Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia

Roth, Bryan L.; Sheffler, Douglas J.; Kroeze, Wesley K.

doi:10.1038/nrd1346

Cited by 1,074 publications

(927 citation statements)

References 55 publications

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“…Indeed, the medications that have proven successful for treating schizophrenia/psychosis are drugs that primarily antagonize D 2 receptors [76,358]; however, most clinically effective antipsychotics also exhibit a myriad of other actions that contribute to both therapeutic and side-effect profiles [359,360]. …”

Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

254

207

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This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

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Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

254

207

View full text Add to dashboard Cite

show abstract

“…Because antipsychotic drugs bind to at least 50 distinct molecular targets 15 -each of which has numerous variants -it is essentially impossible to predict a priori which particular drug-variant response is likely to be involved in a particular drug response. As we have clearly demonstrated in the current study, even polymorphisms predicted to induce relatively trivial changes in the overall three-dimensional structure of a given molecular target (T25N for instance) can have unpredictably substantial effects on a given drug's in vitro pharmacology.…”

Section: Differential Pharmacology Of 5-ht 2a Snpsmentioning

confidence: 99%

“…Accordingly, we have begun a comprehensive survey of atypical antipsychotic drug actions at various polymorphic GPCRs implicated in antipsychotic drug actions as a prelude to clinical trials aimed at elucidating the effects of various SNPs on antipsychotic drug responses. In this, our initial survey, we have focused on the serotonin 5-HT 2A receptor because it is a major molecular target for many atypical antipsychotic drugs and some antidepressants, 3,15 as well as classical hallucinogens like LSD and psilocybin [16][17][18][19] that mimic and exacerbate psychotic symptoms.…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

et al. 2005

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The 5-HT 2A -serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT 2A -serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT 2A -serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT 2A receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.

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“…Although the precise molecular mechanisms mediating the atypical antipsychotic profile of clozapine are still unknown, it is likely that both antagonist and agonist actions of the drug and its metabolite(s) at multiple neurotransmitter receptor systems may be involved (Roth et al, 2004). As NDMC is less characterized than its parent compound, the understanding of the role of NDMC in the therapeutic activity of clozapine requires the definition of its whole spectrum of pharmacological activities and molecular targets.…”

Section: Introductionmentioning

confidence: 99%

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

Onali

Olianas

2006

Neuropsychopharmacol

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The present study examined the effects of N-desmethylclozapine (NDMC), a biologically active metabolite of the atypical antipsychotic clozapine, at cloned human opioid receptors stably expressed in Chinese hamster ovary (CHO) cells and at native opioid receptors present in NG108-15 cells and rat brain. In CHO cells expressing the d-opioid receptor (CHO/DOR), NDMC behaved as a full agonist both in stimulating [ 35 S]GTPgS binding (pEC 50 ¼ 7.24) and in inhibiting cyclic AMP formation (pEC 50 ¼ 6.40). NDMC inhibited [ 3 H]naltrindole binding to CHO/DOR membranes with competition curves that were modulated by guanine nucleotides in an agonistlike manner. Determination of intrinsic efficacies by taking into consideration both the maximal [ 35 S]GTPgS binding stimulation and the extent of receptor occupancy at which half-maximal effect occurred indicated that NDMC had an efficacy value equal to 82% of that of the full d-opioid receptor agonist DPDPE, whereas clozapine and the other clozapine metabolite clozapine N-oxide displayed much lower levels of agonist efficacy. NDMC exhibited poor agonist activity and lower affinity at the k-opioid receptor and was inactive at m-opioid and NOP receptors. In NG108-15 cells, NDMC inhibited cyclic AMP formation and stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 by activating the endogenously expressed d-opioid receptor. Moreover, in membranes of different brain regions, NDMC stimulated [ 35 S]GTPgS binding and regulated adenylyl cyclase activity and the effects were potently antagonized by naltrindole. These data demonstrate for the first time that NDMC acts as a selective and efficacious d-opioid receptor agonist and suggest that this unique property may contribute, at least in part, to the clinical actions of the atypical antipsychotic clozapine. Neuropsychopharmacology (2007) 32, 773-785.

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Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia

Cited by 1,074 publications

References 55 publications

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

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