Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

Venlafaxine's therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis.

INTRODUCTION: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. OBJECTIVES: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. METHODS: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. RESULTS: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml. CONCLUSION: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

Neonatal withdrawal syndrome following in utero exposure to antidepressants: a disproportionality analysis of VigiBase, the WHO spontaneous reporting database.

BACKGROUND: Evidence on neonatal withdrawal syndrome following antidepressant intrauterine exposure is limited, particularly for antidepressants other than selective serotonin reuptake inhibitor (SSRIs). METHODS: In our case/non-case pharmacovigilance study, based on VigiBase®, the WHO database of suspected adverse drug reactions, we estimated reporting odds ratio (ROR) and the Bayesian information component (IC) with 95% confidence/credibility intervals (CI) as measures of disproportionate reporting of antidepressant-related neonatal withdrawal syndrome. Antidepressants were first compared to all other medications, then to methadone, and finally within each class of antidepressants: SSRIs, tricyclics (TCA) and other antidepressants. Antidepressants were ranked in terms of clinical priority, based on semiquantitative score ratings. Serious v. non-serious reports were compared. RESULTS: A total of 406 reports of neonatal withdrawal syndrome in 379 neonates related to 15 antidepressants were included. Disproportionate reporting was detected for antidepressants as a group as compared to all other drugs (ROR: 6.18, 95% CI 5.45-7.01, IC: 2.07, 95% CI 1.92-2.21). Signals were found for TCAs (10.55, 95% CI 8.02-13.88), followed by other antidepressants (ROR: 5.90, 95% CI 4.74-7.36) and SSRIs (ROR: 4.68, 95% CI 4.04-5.42). Significant disproportionality emerged for all individual antidepressants except for bupropion, whereas no disproportionality for any antidepressant was detected v. methadone. Eleven antidepressants had a moderate clinical priority score and four had a weak one. Most frequent symptoms included respiratory symptoms (n = 106), irritability/agitation (n = 75), tremor (n = 52) and feeding problems (n = 40). CONCLUSIONS: Most antidepressants are associated with moderate signals of disproportionate reporting for neonatal withdrawal syndrome, which should be considered when prescribing an antidepressant during pregnancy, irrespective of class.

No differences in olanzapine- and risperidone-related weight gain between women and men: a meta-analysis of short- and middle-term treatment.

OBJECTIVE: A plethora of data deriving from single studies as well as meta-analyses demonstrates that weight gain is associated with the exposure to the majority of antipsychotics (AP). However, potential sex differences have widely evaded the attention of AP treatment trials. It is hypothesised that female patients gain more weight compared with male patients due to their enhanced susceptibility to adverse drug reactions. METHOD: A meta-analysis was conducted using clinical trials of AP that reported weight change separately for female and male patients. Duration of AP use was stratified in four categories: <6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots were generated for men and women separately, stratified by AP as well as by duration of use. Sex differences were tested by performing meta-regression. RESULTS: Data of 26 studies were used in the present analysis because sufficient data were available only for olanzapine, risperidone and the no-medication group. Both female and male patients showed considerable weight gain after switch or initiate of olanzapine or risperidone, but meta-regression analyses did not show significant sex differences. CONCLUSION: The present meta-analysis revealed that sex differences in AP-related weight gain have been under investigated hampering the detection of sex-specific patterns. In chronic patients switching to olanzapine or risperidone receiving short-or middle-term treatment, AP were associated with weight gain in both sex subgroups and no significant differences were reported.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Keep at bay!--Abnormal personal space regulation as marker of paranoia in schizophrenia.

BACKGROUND: During threat, interpersonal distance is deliberately increased. Personal space regulation is related to amygdala function and altered in schizophrenia, but it remains unknown whether it is particularly associated with paranoid threat. METHODS: We compared performance in two tests on personal space between 64 patients with schizophrenia spectrum disorders and 24 matched controls. Patients were stratified in those with paranoid threat, neutral affect or paranoid experience of power. In the stop-distance paradigm, participants indicated the minimum tolerable interpersonal distance. In the fixed-distance paradigm, they indicated the level of comfort at fixed interpersonal distances. RESULTS: Paranoid threat increased interpersonal distance two-fold in the stop-distance paradigm, and reduced comfort ratings in the fixed-distance paradigm. In contrast, patients experiencing paranoid power had high comfort ratings at any distance. Patients with neutral affect did not differ from controls in the stop-distance paradigm. Differences between groups remained when controlling for gender and positive symptom severity. Among schizophrenia patients, the stop-distance paradigm detected paranoid threat with 93% sensitivity and 83% specificity. CONCLUSIONS: Personal space regulation is not generally altered in schizophrenia. However, state paranoid experience has distinct contributions to personal space regulation. Subjects experiencing current paranoid threat share increased safety-seeking behavior.

