Effects of morphine administration and its withdrawal on rat brain aminopeptidase activities

The endogenous opioid neuropeptide system seems to be involved in the neural processes which underlie drug addiction. Several studies have reported that the administration of morphine induces changes in the levels and/or activity of endogenous opioid peptides (enkephalin, dynorphin) and their precursors in specific brain regions of the adult CNS. The aim of this work was to study the effects of chronic morphine exposure and its withdrawal on certain aminopeptidases capable of degrading opioid peptides in brain areas including the amygdala, hypothalamus, hippocampus, striatum and brain cortices. In animals treated with morphine, aminopeptidase N presented higher enzyme activity levels in the striatum, the hypothalamus and the amygdala compared to control animals, although statistically significant differences were observed only in the case of the striatum. In addition, the activity of soluble puromycin-sensitive aminopeptidase (PSA) was found to be higher in the frontal cortex of these rats. In contrast, rats experiencing withdrawal symptoms presented decreased levels of aminopeptidase activity in certain brain areas. Thus, the activity of aminopeptidase N in the hippocampus and soluble puromycin-sensitive aminopeptidase in the frontal cortex were found to be lower in rats experiencing naloxone precipitated withdrawal symptoms, compared to the corresponding controls. Finally, the activity of the three studied aminopeptidases in vitro was unaltered by incubation with morphine, suggesting that the observed effects are not due to a direct action of this opioid upon the aminopeptidases. The results of the present report indicate that aminopeptidases may play an important role in the processes of tolerance and withdrawal associated with morphine administration.     

Multiple 100 Hz electroacupuncture treatments produced cumulative effect on the suppression of morphine withdrawal syndrome: Central preprodynorphin mRNA and p-CREB implicated

Alleviating opiate withdrawal syndrome in addicts is a critical precondition to break away from drug and further to prevent reuse. Electroacupuncture (EA) was claimed to be effective for alleviating withdrawal syndrome, but the optimal protocol remained unclear. In the present study we found that (1) 100 Hz EA administered 12-24 h after the last morphine injection suppressed the withdrawal syndrome in rats, multiple sessions of EA were more effective than single session, with the after-effect lasting for at least 7 days. (2) A down-regulation of preprodynorphin (PPD) mRNA level was observed in spinal cord, PAG and hypothalamus 60 h after the last morphine injection, which could be reversed by multiple sessions, but not a single session of EA. (3) Accompanied with the decrease of PPD mRNA level, there was an up-regulation of p-CREB in the three CNS regions, which was abolished by 100 Hz EA treatment. The findings suggest that down-regulation of p-CREB and acceleration of dynorphin synthesis in spinal cord, PAG and hypothalamus may be implicated in the cumulative effect of multiple 100 Hz EA treatment for opioid detoxification.     

Chronic morphine treatment and withdrawal increase extracellular levels of norepinephrine in the rat bed nucleus of the stria terminalis

Extracellular levels of norepinephrine (NE) and glutamate (Glu) in the ventral bed nucleus of the stria terminalis (vBNST) of saline- and chronic morphine-treated rats, with or without withdrawal, were studied by means of the in vivo microdialysis technique in anesthetized rats. In addition, the tissue concentration of NE was studied at different rostrocaudal levels of the vBNST. Chronic morphine treatment significantly increased extracellular levels of NE, but not Glu, in vBNST. At 48 h after naloxone-induced morphine withdrawal there was a further significant increase in the extracellular levels of NE, but not Glu, in vBNST. The presence of UK 14304, an alpha(2)-adrenergic agonist, induced a significant decrease in NE extracellular levels in all experimental groups. In contrast, UK 14304 induced a significant decrease in Glu extracellular levels only in saline-treated rats. The results also show that the vBNST presents a rostrocaudal gradient of NE and contains 9.4% of total brain NE. The increase in NE extracellular levels in vBNST induced by chronic morphine treatment and the further increase in NE levels 48 h after naloxone-induced morphine withdrawal suggest that NE in vBNST may be involved in the pharmacological effects of chronic morphine and withdrawal.     

