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Biomedical subjects

K Wahlbeck

Publications and source records attributed to K Wahlbeck.

At least 19 recordsLinked to original sources
PubMed2002

Randomized controlled trials in schizophrenia: a critical perspective on the literature.

OBJECTIVE: The randomized trial provides an opportunity to minimize the inclusion of biases in the evaluation of interventions in psychiatry. Difficulties arise, however, when applying their results to 'real world' clinical practice and decision-making. We, therefore, examined the real world applicability of schizophrenia trials. METHOD: A narrative overview of the content and quality of the randomized trials relevant to the care of those with schizophrenia is provided. RESULTS: Complex, explanatory, under-powered randomized drug trials dominate evaluative research in schizophrenia. CONCLUSION: Explanatory designs are a necessary but insufficient step in establishing the true worth of interventions in schizophrenia. Research from other spheres of mental health and wider health care suggest that pragmatic trials are feasible. This design allows large scale trials to be conducted which include patients which we would recognize from routine practice and which record outcomes which are of genuine interest to decision-makers.

Humans↗
PubMed2002

Decrease of energy expenditure causes weight increase in olanzapine treatment - a case study.

The aim of this study was to evaluate the mechanisms underlying weight gain induced by the atypical antipsychotic, olanzapine. We performed euglycemic, hyperinsulinemic clamp combined with indirect calorimetry on a 48-year-old male with antisocial personality disorder, alcohol dependence and paranoid ideation before and after one month of olanzapine (10 - 15 mg/day) therapy. The patient gave his informed, written consent for this study. The results were a weight gain of 6 kg and a decrease in both basal (from 1673 to 1613 kcal/24 h) and 3-hour (from 22.8 to 20.2 cal/kg fat free mass/min) energy expenditure. Serum thyroid hormone and high-density lipoprotein cholesterol levels decreased, and the triglyceride and low-density lipoprotein cholesterol levels increased. Insulin sensitivity did not change. We conclude that decreased basal energy expenditure may contribute to weight gain in olanzapine treatment.

Antipsychotic Agents↗
PubMed2001

Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood.

BACKGROUND: Nutritional factors in early life may contribute to the neurodevelopmental deficit in schizophrenia. This study explores the influence of maternal body size, size at birth, and childhood growth on future risk for schizophrenia. SUBJECTS AND METHODS: This population-based cohort study comprised births at Helsinki University Central Hospital in Helsinki, Finland, from 1924 to 1933. Prospective data from birth and school health records of 7086 individuals were collected and linked to the Finnish Hospital Discharge Register. RESULTS: Schizophrenia or schizoaffective disorder had been diagnosed in 114 individuals. A lower late-pregnancy maternal body mass index (BMI) increased the risk (odds ratio [OR], 1.09 per kilogram/meter(2); 95% confidence interval [CI], 1.02-1.17) for schizophrenia among the offspring. The risk of schizophrenia increased with low birth weight (OR, 1.48 per kilogram; 95% CI, 1.03-2.13), shortness at birth (OR, 1.12 per centimeter; 95% CI, 1.03-1.22), and low placental weight (OR, 1.22 per 100 g; 95% CI, 1.04-1.43). Schizophrenia cases were thinner than comparison subjects from 7 to 15 years of age. In a joint model comprising late-pregnancy maternal BMI, body size at birth, and childhood BMI, childhood BMI was an independent predictor of schizophrenia, whereas other factors exhibited attenuated effects. CONCLUSION: Indicators of intrauterine and childhood undernutrition are associated with an increased lifetime risk of schizophrenia.

Adolescent↗
PubMed2001

Dropout rates in randomised antipsychotic drug trials.

