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One of the most remarkable aspects of human homoeostasis is bone remodelling. This term denotes the continuous renewal of bone that takes place at a microscopic scale and ensures that our skeleton preserves its full mechanical compliance during our lives. We propose here that a renewal process of this type can be represented at an algorithmic level as the interplay of two different but related mechanisms. The first of them is a preliminary screening process, by means of which the whole skeleton is thoroughly and continuously explored. This is followed by a renovation process, whereby regions previously marked for renewal are first destroyed and then rebuilt, in such a way that global mechanical compliance is never compromised. In this work, we pay attention to the first of these two stages. In particular, we show that an efficient screening mechanism may arise out of simple local rules, which at the biological level are inspired by the possibility that individual bone cells compute signals from their nearest local neighbours. This is shown to be enough to put in place a process which thoroughly explores the region where such mechanism operates.
The inhibitory effect of positional syllable frequency is a well-known phenomenon in visual word recognition: words with high-frequency syllables require extra time for deactivating the lexical syllabic neighbors. The inhibitory effect implies that a connection exists between graphemes, phonemes, the first syllable, and the phonological lexicon. However, experimental results of the first developmental stages of occurrence are scarce and inconclusive. A second- and fourth-grade sample of typical school readers participated in a lexical decision task containing high/low frequency words and high/low syllable frequency words. Our primary hypothesis was that the inhibitory effect would be found on both school grade groups. We did not predict significant differences in magnitude of effect between second- and fourth-grade participants. A general inhibitory effect was found, and separate analyses by school grade groups also indicated significant inhibitory effects. Furthermore, second- and fourth-grade children showed small sizes of the inhibitory effect, resembling the sizes found in adult normal readers. Our results suggest that Spanish readers reach a functional connection between syllables and words at an early stage. The straightforward theoretical implication is that the inhibitory effect relies heavily on the structural properties of the lexical access system that are acquired at an early age.
Most of the existing prediction models for COVID-19 lack validation, are inadequately reported or are at high risk of bias, a reason which has led to discourage their use. Few existing models have the potential to be extensively used by healthcare providers in low-resource settings since many require laboratory and imaging predictors. Therefore, we sought to develop and validate a multivariable prediction model of death in Mexican patients with COVID-19, by using demographic and patient history predictors. We conducted a national retrospective cohort study in two different sets of patients from the Mexican COVID-19 Epidemiologic Surveillance Study. Patients with a positive reverse transcription-polymerase chain reaction for SARS-CoV-2 and complete unduplicated data were eligible. In total, 83 779 patients were included to develop the scoring system through a multivariable Cox regression model; 100 000, to validate the model. Eight predictors (age, sex, diabetes, chronic obstructive pulmonary disease, immunosuppression, hypertension, obesity and chronic kidney disease) were included in the scoring system called PH-Covid19 (range of values: −2 to 25 points). The predictive model has a discrimination of death of 0.8 (95% confidence interval (CI) 0.796–0.804). The PH-Covid19 scoring system was developed and validated in Mexican patients to aid clinicians to stratify patients with COVID-19 at risk of fatal outcomes, allowing for better and efficient use of resources.
Through diversity of composition, sequence, and interfacial structure, hybrid materials greatly expand the palette of materials available to access novel functionality. The NSF Division of Materials Research recently supported a workshop (October 17–18, 2019) aiming to (1) identify fundamental questions and potential solutions common to multiple disciplines within the hybrid materials community; (2) initiate interfield collaborations between hybrid materials researchers; and (3) raise awareness in the wider community about experimental toolsets, simulation capabilities, and shared facilities that can accelerate this research. This article reports on the outcomes of the workshop as a basis for cross-community discussion. The interdisciplinary challenges and opportunities are presented, and followed with a discussion of current areas of progress in subdisciplines including hybrid synthesis, functional surfaces, and functional interfaces.
There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.
We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.
The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: −0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).
The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.
This study attempted to replicate whether a bias in probabilistic reasoning, or ‘jumping to conclusions’(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation.
Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses.
JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46–5.17 for siblings and aRR: 5.07 CI 95% 4.13–6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67–8.51, and in patients: 2.15 CI 95% 0.94–4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences.
These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.