Up-regulation of central mu-opioid receptors in a model of hepatic encephalopathy: a potential mechanism for increased sensitivity to morphine in liver failure

Increased GABA-mediated neurotransmission, reported to occur in hepatic encephalopathy (HE), is associated with a decrease in the release of Met-enkephalin and the expression of its coding gene in the brain. Furthermore, patients with cirrhosis and a history of HE exhibit increased sensitivity to the neuroinhibitory effects of morphine. Thus, there is a rationale to study the status of the endogenous opioid system in HE. The aim of this study was to determine whether mu-opioid receptors in the brain are up-regulated in a well characterized model of HE. Binding parameters of mu-opioid receptors were derived by assaying the binding of the opiate agonist [3H]-tyr-D-Ala-Gly-N-Methyl-Phe-Gly-ol (DAMGO) to brain membranes from rats with precisely defined stages of HE and control animals. The mean density of mu-opioid receptor sites (Bmax) in rats with stage II, III, and IV HE was 15, 29, and 33% higher, respectively, than the corresponding control value (p<0.01). In addition, the affinity of mu opioid receptors for the agonist (1/Kd) also increased with progression of HE (mean for stage IV HE vs. corresponding control mean, p<0.01). In conclusion, in liver failure, increased density and affinity of central mu-opioid receptors in the brain may: (i) be the basis for the documented increased sensitivity to opiate agonists; and (ii) occur as a consequence of increased GABAergic tone reducing neuronal synthesis and release of opioid agonist peptides.     

Effects of naloxone-precipitated withdrawal after a single dose of morphine on catecholamine concentrations in guinea-pig brain

The effect of naloxone-precipitated withdrawal after acute morphine was studied on the concentrations of noradrenaline (NA), 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and on the metabolite/parent amine ratios MHPG/NA, DOPAC/DA and HVA/DA, in eight regions of the guineapig brain. Guinea-pigs were treated with a single dose of morphine sulphate (15 mg/kg s.c.) or saline (control) and 2h later with naloxone hydrochloride (15 mg/kg s.c.) to precipitate withdrawal. The animals were decapitated at 0.5 h or 1 h after naloxone injections and their brains analysed for monoamine concentrations by HPLC-ECD. At 0.5 h after naloxone-precipitated withdrawal NA and MHPG levels, and the MHPG/NA ratio, were increased in the hypothalamus, and the NA levels were increased in the hypothalamus, medulla/pons and cortex 1 h after naloxone. Naloxoneprecipitated withdrawal also produced increased DA metabolism in the cortex, midbrain and medulla 0.5 h later, and in the cortex, hypothalamus and striatum 1 h later. Hence naloxone-precipitated withdrawal from acute morphine treatment produced a complex pattern of increased synthesis and metabolism of NA and DA which varied over time and with the brain region examined.     

L-type calcium channel blockade attenuates morphine withdrawal: in vivo interaction between L-type calcium channels and corticosterone

Both opioids and calcium channel blockers could affect hypothalamic-pituitary-adrenal (HPA) axis function. Nifedipine, as a calcium channel blocker, can attenuate the development of morphine dependence; however, the role of the HPA axis in this effect has not been elucidated. We examined the effect of nifedipine on the induction of morphine dependency in intact and adrenalectomized (ADX) male rats, as assessed by the naloxone precipitation test. We also evaluated the effect of this drug on HPA activity induced by naloxone. Our results showed that despite the demonstration of dependence in both groups of rats, nifedipine is more effective in preventing of withdrawal signs in ADX rats than in sham-operated rats. In groups that received morphine and nifedipine concomitantly, naloxone-induced corticosterone secretion was attenuated. Thus, we have shown the involvement of the HPA axis in the effect of nifedipine on the development of morphine dependency and additionally demonstrated an in vivo interaction between the L-type Ca2+ channels and corticosterone.     