RATIONALE: It has been assumed that new atypical drugs improve treatment compliance due to fewer adverse effects. Data supporting this assumption are scarce. OBJECTIVES: The aim of this study was to study attrition rates in randomised controlled trials of oral administration of conventional antipsychotic drugs, atypical antipsychotic drugs and placebo. METHODS: The database of the Schizophrenia Module of the Cochrane Library was utilised for the present study. The data in the Cochrane Module are collected by identifying relevant randomised controlled trials from several electronic databases and other sources. Number of dropouts was defined as patients leaving the study preterm due to any reason. RESULTS: Data from 328 treatment groups, consisting of 18,585 randomised subjects from 163 drug trials, were entered in the analysis. One-third of the subjects had dropped out of the trials. The dropout rates significantly increased for each calendar year. Year of trial publication, type of drug and trial length remained statistically significant contributors to dropout rates. In a model incorporating year of publication and trial length, placebo groups and groups treated with conventional antipsychotics had significantly higher attrition rates than groups treated with atypical drugs. When clozapine-treated groups were excluded from the analysis, no statistically significant advantage for atypical drugs over conventional drugs remained. CONCLUSIONS: Trial data implicate that a better compliance can be achieved by favouring atypical drugs rather than conventional alternatives in the treatment of schizophrenia. However, this effect is found only when groups treated with the atypical antipsychotic clozapine are included in the analysis. Our study did not find evidence for a statistically significant superiority in acceptability of novel atypical drugs when compared to conventional antipsychotics.

Antipsychotic Agents↗
PubMed2001

Associations between childhood living circumstances and schizophrenia: a population-based cohort study.

OBJECTIVE: It has been suggested that household crowding may constitute an environmental risk factor for schizophrenia. The present population-based cohort study explores the associations of childhood family size and living conditions to schizophrenia. METHOD: The cohort comprised people born at Helsinki University Central Hospital from 1924 to 1933, who went to school in the city and were still living in Finland in 1971. Prospectively gathered data from birth and school health records of these 7086 individuals were collected and linked to the Finnish Hospital Discharge Register. RESULTS: Ninety-eight cases of schizophrenia were identified in the cohort. Number of siblings at school start was significantly associated with schizophrenia when adjusted for sex and age of mother. Number of siblings was negatively correlated with body mass index at age 7. Childhood household crowding, defined as number of people per room, and total number of rooms in household were not significantly associated with schizophrenia. CONCLUSION: Our study indicates that the total number siblings in household during childhood is of greater importance than childhood number of inhabitants per room. Subjects who originated from families with many children had been leaner, which may imply that childhood nutritional factors partly is the mediating factor between number of siblings and schizophrenia. Other possible underlying mechanisms of the associations found include infectious and psychological factors.

Adolescent↗
PubMed2001

Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17beta-estradiol: a preliminary study.

BACKGROUND: The postpartum period is a time when women are vulnerable to depressive disorders, which can be severe and have long-lasting adverse sequelae. In spite of multiple contacts with health care providers, women with postpartum depression often remain unrecognized and untreated. To evaluate the association between estradiol and postpartum depression, we measured serum estradiol concentration and performed an open-label study of physiologic 17beta-estradiol. METHOD: Twenty-three women fulfilling ICD-10 criteria for major depression with postpartum onset were consecutively recruited from a psychiatric emergency unit. Serum estradiol concentrations were measured at baseline and weekly during sublingual 17beta-estradiol treatment for 8 weeks. The treatment effect was assessed using a clinician-rated depression symptom scale, the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: At baseline, all patients were severely depressed (mean MADRS total score = 40.7; range, 35-45) and had a low serum estradiol concentration (mean = 79.8 pmol/L; range, 23-140 pmol/L); in 16/23 patients, the concentration was even lower than the threshold value for gonadal failure. During the first week of estradiol treatment, depressive symptoms diminished significantly, resulting in a mean MADRS score of 11.0 (Z = -4.20, p < .001), and serum estradiol concentrations approached those of the follicular phase (mean +/- SD = 342 +/- 141 pmol/L). At the end of the second week of treatment, the MADRS scores were compatible with clinical recovery in 19/23 patients. CONCLUSION: This preliminary study shows that depression symptoms may be rapidly reduced in patients with postpartum depression who have documented estradiol deficiency by treatment with 17beta-estradiol and suggests that estradiol can have significance in the pathophysiology of this condition and may be an option in the treatment of women vulnerable to postpartum depression.

