Past and Present Progress in the Pharmacologic Treatment of Schizophrenia

Albert Einstein College of Medicine, New York, New York, United States
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 09/2010; 71(9):1115-24. DOI: 10.4088/JCP.10r06264yel
Source: PubMed


Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.

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    • "chlorpromazine, promethazine and thioridazine. These derivatives have also excellent antipsychotic and antiemetic activities, although they may possibly give rise to serious side effects, such as extrapyramidal symptoms, including akathisia and tardive dyskinesia, hyperprolactinaemia, and the scarce but potentially mortal neuroleptic malignant syndrome as well as substantial weight gain [11] [12] [13]. Moreover, phenothiazine derivatives are employed as inodilator in congestive heart failure, acting upon the phosphodiesterase I; and chlorpromazine and prochlorperazine are especially exploited in emergency rooms to cure migraine and other intractable headaches [14] [15]. "
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    ABSTRACT: Phenothiazine and its derivatives are the most effective antipsychotic drugs. They have been used in the treatment of serious mental and emotional symptoms including bipolar disorder, organic psychoses, psychotic depression and schizophrenia. However, these drugs cause serious side effects such as akathisia, hyperprolactinaemia and neuroleptic malignant syndrome. In this work we investigated the molecular recognition of two typical phenothiazine compounds, phenosafranin and safranin O by the most pivotal heme protein hemoglobin using steady state and time-resolved fluorescence, extrinsic 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescent probe, circular dichroism (CD) along with computational modeling. Results show phenothiazines complex with protein via formation of adducts at 298K with moderate strengths of 3.555×10(4)M(-1) and 2.567×10(4)M(-1) for the hemoglobin-phenosafranin and hemoglobin-safranin O, respectively. We also found phenothiazines were effectors at the protein allosteric site, which affects the allosteric equilibrium. Further, time-resolved fluorescence and hydrophobic ANS experiments showed the static mechanism is dominated for the shrinkage in the fluorescence intensity of β-37 Trp residue at the α1β2 interface. The stoichiometric proportion of the protein-drug adduct is 1:1, as derived from Job's plot. Several crucial noncovalent bonds, including hydrogen bonds, π-π stacking and hydrophobic interactions played a major role in stabilizing the noncovalent conjugates. Based on three-dimensional fluorescence, we concluded that the conformation of hemoglobin is partially destabilized after recognition with phenothiazines. These alterations were confirmed by far-UV CD spectra that showed the α-helix of protein decreased from 78.3% in free hemoglobin to 62.8% and 64.8% in hemoglobin-phenosafranin and hemoglobin-safranin O, respectively. Computer-aided molecular docking was consistent, indicating that both phenothiazines are situated within the pocket composed of α1 and β2 subunits. Affinity of hemoglobin to phenosafranin is superior compared with safranin O. This difference may be explained by the methyl group substituent on A- and C-rings, and by the different molecular volume between phenosafranin and safranin O. Our data provides further explanation of the overall pharmacokinetics of phenothiazines and sheds light on the allosteric regulation of heme proteins. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of photochemistry and photobiology. B, Biology 04/2015; 148:21-30. DOI:10.1016/j.jphotobiol.2015.03.022 · 2.96 Impact Factor
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    • "The onset of schizophrenia is typically in late adolescence or early adulthood, and includes distinctive symptoms, commonly referred to as positive, negative, and cognitive. To date, effective treatments for schizophrenia have been limited to medications with antidopaminergic activity, which alleviate symptoms by augmenting dysfunctional neurotransmitter systems.2 While antipsychotics are most effective for positive symptoms, negative and cognitive symptoms are less well addressed.3 "
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    ABSTRACT: Accumulating evidence suggests that neuroinflammation affecting microglia plays an important role in the etiology of schizophrenia, and appropriate control of microglial activation may be a promising therapeutic strategy for schizophrenia. Minocycline, a second-generation tetracycline that inhibits microglial activation, has been shown to have a neuroprotective effect in various models of neurodegenerative disease, including anti-inflammatory, antioxidant, and antiapoptotic properties, and an ability to modulate glutamate-induced excitotoxicity. Given that these mechanisms overlap with neuropathologic pathways, minocycline may have a potential role in the adjuvant treatment of schizophrenia, and improve its negative symptoms. Here, we review the relevant studies of minocycline, ranging from preclinical research to human clinical trials.
    Neuropsychiatric Disease and Treatment 06/2014; 10:1103-11. DOI:10.2147/NDT.S64236 · 1.74 Impact Factor
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    • "Atypical antipsychotics (also known as second generation antipsychotics, SGAs) have proven effective in the treatment of schizophrenia and schizoaffective disorder yielding improvements in both positive and negative symptoms [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]. Many SGAs are also indicated for the treatment of the different phases of bipolar disorder (BD) (i.e. "
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    ABSTRACT: Aim. To confirm the efficacy and tolerability of ziprasidone as adjunctive therapy in bipolar patients partially responding to clozapine or with persisting negative symptoms, overweight, or with metabolic syndrome. Methods. Eight patients with psychotic bipolar disorder were tested with the BPRS, the HAM-D, and the CGI at T0 and retested after 2 weeks (T1). Plasma clozapine and norclozapine levels and BMI were tested at T0 and T1. Results. Ziprasidone was well tolerated by all the patients. BPRS and HAM-D scores were reduced in all patients. BMI was reduced in patients with a BMI at T0 higher than 25. Plasma levels of clozapine and norclozapine showed an irregular course.
    04/2014; 2014:904829. DOI:10.1155/2014/904829
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