Explanatory models of medically unexplained symptoms: a qualitative analysis of the literature

Background Medically unexplained symptoms (MUS) are common in primary health care. Both patients and doctors are burdened with the symptoms that negatively affect patients' quality of life. General practitioners (GPs) often face difficulties when giving patients legitimate and convincing explanations for their symptoms. This explanation is important for reassuring patients and for maintaining a good doctor-patient communication and relationship.Objective To provide an overview of explanatory models for MUS.Study design We performed a systematic search of reviews in PsycINFO and PubMed about explanatory models of MUS. We performed a qualitative analysis of the data according to the principles of constant comparative analysis to identify specific explanatory models.Results We distinguished nine specific explanatory models of MUS in the literature: somatosensory amplification, sensitisation, sensitivity, immune system sensitisation, endocrine dysregulation, signal filter model, illness behaviour model, autonomous nervous system dysfunction and abnormal proprioception. The nine different explanatory models focus on different domains, including somatic causes, perception, illness behaviour and predisposition. We also found one meta-model, which incorporates these four domains: the cognitive behavioural therapy model.Conclusion Although GPs often face difficulties when providing explanations to patients with MUS, there are multiple explanatory models in the scientific literature that may be of use in daily medical practice.     

The life cycle of a connexin: Gap junction formation,removal, and degradation

Gap junction proteins, connexins, possess many properties that are atypical of other well-characterized integral membrane proteins. Oligomerization of connexins into hemichannels (connexons) has been shown to occur after the protein exits the endoplasmic reticulum. Once delivered to the cell surface, connexons from one cell pair with connexons from a neighboring cell, a process that is facilitated by calcium-dependent cell adhesion molecules. Channels cluster into defined plasma membrane domains to form plaques. Unexpectedly, gap junctions are not stable (half-life <5 h) and are thought to be retrieved back into the cell in the form of double membrane structures when one cell internalizes the entire gap junction through endocytosis. Evidence exists for both proteasomal and lysosomal degradation of gap junctions, and it remains possible that both mechanisms are involved in connexin degradation. In addition to opening and closing of gap junction channels (gating), the formation and removal of gap junctions play an essential role in regulating the level of intercellular communication.     

Photoantimicrobials as a potential local approach to geriatric UTIs

Aims: To test the efficacy of acceptable photoantimicrobial agents against bacterial pathogens implicated in complicated urinary tract infection (UTI) in comparison with conventionally employed antibacterials. Methods and Results: Toluidine blue (TB), methylene blue (MB), 5‐aminolaevulinic acid (ALA), trimethoprim and levofloxacin were employed in the study against the typical UTI‐implicated pathogens Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis and Proteus mirabilis. Standard bacterial cell culture was used to assay the activity both in the dark and under 660‐nm LED‐illuminated conditions. TB and MB were highly photoactive across the range and exhibited rapid kill rates, their effects being assayed after 20‐min illumination, rather than the 18‐h incubation employed with the other compounds. Trimethoprim was inactive against all bacteria except Pr. mirabilis, while levofloxacin maintained highly bactericidal activity throughout. ALA required high concentrations for effective action but, for porphyrin production in situ, also required an 18‐h incubation. Conclusions: TB and MB were highly and rapidly photobactericidal in comparison with the remaining agents tested. Significance and Impact of the Study: Ubiquitous catheterization of geriatric patients offers a portal for light delivery to the urinary tract. The photoantimicrobial approach thus offers considerable potential.     

Disruption of the viral polymerase complex assembly as a novel approach to attenuate influenza A virus

To develop a novel attenuation strategy applicable to all influenza A viruses, we targeted the highly conserved protein-protein interaction of the viral polymerase subunits PA and PB1. We postulated that impaired binding between PA and PB1 would negatively affect trimeric polymerase complex formation, leading to reduced viral replication efficiency in vivo. As proof of concept, we introduced single or multiple amino acid substitutions into the protein-protein-binding domains of either PB1 or PA, or both, to decrease binding affinity and polymerase activity substantially. As expected, upon generation of recombinant influenza A viruses (SC35M strain) containing these mutations, many pseudo-revertants appeared that partially restored PA-PB1 binding and polymerase activity. These polymerase assembly mutants displayed drastic attenuation in cell culture and mice. The attenuation of the polymerase assembly mutants was maintained in IFNα/β receptor knock-out mice. As exemplified using a H5N1 polymerase assembly mutant, this attenuation strategy can be also applied to other highly pathogenic influenza A virus strains. Thus, we provide proof of principle that targeted mutation of the highly conserved interaction domains of PA and PB1 represents a novel strategy to attenuate influenza A viruses.     