Previous studies attest that early bilinguals can modify their perceptual identification according to the fine-grained phonetic detail of the language they believe they are hearing. Following Gonzales et al. (2019), we replicate the double phonemic boundary effect in late learners (LBs) using conceptual-based cueing. We administered a forced choice identification task to 169 native English adult learners of Spanish in two sessions. In both sessions, participants identified the same /b/-/p/ voicing continuum, but language context was cued conceptually using the instructions. The data were analyzed using Bayesian multilevel regression. Learners categorized the continuum in a similar manner when they believed they were hearing English. However, when they believed they were hearing Spanish, “voiceless” responses increased as a function of L2 proficiency. This research demonstrates the double phonemic boundary effect can be conceptually cued in LBs and supports accounts positing selective activation of independent perception grammars in L2 learning.
To verify the main advantages and drawbacks of mechanical suturing for pharyngeal closure after total laryngectomy versus a manual suturing technique.
A retrospective review was carried out of 126 total laryngectomies performed between 2008 and 2018. Manual closure was performed in 80 cases (63.5 per cent) and mechanical suturing was performed in 46 cases (36.5 per cent).
Mechanical suturing was used significantly more frequently in patients with: glottic tumours (p = 0.008), less local tumour extension (p = 0.017) and less pre-operative morbidity (p = 0.014). There were no significant differences in the incidence of pharyngocutaneous fistula between the manual suture group (16.3 per cent) and the mechanical suture group (13.0 per cent) (p = 0.628). None of the patients treated with mechanical suturing had positive surgical margins. Cancer-specific survival for the mechanical suture group was higher than that for the manual suture group (p = 0.009).
Mechanical suturing of the pharynx after total laryngectomy is an oncologically safe technique if used in suitable cases.
The majority of available US-published reports present populations with community spread in urban areas. The objective of this report is to describe a rural healthcare system's utilisation of therapeutic options available to treat Coronavirus Disease 2019 (COVID-19) and subsequent patient outcomes. A total of 150 patients were treated for COVID-19 at three hospitals in the Dakotas from 21 March 2020 to 30 April 2020. The most common pharmacological treatment regimens administered were zinc, hydroxychloroquine plus azithromycin and convalescent plasma. Adjunctive treatments included therapeutic anticoagulation, tocilizumab and corticosteroids. As of 1 June 2020, 127 patients have survived to hospital discharge, 12 patients remain hospitalised and 11 patients have expired. The efficacy of hydroxychloroquine and azithromycin use has yet to be determined but was not without risks of corrected QT interval prolongation and arrhythmias in our cohort. We did not appreciate any adverse effects that appeared related to tocilizumab or convalescent plasma administration in those patient subsets. These findings may provide insight into disease severity and treatment options in the rural setting with limited resources to participate in clinical trials and encourage larger comparative studies evaluating treatment efficacy.
Previous literature supports antipsychotics’ (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning.
A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables.
Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011–0.0091) and (b = 0.0026, 95% CI 0.0001–0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033–0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden.
CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.
Schizophrenia is a chronic disease. Several etiopathogenic aetiologies have been posed, among them the existence of cerebral inflammation. S100B is a calcium-binding protein, mainly produced and secreted by astrocytes, that mediates the interaction among glial cells and between glial cells and neurons. Serum S100B levels have been proposed as a peripheral marker of brain inflammation.
The aim of this research is to study if the serum level of the protein S100B has relationship with positive psychopathology.
31 paranoid schizophrenic inpatients (22 male and 9 female, 36.7±10.3 years) meeting DSM-IV criteria participated in the study. Blood was sampled by venipuncture at 12:00 and 24:00 hours. Blood extractions were carried out during the first 48 hours after hospital admission. Psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). Serum S100B levels were measured by sandwich ELISA techniques.
Correlations between serum levels of S100B protein and PANSS positive scores are shown in the following table. The first figure corresponds to the Pearson's correlation coefficient, while the figure in brackets corresponds to its statistical significance.
Total Positive Score
Serum levels of S100B protein may be used as a biological marker of positive psychopathology in paranoid schizophrenia.Acknowledgement
To analyse the consequences of broadening DSM-IV criteria for generalized anxiety disorder (GAD) on the utilization of health care resources and corresponding costs.