Administration, Sublingual↗
PubMed2000

Current antipsychotic dose correlates to mononuclear cell counts in the cerebrospinal fluid of psychotic patients.

Elevated cerebrospinal fluid (CSF) angiotensin I-converting enzyme (ACE) levels have been evidenced in patients with schizophrenia who have been treated with antipsychotics. In order to explore a possible mononuclear cell origin of CSF ACE, the authors determined CSF ACE and CSF mononuclear cell counts from 25 acutely psychotic patients, who had been drug-free for at least 4 months but started on conventional antipsychotic medication within a few days before sampling. No correlations were found between CSF to serum ACE ratio and CSF mononuclear cell counts. However, CSF total mononuclear cell count, CSF lymphocyte count, and CSF mononuclear phagocyte count evidenced significant positive correlations with current dose of antipsychotic medication expressed as chlorpromazine equivalents. The authors conclude that no indication of a relationship between mononuclear cells and CSF ACE activity was found. Surprisingly, a relationship between chlorpromazine dose and CSF mononuclear cell counts was found, which may indicate drug-related changes in cell-mediated immunity. This finding needs replication and further corroboration in well-designed studies.

Acute Disease↗
PubMed2000

Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia.

The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0.001). These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process.

Acute Disease↗
PubMed2000

Efficacy of beta-blocker supplementation for schizophrenia: a systematic review of randomized trials.

Adrenergic beta-receptor antagonists, commonly used in the field of cardiovascular diseases, have also been recommended for treatment-resistant schizophrenia. We systematically review quality assessed trials on beta-blocker supplementation of antipsychotic treatment for schizophrenia. All randomized controlled trials comparing any beta-blocking agent added to any antipsychotic with a placebo added to any antipsychotic, and lasting for at least 1 week, were located through electronic searches in all languages of several databases. The trials were assessed by at least two independent reviewers for inclusion, quality score, and data extraction. The reviewers located five studies with 117 participants. The data were poorly presented in these short-term studies and did not evidence any effect of beta-blockers as an adjunct to conventional antipsychotic medication. At present beta-blockers cannot be recommended in the treatment of schizophrenia, and schizophrenia treatment guidelines advocating use of beta-blockers should be revised.

Adrenergic beta-Antagonists↗
PubMed2000

Clozapine versus typical neuroleptic medication for schizophrenia.