Morphine metabolism revisited: I. Metabolic activation of morphine to a reactive species in rats

Treatment of fasted rats with relatively high doses of morphine rapidly results in depletion of hepatic glutathione (GSH) content and marked elevation of serum transaminase activity. Such morphine-induced response has been generally attributed to central nervous system mediated effects of the drug. We now report that this response might be due to a direct effect of the drug in the liver. That is, its metabolic activation to reactive electrophilic metabolite(s), by the hepatic cytochrome P-450-dependent mixed function oxidase system. Structure-activity relationships of morphine and its congeners indicate that the (-)-3-hydroxy-N- methylmorphinan moiety is linked with the potential of these opioids to deplete hepatic GSH and to raise serum transaminases in rats.     

Gap junction amplification in rat ovarian granulosa cells: I. A direct response to follicle-stimulating hormone

The ability of follicle-stimulating hormone (FSH), the estrogens, estradiol-17β and diethylstilbestrol, and the estrogen antagonists, clomiphene and enclomiphene citrate to affect the growth and internalization of hypophysectomized rat granulosa cell gap junction membranes was compared in ovarian follicles assigned to one of four follicle size classes (60–149, 150–249, 250–319, and 320–450 μm diameter). In the absence of exogenous hormone stimulation, atresia prevents follicle growth beyond 320 μm in diameter but surface gap junction membrane increases throughout this early follicle growth. Internalization of gap junction membrane is first detected at the 150- to 249-μm follicle stage and also increases with follicle size. Therefore, growth and turnover of gap junction membrane occur at a basal rate in the absence of gonadotropin or steroid hormone stimulation. Estrogen and estrogen antagonist injections result in no significant differences in the amount of surface or internalized junction membrane in the three smallest follicle size classes when compared to the untreated hypophysectomized animals. However, estrogen but not estrogen antagonists rescues growing follicles from atresia and permits their further growth into the 320- to 450-μm follicle size class. As a result of the additional follicle growth, both surface and internalized junction membrane increase beyond that seen in the largest follicles from hypophysectomized animals. In contrast to other treatments, FSH stimulation promotes amplification of gap junction membrane in all size classes and, like estrogen, rescues follicles from atresia and promotes their entry into the 320- to 450-μm follicle size class. Surface gap junction membrane is amplified two- to fourfold over other treatments in the first three follicle size classes, but reaches maximal levels in the 250- to 319-μm follicles. The internalized junction membrane which first appears in the 150- to 249-μm size class is dramatically increased over other treatments in the 250- to 319- and 320- to 450-μm size classes. These studies indicate that exogenous estrogen stimulation promotes gap junction growth indirectly by sustaining the basal rate of junction synthesis in follicles rescued from atresia. In contrast, exogenous FSH stimulation directly amplifies the developmental sequence of gap junction growth and turnover. During early follicle growth, FSH stimulation preferentially promotes increases in surface gap junctions while internalization of surface junctions is increased during later follicle growth.     

Gastrointestinal symptoms in low-dose aspirin users: a comparison between plain and buffered aspirin

Background

Aspirin is associated with gastrointestinal side effects such as gastric ulcers, gastric bleeding and dyspepsia. High-dose effervescent calcium carbasalate (ECC), a buffered formulation of aspirin, is associated with reduced gastric toxicity compared with plain aspirin in healthy volunteers, but at lower cardiovascular doses no beneficial effects were observed.

Aim

To compare the prevalence of self-reported gastrointestinal symptoms between low-dose plain aspirin and ECC.

Methods

A total of 51,869 questionnaires were sent to a representative sample of the Dutch adult general population in December 2008. Questions about demographics, gastrointestinal symptoms in general and specific symptoms, comorbidity, and medication use including bioequivalent doses of ECC (100 mg) and plain aspirin (80 mg) were stated. We investigated the prevalence of self-reported gastrointestinal symptoms on ECC compared with plain aspirin using univariate and multivariate logistic regression analyses.

Results

A total of 16,715 questionnaires (32 %) were returned and eligible for analysis. Of these, 911 (5 %) respondents reported the use of plain aspirin, 633 (4 %) ECC and 15,171 reported using neither form of aspirin (91 %). The prevalence of self-reported gastrointestinal symptoms in general was higher in respondents using ECC (27.5 %) compared with plain aspirin (26.3 %), but did not differ significantly with either univariate (OR 1.06, 95 %CI 0.84–1.33), or multivariate analysis (aOR 1.08, 95 %CI 0.83–1.41). Also, none of the specific types of symptoms differed between the two aspirin formulations.