Multicentre, prospective and observational study conducted in outpatient psychiatric clinics selected at random and weighted by geographical density of population. Patients with GAD according to DSM-IV criteria and subjects with anxiety symptoms fulfilling broader criteria were compared. Broadening criteria was considered 1-month of excessive or non-excessive worry and only 2 associated symptoms listed on DSM-IV for GAD. Socio-demographic data, medical history and health care resources and corresponding costs were recorded during a 6-month period.
A total of 3,549 patients were systematically recruited; 12.8% excluded because not fulfilling inclusion criteria, 1,815 patients in DSM-IV criteria group (DG) and 1,264 in broad criteria group (BG). Both groups were similar on their sociodemographic characteristics at baseline. Type of treatments prescribed at psychiatric clinics during the study were similar in frequency; anti-depressives (77.0% in DG vs. 75.3% in BG, ns), benzodiazepines (71.5% vs. 67.2% respectively, ns), and anti-convulsants (72.1% vs. 67.0% respectively, ns). Health care resources utilization were statistically reduced to a similar extent in both groups as a consequences of treatments yielding to a cost-of-illness in the 6-month period of 1,196 (1,158) and 1,112 (874), respectively; p=0.304.
In a large sample of subjects, broadening of GAD criteria could lead to earlier diagnosis that would not be associated necessarily to an increase in health care resources utilization or costs to the National Health System.
According to 2008 data, there are 80.000 patients undergoing replacement opiate programs (RMP) in Spain. However, the clinical therapeutic management and the psychiatric and medical comorbidities have not been well described.
To describe the current therapeutic management and psychiatric comorbilities of opiate-dependent patients undergoing a RMP in Spain.
We carried out an observational, cross-sectional, multicenter study from September 2008 to February 2009. Patients > 18 years, with written informed consent, with a opiate-dependence according to DSM-IV-TR criteria and currently scheduled in a RMP in Spain were included.
624 patients (38.89±7.95 y.o.,84% men) were included in the study from 74 centers.
Psychiatric comorbidities were clinically detected in 68% of all valuable patients, most frequently anxiety (53%), mood (48%) and sleep disorders (41%). Patients receiving buprenorphine-naloxone suffered less sleep disorders (19% vs. 43%; p=0.0327) The proportion of patients with at least one psychiatric comorbidity was directly related to methadone dose (p=0.0066).
The most frequent replacement therapy was methadone (94%), usually in ≤ 40 mg/day (38%) and 40-80 mg/day doses (40%); mean follow up period being 45.88±51.86 months. Significant differences were found between methadone doses and retention. Patients with HIV and HCV infection received higher doses of methadone (HIV+ patients (p=0.0024) and HCV+/ HIV+ patients (p=0.0250) due to ARV treatment; and showed less PMM retention.
Patients present high rates of dual diagnosis, and infectious and non-infectious comorbidities, expecting higher doses of methadone than found (54.04±47.26 mg/day) in the study to assure a proper retention in the maintenance programs.
To evaluate the effect of pregabalin as a tapering therapy over the subjective sleep quality of patients who underwent a benzodiazepine withdrawal program.
This was a secondary analysis of a 12-week, prospective, and observational study carried out in patients aged 18 years or over, who met DSM-IV-TR criteria for benzodiazepine dependence without other major psychiatry disorder. Evaluations included the Benzodiazepine Withdrawal Symptom Questionnaire, the Hamilton Anxiety Rating Scale, the Clinical Global Impression scale, and the MOS-Sleep Scale. Changes from baseline to the endpoint in the different scales’ scores as well as correlations of these changes with those of the MOS-Sleep scores were calculated.
282 patients met the criteria for analysis. Mean pregabalin dose was 315 (166) mg/day at end-of-trial. We observed a significant and clinically relevant improvement in sleep outcomes at the study endpoint as measured with the MOS-Sleep Summary Index, that was reduced from 55.8 (18.9) pts at baseline to 25.1 (18.0) pts at week 12 (55% reduction), as well as with the six dimensions of the MOS-Sleep Scale. Moderate correlations were observed between Summary Index and sleep domains with improvements in the anxiety symptoms and in the disease severity as well. Also, sleep ameliorations were observed in the 52% successfully benzodiazepines withdrawals but, although to a lesser extent, in the remaining failures as well.
Pregabalin treatment improves subjective sleep quality in patients who underwent a benzodiazepine withdrawal program and this effect appears partly independent of the improvement of anxiety or withdrawal symptoms.