BACKGROUND: Long-term drug treatment of schizophrenia with conventional antipsychotics has limitations: 25-33% of patients have illnesses that are treatment-resistant. Clozapine is an atypical antipsychotic drug, which is claimed to have superior efficacy and to cause fewer motor adverse effects than typical drugs for people with treatment-resistant illnesses. Clozapine carries a significant risk of serious blood disorders, which necessitates mandatory weekly blood monitoring at least during the first months of treatment. OBJECTIVES: To evaluate the effects of clozapine for schizophrenia in comparison to typical antipsychotic drugs. SEARCH STRATEGY: Publications in all languages were searched from the following databases: Biological Abstracts (1982-1999), The Cochrane Library CENTRAL (Issue 2, 1999), Cochrane Schizophrenia Group's Specialised Register (1999), EMbase (1980-1999), ISI Citation Index, LILACS (1982-1999), MEDLINE (1966-1999), and PsycLIT (1974-1999). Reference list screening of included papers was performed. Authors of recent trials and the manufacturer of clozapine contacted. SELECTION CRITERIA: All randomised controlled trials comparing clozapine with typical antipsychotic drugs were included by independent assessment by at least two reviewers. DATA COLLECTION AND ANALYSIS: Data were extracted independently by at least two reviewers. Authors of trials published since 1980 were contacted for additional and missing data. Odds ratios (OR) and 95% confidence intervals (CI) of homogeneous dichotomous data were calculated with the Peto method. A random effects model was used for heterogeneous dichotomous data. Where possible the numbers needed to treat (NNT) or needed to harm (NNH) were also calculated. Weighted or standardised means were calculated for continuous data. MAIN RESULTS: Currently the review includes 31 studies, 26 of which are less than 13 weeks in duration. These studies include 2589 participants, most of whom were men (74%). The average age was 38 years. There was no difference in the effects of clozapine and typical neuroleptic drugs for broad outcomes such as mortality, ability to work or suitability for discharge at end of the study. Clinical improvement was seen more frequently in those taking clozapine (random effects OR 0.4 CI 0.2-0.6, NNT 6) both in the short and the long term. Also, in the short term, participants on clozapine had fewer relapses than those on typical antipsychotic drugs (OR 0.6 CI 0.4-0.8, NNT 20 CI 17-38), and this may be true for long-term treatment as well. Symptom assessment scales showed a greater reduction of symptoms in clozapine-treated patients. Clozapine treatment was more acceptable than low-potency antipsychotics such as chlorpromazine (OR 0.6 CI 0.4-0.9) but did not differ from acceptability of high-potency neuroleptics such as haloperidol (random effects OR 0.8 CI 0.4-1.5). Clozapine was more acceptable in long-term treatment than conventional antipsychotic drugs (random effects OR 0.4 CI 0.2-0.7, NNT 6 CI 3-111). Patients were more satisfied with clozapine treatment (OR 0.5 CI 0.3-0.8, NNT 12 CI 7-37), but they experienced more hypersalivation, temperature increase, and drowsiness than those given conventional neuroleptics. However, clozapine patients experience fewer motor side effects and less dry mouth. The clinical efficacy of clozapine was more pronounced in participants resistant to typical neuroleptics in terms of clinical improvement (random effects OR 0.2 CI 0.1-0.5, NNT 5 CI 4-7) and symptom reduction. Thirty-two percent of treatment resistant people had a clinical improvement with clozapine treatment. REVIEWER'S CONCLUSIONS: This systematic review confirms that clozapine is convincingly more effective than typical antipsychotic drugs in reducing symptoms of schizophrenia, producing clinically meaningful improvements and postponing relapse. Patients were more satisfied with clozapine treatment than with typical neuroleptic treatment. (ABSTRACT TRUNCATED

Antipsychotic Agents↗
PubMed2000

Beta-blocker supplementation of standard drug treatment for schizophrenia.

BACKGROUND: Many people with schizophrenia or similar severe mental disorders do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, among them beta-adrenergic receptor antagonists (beta-blockers). OBJECTIVES: To evaluate the clinical effectiveness of beta-blockers as an adjunct to antipsychotic medication in schizophrenia or similar severe mental disorders. SEARCH STRATEGY: Publications in all languages were searched from the following databases: Biological Abstracts, CENTRAL of The Cochrane Library, Cochrane Schizophrenia Group's Specialised Register, EMBASE, LILACS, MEDLINE, and PsycLIT. The reference section of papers included were screened. SELECTION CRITERIA: All randomised controlled trials comparing beta-blockers with placebo as an adjunct to conventional antipsychotic medication for those with schizophrenia. DATA COLLECTION AND ANALYSIS: Studies were selected and then data extracted, independently, by at least two reviewers. Odds ratios and 95% confidence intervals of homogeneous dichotomous data were calculated with the Peto method. A random effects model was used for heterogeneous dichotomous data. Weighted mean differences were calculated for continuous data. MAIN RESULTS: Currently the review includes five studies but data are poorly presented and do not evidence any effect of beta-blockers as an adjunct to conventional antipsychotic medication. REVIEWER'S CONCLUSIONS: At present beta-blockers cannot be recommended in the treatment of schizophrenia. Any possible benefit of adjunctive beta-blockers is obscured by the poor reporting of the included studies. Existing data on beta-blockers as adjunctive medication to antipsychotics for those with schizophrenia should be collected and re-analysed in order to allow confident conclusions about the effect of this treatment or the need for further trials.