Conclusions

In this large cohort representative of the general Dutch population, low-dose ECC is not associated with a reduction in self-reported gastrointestinal symptoms compared with plain aspirin.     

Problems in recognizing the self: a neuropsychological approach to the positive symptoms of schizophrenia

This article present a review of recent work on cognitive neuroscience approaches of schizophrenia. Some of the symptoms displayed by schizophrenic patients can be reconsidered within the framework of disorganization of well identified cognitive functions, like self-recognition. Neuroimaging techniques can reveal in these patients disruption of neural networks normally involved in such functions.     

Detecting psychogeriatric problems in primary care: factors related to psychiatric symptoms in older community patients

Objective The aim was to determine the relationship and influence of different variables on the psychiatric symptomatology of older people who reside in the community, as detected by family practitioners.Design A cross-sectional and multi-centre study.Setting Twenty-eight general practices and two psychiatric practices in Huesca, Spain, from 19 primary care health centres.Subjects A sample of 324 patients aged over 65 years, representative of the older people who reside in the community in the province of Huesca.Main outcome measures Symptoms of depression (Yesavage GDS), cognitive impairment (MMSE), anxiety (GADS), psychotic symptoms, obsessive symptoms and hypochondriacal ideas (GMS) were measured by family practitioner and were detected following specific questions from the Geriatric Mental State (GMS-B) examination, following DSM-IV criteria, being defined as 'concern and fear of suffering, or the idea of having a serious disease based on the interpretation of somatic symptoms'. Sociodemographic, physical and somatic, functional and social data were evaluated. Analysis was carried out in three phases: univariate, bivariate and multivariate with logistic regression.Results At the time of the study, 46.1% of the older people studied suffered from some psychiatric symptom; 16.4% had cognitive impairment, 15.7% anxiety, 14.3% depression, 6.1% hallucinations and delusions, 7.2% hypochondriacal ideas and 4.4% obsessive symptoms. Female gender was significantly associated with depression (prevalence ration (PR) 3.3) and anxiety (PR 3.9). Age was a factor associated with cognitive impairment (PR 4.4). Depression was significantly related to severity of the physical illness (PR 61.7 in extremely severe impairment). Isolation (PR 16.3) and being single (PR 13.4) were factors which were strongly associated with anxiety; living in a nursing home was associated with psychotic symptoms (PR 7.6).Conclusions Severity of physical illness, isolation, living in a nursing home and female gender, among others, are related to psychiatric symptoms in community-residing older people identified in primary healthcare centres.     

Bioactivation of free-fat transfers: a potential new approach to improving graft survival.

A new approach to free-fat autotransplantation resorption was evaluated experimentally in a rat animal model. Bioactive fat grafts were created by the addition of basic fibroblast growth factor delivered by dextran beads to the grafts and compared with free fat alone, free fat plus beads, and free fat plus beads and a control solution in the same animal. The grafts were assessed by weight and histology at 1 and 12 months postoperatively in 40 animals. A graded response in weight retention was observed at 1 and 12 months, with the growth factor-treated grafts exhibiting near complete weight maintenance after 1 year. All other bead-containing grafts had an intermediate response, with free fat alone averaging more than one-half graft weight loss after 1 year. Histologically, the bead-containing grafts had good fibroblastic ingrowth, but extensive intercellular collagen formation and the occurrence of small-sized adipocytes among the larger adipocytes were seen only in the growth factor-treated grafts. These findings indicate that graft manipulations that affect the preadipocyte cells of the graft or fibroblastic components of the recipient site, either through polypeptide stimulation or surface charge attraction, may offer a viable approach to postoperative fat-graft volume maintenance.     