Benzodiazepines are widely used drugs. However, their chronic use has revealed that they can lead to dependence. The objective of this study is to review the different pharmacological strategies used in the management of benzodiazepine dependence and new trends in pharmacological interventions.
We searched in MEDLINE and in the Cochrane Database System Review, selecting studies from 1980 until the present, in which a pharmacological intervention was made for benzodiazepine detoxification in mono-dependence cases.
There is a consensus about gradual rather than abrupt tapering benzodiazepines in benzodiazepine discontinuation. Other extended traditional strategy has been switching from short half-life to long half-life benzodiazepines before gradual taper. A great variety of agents have been used as adjuvant medication in Benzodiazepine Withdrawal Syndrome (BWS) with varying degrees of success. In the last years research has focus in the use of anticonvulsant drugs. Both carbamzepine and valproate, have demonstrated to be beneficial in benzodiazepine discontinuation. Also, preliminary data suggest that new anticonvulsant agents (gabapentin, pregabalin, oxcarbazepine and topiramate) could be helpful.
Although multiple drugs have been investigated for pharmacological management of BWS, only few have demonstrated significant efficacy. Anticonvulsant drugs are one of them. Both, carbamazepine and valproate, have shown benefits in reducing withdrawal severity. The available data currently support the use of new anticonvulsant (gabapentin, pregabalin, oxacarbazepine and topiramate), in the treatment of different drug-dependences such as alcohol, cocaine and opiate dependence. Moreover, there is a growing trend in the literature toward the use of these agents in benzodiazepine mono-dependence.
Suicide is a major public health problem, one of the leading causes of death and one of the first causes of years of life lost. It is a voluntary act that can be carried out by men and women, children and adults, rich and poor, people of every race and religion.
The aim of this text is to outline the most popular suicides and briefly discuss the representation of suicide in art. Painters such as Vincent Van Gogh, Edvard Munch, Jackson Pollock, musicians as Kurt Cobain, Jim Morrison, Janis Joplin, Jimi Hendrix, the actresses Lupe Vélez, Carole Landis, Pier Angeli, Capucine, Marylin Monroe, Lucy Gordon and the actors Heath Ledger and Freddie Prinze decided the end of their lives in different ways and at different stages.
In the literary field, we find the world renowned suicides of Socrates, Seneca and Caton. Other famous and more recent suicidal writers are Ernest Hemingway, Dylan Thomas, Virginia Woolf, Yukio Mishima, Alfonsina Stormi and Cesare Pavese among others.
Suicide has been represented in several plays and operas, not only people of flesh and blood kill themselves but also fictional characters. the love-death of Liu in Turandot and Tosca in the opera of the same name Are noteworthy, both were composed by Giacomo Puccini. In Hamlet, tragedy written by William Shakespeare, is Ophelia who dies drowning at the sea.
Immigrant population has been growing up in Spain in the last decades. The immigration process constitutes a vulnerability factor for the development of psychological issues. Moreover, ethnicity determines a great variability in the symptomatic expression of psychiatric diseases. The objective of this study was to investigate the demographical characteristics and clinical profiles of immigrant patients that visit the emergency services of general hospitals.
An epidemiological study was conducted to evaluate profiles and demographical characteristics of immigrant population attended at the emergency services of the “Hospital 12 de Octubre” Madrid, during 2007. The data were acquired through a protocol developed for this study and applied to all foreign patients attended.
2976 patients were attended during 2007. Immigrant patients were 10% of the sample. There mean age was 29.46 years. 42.1% were men and 57.9% were women. The nationalities of the sample were as follow: 47.8% were Latin American, 23.7% Eastern Europeans, 16.1% were Maghribian and 4.7% were Africans. 48.2% were attended because of suicide attempt (the 59% of Latin Americans and the 54.5% of Eastern Europeans) and 14.3% had psychosis (the 42.9% of Africans and the 36.2% of Maghribians). 30% were diagnosed of a current Substance Use Disorder (the 16.9% of Eastern Europeans).
We found several clinical and demographical differences within the ethnic groups studied. Latin Americans and Eastern Europeans consult for suicide attempt, whereas Maghribians and Africans are attended for psychosis. Psychiatrists should consider cultural and ethnic factors when interviewing foreign population.