Adrenergic beta-Antagonists↗
PubMed2000

Newer atypical antipsychotic medication versus clozapine for schizophrenia.

BACKGROUND: Clozapine is an atypical antipsychotic drug, which is claimed to have superior efficacy and to cause fewer movement disorders. However, clozapine carries a significant risk of serious blood disorders. Newer atypical antipsychotics are safer alternatives that might share the benefits of clozapine. It is thus of interest to compare the effectiveness of newer atypical antipsychotics with the effectiveness of clozapine. OBJECTIVES: To evaluate the clinical effects of newer atypical antipsychotic drugs in comparison to clozapine for schizophrenia. SEARCH STRATEGY: Publications in all languages were searched from the following databases: Biological Abstracts/BIOSIS (1980-1999), The Cochrane Schizophrenia Group's Register of Trials (1998), The Cochrane Library CENTRAL Register (Issue 4, 1999), EMBASE (1980-1998), MEDLINE (1966-1999), LILACS/CD-ROM (1998), and PsycLIT/PsycINFO (1974-1999). Trials were also sought from recent conference proceedings and reference lists of included papers. Authors of recent trials and the manufacturers of clozapine, iloperidone, olanzapine, quetiapine, remoxipride, risperidone, sertindole, ziprasidone and zotepine were contacted. SELECTION CRITERIA: All randomised controlled trials comparing clozapine with newer atypical antipsychotic drugs were included by independent assessment by two reviewers. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Relative risks (RR) and 95% confidence intervals (CI) of homogenous dichotomous data were calculated. A random effects model was used for heterogeneous dichotomous data. Where possible the number needed to treat (NNT) statistic with 95%CI were also calculated. Weighted or standardised means were calculated for continuous data. Due to the small number of included studies, sensitivity analyses or funnel plot statistics were not undertaken for this version of the review. MAIN RESULTS: The current review includes eight studies (22 papers), of which three studies are 4-6 weeks in duration and only one study is of more than 12 weeks' duration. Newer atypical drugs seemed to be broadly similar to clozapine using a clinical global index or trialists' definitions of improvement, but this result was obtained from a relatively small number of studies. Due to the small number of studies and patients, wide confidence intervals were seen when their effectiveness as measured by symptom rating scales was compared. Social functioning was better in patients on newer atypical medication (risperidone) than in those on clozapine, but this finding is based on a single underpowered trial and has to be interpreted with caution. Clozapine and newer atypical drugs showed their adverse effect profile to be dissimilar: while clozapine produced more fatigue, hypersalivation, nausea, and orthostatic dizziness, new atypical drugs, with the exception of olanzapine, produced more extrapyramidal symptoms. The impact of these drugs and their effects on patients' day-to-day quality of life, service use, hospital admission, and pharmacoeconomics was not measured. REVIEWER'S CONCLUSIONS: The equal effectiveness and tolerability of new atypical drugs in comparison with clozapine is not yet demonstrated. Lack of statistical power to determine the comparative efficacy and effectiveness of newer atypical drugs makes it difficult to judge whether newer drugs are more effective, less effective or equivalent. Trials of sufficient power, with longer duration, measuring clinically important outcomes, are needed to assess the true comparative clinical effectiveness, tolerability and cost effectiveness of newer drugs in relation to clozapine.

Antipsychotic Agents↗
PubMed2000

Risperidone versus clozapine in treatment-resistant schizophrenia: a randomized pilot study.

1. The atypical antipsychotic risperidone may constitute an alternative to clozapine, the current treatment of choice for refractory schizophrenia. The objectives of this study were to evaluate the effectiveness of risperidone in comparison to clozapine in everyday practice and to assess the feasibility of a pragmatic trial procedure. 2. Patients were randomly assigned to open-label clozapine or risperidone treatment for 10 weeks and treatment outcomes were assessed blindly. Twenty-one patients were recruited and nineteen entered the randomized phase. 3. Five of 10 participants allocated to clozapine and one of nine risperidone participants dropped out before study completion. Five clozapine patients and six risperidone patients achieved clinical improvement, defined as a 20% decrease in the Positive and Negative Symptom Scale (PANSS) total score. No significant differences between the groups were detected in baseline or endpoint positive or negative symptoms, disease severity, or global or social functioning scores. Patients' opinion on the drugs did not differ between groups. 4. The findings of the intention-to-treat analysis of this study corroborates previous findings that risperidone may be equally effective as clozapine, and supports the feasibility and need of a multicenter randomized pragmatic trial with sufficient power to detect differences between treatments.

