competentcounterparts. Regeneration of the ability to remove O⁶MeG requiresincubation of cells for periods > 24 h. The O⁶MeG removalsystem is similar to that found in adapted Escherichia colialthough the capacity of the Raji lymphoma line is much lowerthan that of the induced bacteria per unit of DNA.     

Local secretion of a chimeric anti-CD4 antibody protects against graft rejection in the NOD mouse

BACKGROUND: Engineering a graft to secrete its own immunosuppressive antibodies may minimize the risks associated with current high dose systemic immunosuppression. METHODS AND RESULTS: A beta cell insulinoma cell line (NIT-1) was transfected with genes encoding a chimeric anti-CD4 antibody. The NIT-1 cells secreted functional chimeric anti-CD4 antibody that bound to the CD4 molecule on mouse thymocytes and inhibited in vitro proliferation of CD4+ve T cells. Both test and control transfected cell lines grew at a similar rate in immunodeficient mice. In immunocompetent NOD mice, NIT-1 cells are normally rejected by a cellular immune response against the SV40 T antigen. Although control transfected NIT-1 cells were rapidly rejected by NOD mice, anti-CD4 secreting NIT-1 cells grew significantly better and were able to form tumors at the site of injection. CONCLUSIONS: The local secretion of chimeric anti-CD4 antibody from transfected cells can contribute to graft survival in our transplantation model.     

Effect of a cognitive behavioral intervention on reducing symptom severity during chemotherapy.

PURPOSE: To describe a randomized trial of a cognitive behavioral intervention on reducing symptom severity among patients diagnosed with solid tumors and undergoing a first course of chemotherapy and to determine whether the intervention had an additive or interactive effect on symptom severity in the presence of supportive care medications. PATIENTS AND METHODS: Patients (N = 237) were accrued from comprehensive and community cancer centers, interviewed, and randomly assigned to either the experimental intervention (n = 118) or conventional care (n = 119). A symptom severity index, based on summed severity scores across 15 symptoms, was the primary outcome. Each patient's site of cancer, stage at diagnosis, chemotherapy protocols, and use of supportive medications were learned from medical records. RESULTS: Groups were equivalent at baseline, and attrition by characteristics by group was not different. The proportion of patients not receiving chemotherapy at 10 and 20 weeks did not differ by group. At the 10- and 20-week observations, there was a significant interaction between the experimental group and baseline symptom severity. Patients in the experimental group who entered the trial with higher symptom severity reported significantly lower severity at 10 and 20 weeks. Controlling for chemotherapy treatment status at follow-up and supportive care medications did not alter the effect of the experimental intervention. CONCLUSION: Compared with conventional care alone, the experimental intervention was effective among patients who entered the trial with higher levels of symptom severity. Age, sex, site or stage of cancer, and supportive medications did not modify the effect of this cognitive behavioral intervention on symptom severity.     

Additive efficacy of CTLA4Ig and OX40Ig secreted by genetically modified grafts

BACKGROUND: The use of systemic immunosuppressive drugs have been paramount in the success in transplantation, but there are serious deleterious effects. Genetic modification of grafts to secrete immunomodulators locally may be a way to reduce the need for systemic immunosuppression. METHODS AND RESULTS: An insulinoma cell line, NIT, having the nonobese diabetic (NOD) genotype but also expressing the SV40 large T Ag, was transfected with CTLA4Ig or OX40Ig in an attempt to block signals in the costimulatory/adhesion pathways. The extracellular domains of these molecules have been fused to the Fc of IgG2c derived from the NOD mouse strain. This resulted in secreted and dimerized proteins. SV40 T Ag is potent at inducing graft rejection. Test and control transfectants were transplanted subcutaneously into young NOD mice to determine whether secretion of CTLA4Ig and OX40Ig would promote survival of the insulinoma graft. In immunodeficient mice, cell growth was similar for all transfectants. However, in immunocompetent NOD mice, the survival/growth of test grafts was significantly better than that of controls. By combining test transfectants, we found that graft survival was enhanced in an additive and significant fashion. In vitro, there was a significant reduction in immune responses-compared with control-when purified fusion proteins were added to mixed leukocyte reaction cultures. CONCLUSIONS: We conclude that blockade of individual costimulatory/adhesion signals by graft manipulation can contribute to transplantation success and that blockade of combinations of signals in these pathways enhances this success. Successful immunomodulation by the graft itself can be achieved.