Startle reflex (SR) is a defensive response to sudden, intense stimuli. Prepulse inhibition (PPI) refers to the ability of innocuous sensory events to reduce SR. PPI has been described as an operational measure of sensorimotor gating that is reduced in several neuropsychiatric disorders, such as schizophrenia, but there is no extensive experience in addictions and alcoholism. The objective of this study was to examine the existence of impairments on SR and PPI in abstinent alcoholic males.
Subjects were 40 abstinent alcoholic males, aged 18 to 65 years (mean age 44.73), who had met DSM-IV criteria for Alcohol Dependence, being abstinent for more than a month at the moment they were tested. Participants underwent testing for PPI. Subjects were then compared with 35 equal controls.
Magnitudes of the SR were lower in abstinent alcoholic males when compared with controls. This differences were significant (p< 0,05) in trials with prepulse presented 30, 60 or 120 msec before the onset of startle stimulus. There was a significant less percentage of PPI when prepulse was presented 30 msec before the startle stimulus (p< 0,05).
Abstinent alcoholic males exhibit a decrease in the startle response magnitude and in the PPI of the SR. These data suggest that sensory information processing mechanisms could be damaged in abstinent alcoholic patients. The fact that these findings are common to other psychiatric disorders, could indicate the existence of a common vulnerability marker, and could explain the important comorbidity between alcoholism and other mental illness.
Stress and trauma have been reported as leading contributing factors in schizophrenia. And certainly child abuse (neglect, emotional, physical and sexual abuse among others) has a lasting negative impact, which is well established in literature.
To consider the presence of infant trauma and its relationship with psychopathology in paranoid schizophrenics.Methods. 37 patients (mean age 29±6.3; years from onset 9.20±4.7), meeting DSM IV paranoid schizophrenia criteria, undergoing treatment in a university hospital are studied. The PANSS is administered in order to rate psychopathology.
27 patients had infant trauma (55.8%). Main traumas are: sexual abuse (12.8%), child abuse (7.7%), both sexual and child abuse (5.18%), parental separation (7.7%), extra-rigid parents (2.6%), alcoholic parents (18.2%), child abuse and mother's death in childhood (2.6%). Infant trauma and psychopathology showed a significant relationship concerning Hostility (No 1.75±1.209, Yes 2.26±1.759), Unnatural Movements and Posture (No 1.55±0.945, Yes 1.16±0.545), Depression (No 1.25±0.550, Yes 1.74±1.284) and Preoccupation (No 2.75±1.410, Yes 3.26±1.996).
Infant trauma is common in paranoid schizophrenia and our findings give some evidence to a relationship with psychopathology, especially with dimensions as Hostility, Unnatural Movements and Posture, Depression and Preoccupation. Despite sample size, a high proportion (55.8%) of the patients presented infant trauma and future research is needed in order to open new avenues in this field, particularly studies concerning infant trauma and symptomatology specificity will be greatly appreciated as well as the plausible link to personality traits and personality disorders.
There are few studies about the characteristics of Substance Use Disorder patients that relapse, defined by restart of the substance use that motivated the intake, after discharge from a Detoxification Unit.
To analyze the percentage of patients who had a relapse in the following 3 months after discharge and to describe their sociodemographic, clinical and therapeutical characteristics.
We prospectively studied drug dependents patients admitted to our Detoxification Unit from June 2008 to August 2009. Data was gathered at admission on demographic (gender, age), clinical (main abused drug, psychiatric comorbidities, polydrug users) and therapeutical variables (hospitalisation duration, prescribed treatment). Patients were followed up for 3 months and assessed for relapse at 1 and 3 months by clinical interview, alcohol screening test and/or urinalysis. Results from patients with and without relapses were compared.
The study sample included 103 patients (77,7% men, average age 38,31±9). At month 3, 57,3% of the patients had relapsed. We found significant differences between the relapse and the non-relapse group on the percentage of polydrug users (68,6% vs 31,4%, p=0,05), on heroine as main drug of abuse (76% vs 24%, p=0,05) and psychiatric comorbidities (60,8% vs 39,2%, p=0,04), being psychotic disorders the most frequent. No significant differences were found between the 2 groups concerning therapeutical variables.
More than half of the patients that ended the detoxification process relapsed in the first 3 months. Polydrug use, opiate dependence and having a psychiatric comorbidity might be considered as risk factors for relapse.