Adult↗
PubMed2000

Influence of methodology on outcomes of randomised clozapine trials.

The aim of this study was to clarify the impact of various methodological quality factors on reported outcome of randomised clozapine trials. Trials comparing the atypical antipsychotic clozapine with other antipsychotic drugs were identified in extensive electronic searches. Two independent reviewers extracted data on methodology and primary outcomes, and assessed trial quality by use of three sets of criteria (Cochrane, Delphi, and Jadad). There was no association between trial quality, as measured by any of the criteria sets, and primary measures of outcome. Trials with the best score for randomisation and concealment according to the Delphi scale had a significantly lower relative risk for relapse in clozapine-treated groups, and studies with well reported random order generation according to Jadad criteria tended to have better odds ratios for clinical improvement on clozapine. These findings strengthen the evidence of true clozapine superiority in these aspects. No other quality items correlated to the primary outcomes. Inadequate randomisation techniques may be a source of bias in clozapine studies, but much more research is needed on the connections between trial quality and trial outcome.

Antipsychotic Agents↗
PubMed1999

Evidence of clozapine's effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials.

OBJECTIVE: The purpose of this study was to evaluate all available trial-based evidence on the effectiveness of clozapine in schizophrenia as compared with conventional neuroleptics. METHOD: All randomized, controlled trials comparing clozapine with a conventional neuroleptic in which there was satisfactory concealment of patients' treatment allocation were located through electronic searches in all languages of several databases and through contacting authors of recent trials as well as the manufacturer of clozapine. At least two independent reviewers assessed trials for inclusion in the study and extracted data for meta-analysis. RESULTS: The review included 2,530 randomly assigned participants in 30 trials, most of them short-term. Clozapine-treated patients showed more clinical improvement and experienced significantly fewer relapses during treatment, although the risk of blood dyscrasias in long-term treatment may be as high as 7%. Scores on symptom rating scales showed greater improvement among clozapine-treated patients, who were also more satisfied with their treatment. However, there was no evidence that the superior clinical effect of clozapine is reflected in levels of functioning; on the other hand, global functional and pragmatic outcomes were frequently not reported. Clinical improvement was most pronounced in patients with treatment-resistant illness. CONCLUSIONS: This meta-analysis confirms that clozapine is more effective than conventional neuroleptics in reducing symptoms of patients with both treatment-resistant and nonresistant schizophrenia. Future trials should be long-term pragmatic community trials or should address the effectiveness of clozapine in special patient populations. An international standard set of outcomes, including pragmatic assessments of functioning, would greatly enhance the comparison and summation of trials and future assessments of effectiveness.

Adolescent↗
PubMed1999

The impact of pregnancy and puerperium on panic disorder: a review.

There is little known about the effect of pregnancy and the puerperium on the risk for, and course of anxiety disorders. Initial case reports concerning the relationship between panic disorder (PD) and pregnancy/puerperium suggested that pregnancy protected against PD, while the postpartum period seemed to increase the risk for onset or exacerbation of PD. Later studies have offered a more mixed picture. A computerized search identified eight relevant studies in this area. All were non-controlled and all but one retrospective. Out of the total 215 pregnancies that were described in these studies, 89 (41%) were associated with improvement of PD symptoms during the pregnancy, while 38% of the described pregnancies exhibited onset or exacerbation of PD in the postpartum period. No definite conclusions regarding the effect of pregnancy and puerperium on PD can be drawn from these reviewed studies.

Female↗