Behavioural and psychological symptoms of dementia in primary care: a survey of general practitioners in Ireland

Background Management of neuropsychiatric symptoms is a challenging task in primary care. Aims To assess self-reported confidence and knowledge of general practitioners (GPs) regarding the identification and management of behavioural and psychological symptoms of dementia (BPSD).Methods A self-designed two-page paper questionnaire was sent to a random sample of 160 GPs practising in north Dublin. They were asked to evaluate their confidence and knowledge on several aspects of diagnosis and management of BPSD.Results Completed questionnaires were returned from 109 GPs (response rate = 68%), of which 106 were usable. In general, GPs were somewhat critical of their self-reported skills in diagnosing (76.4%) and managing (77.4%) BPSD, as well as in discriminating BPSD from other behavioural disturbances (71.7%). Many of them (67.9%) also encountered difficulty accessing specialist services. There was no correlation between demographic characteristics of GPs or patient caseload with respect to their responses to questionnaire items. Although many GPs (92.5%) highly valued the important role of non-pharmacological interventions in BPSD, none of them reported recommending these in their daily practice.Conclusions Despite the fact that GPs have a wealth of knowledge about BPSD, they are largely critical of their knowledge and management skills of these symptoms. Efforts should be focused on supporting GPs by means of educational interventions that consider all aspects of dementia, but additionally highlight the more challenging neuropsychiatric components of the illness. Health services need to be structured in a way that promotes collaboration between GPs and mental health professionals for a seamless delivery of care.     

Membrane-perturbing activity of Viperidae myotoxins: an electrostatic surface potential approach to a puzzling problem

Phospholipase-like myotoxins are a class of proteins present in Viperidae venom. Despite the high level of amino acid and structural homology with soluble phospholipases A(2), myotoxins are devoid of enzymatic activity and share cytolytic activity by means of a totally unknown mechanism involving the lipid bilayer perturbation. The distribution of electrostatic surface potentials of four myotoxins and seven phospholipases A(2) has been compared. The charge distribution is similar in all active non-cytolytic phospholipases with a strongly positive side corresponding to the domain interacting with the micellar substrate and with the opposite side negatively charged. In contrast, all myotoxins examined are positively charged on both sides. Myotoxin III, the only known example of a myotoxin sharing enzymatic activity, displays the same electrostatic surface potential as other related toxins. Using liposomes made with non-hydrolysable phospholipids, we demonstrate that myotoxin III perturbs the lipid bilayer like other myotoxins. Based on these results, a molecular model for myotoxin-membrane perturbing activity is proposed. In this model, potential double-face binding of myotoxic phospholipases A(2) to lipid surfaces could trigger a lipid bilayer destabilization and could generate a stable fusion pore, probably because of the presence of hydrophobic moieties that flank the cationic sites.     

Psychological interventions to reduce positive symptoms in schizophrenia: systematic review and network meta‐analysis

Psychological treatments are increasingly regarded as useful interventions for schizophrenia. However, a comprehensive evaluation of the available evidence is lacking and the benefit of psychological interventions for patients with current positive symptoms is still debated. The present study aimed to evaluate the efficacy, acceptability and tolerability of psychological treatments for positive symptoms of schizophrenia by applying a network meta‐analysis approach, that can integrate direct and indirect comparisons. We searched EMBASE, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Library, World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov for randomized controlled trials of psychological treatments for positive symptoms of schizophrenia, published up to January 10, 2018. We included studies on adults with a diagnosis of schizophrenia or a related disorder presenting positive symptoms. The primary outcome was change in positive symptoms measured with validated rating scales. We included 53 randomized controlled trials of seven psychological interventions, for a total of 4,068 participants receiving the psychological treatment as add‐on to antipsychotics. On average, patients were moderately ill at baseline. The network meta‐analysis showed that cognitive behavioural therapy (40 studies) reduced positive symptoms more than inactive control (standardized mean difference, SMD=?0.29; 95% CI: –0.55 to ?0.03), treatment as usual (SMD=?0.30; 95% CI: –0.45 to ?0.14) and supportive therapy (SMD=?0.47; 95% CI: –0.91 to ?0.03). Cognitive behavioural therapy was associated with a higher dropout rate compared with treatment as usual (risk ratio, RR=0.74; 95% CI: 0.58 to 0.95). Confidence in the estimates ranged from moderate to very low. The other treatments contributed to the network with a lower number of studies. Results were overall consistent in sensitivity analyses controlling for several factors, including the role of researchers’ allegiance and blinding of outcome assessor. Cognitive behavior therapy seems to be effective on positive symptoms in moderately ill patients with schizophrenia, with effect sizes in the lower to medium range, depending on the control condition.