Experience with benign splenic disease.

PURPOSE: In the ongoing effort to improve patient treatment, a deeper understanding of the symptomatology, physical signs and management options of rare splenic, non-traumatic, benign diseases is extremely important. PATIENTS AND METHODS: The records of eight consecutive patients with benign splenic conditions, other than injury and abscess, were reviewed retrospectively in order to analyse the clinical presentation, diagnostic methodology and therapeutic procedures applied in these rare conditions. Of the eight patients, three were diagnosed with splenic hydatid cyst, two with pseudocysts, one with splenic epidermoid cyst, one with wandering spleen and one with infraction of an ectopic spleen with situs inversus of other intra-abdominal organs. RESULTS: Upper abdominal pain was the most common presenting symptom and a tender palpable mass in the left upper abdominal quadrant, the predominant clinical finding. Pre-operative CT scanning confirmed the diagnosis in six patients, but failed to reveal the splenic pathology in the remaining two cases. Seven patients underwent splenectomy while saving splenic parenchyma was feasible in only one patient (12,5%). CONCLUSIONS: Splenic, non-traumatic, benign diseases have vague clinical presentation and may create diagnostic difficulties. Although spleen saving intervention can be applied in selected cases, splenectomy would be required in most patients.

Pylorus-preserving pancreaticoduodenectomy with external pancreatic remnant drainage.

BACKGROUND: Pancreaticoduodenectomy is the mainstay of surgical treatment for various benign and malignant diseases of the head of the pancreas and the periampullar region. The incidence of postoperative morbidity remains significantly high. Various modifications have been advocated for the restoration of the digestive continuity and drainage of bile and pancreatic ducts in order to diminish this high morbidity rate. METHODS: A new modification with the combination of an end-to-end duodenojejunal anastomosis and creation of an external pancreatic fistula following pylorus-preserving pancreaticoduodenectomy is described. Our initial experience with this modification in seven patients is reported and its advantages are discussed. RESULTS: There was no mortality, while morbidity was 29%, including postoperative pneumonia and psychosis in one patient, and intra-abdominal abscess in another patient. No significantly delayed gastric emptying was observed and no patient developed diabetes, anastomotic ulcer or reflux cholangitis postoperatively. CONCLUSIONS: The reported technique seems to be a safe modification of restoration after pancreaticoduodenectomy, with maintenance of anatomical gastrointestinal continuity, avoidance of complications from anastomosis with the pancreatic remnant, as well as maintenance of endocrine pancreatic function. However, long-term follow-up and larger comparative studies are needed to evaluate the impact of this modification on morbidity and mortality, including long-term nutritional complications.

Primary psoas abscess. Report of three cases.

BACKGROUND: Primary psoas abscesses are a rare clinical entity with subtle and non specific symptoms, most commonly seen in patients predisposed to infections. Early diagnosis and appropriate management are therefore challenging aspects for physicians. PATIENTS AND METHODS: We present three patients with primary pyogenic psoas abscess, treated at the Heraklion University Hospital, during a 5-year period. The two male and one female patient, aged 36-51 years were admitted with fever, abdominal pain and a palpable tender mass. RESULTS: The classical sign of limping was absent in all cases. Positive psoas symptoms were detected in only two patients. CT scan accurately confirmed the diagnosis in all cases. The patients were successfully treated with antibiotics and prolonged surgical drainage. Staphylococcus aureus was the causative microorganism in the first two and Bacteroides fragilis in the third patient. This is the first reported case resulting from this specific bacteria. None of our patients had any predisposing risk factor. CONCLUSIONS: A high index of suspicion is mandatory to enable early recognition of this rare clinical disease. CT scan is the standard diagnostic tool to confirm diagnosis. Prolonged drainage and appropriate antibiotics are essential for the successful treatment of primary psoas abscesses.

Obesity-associated disorders before and after weight reduction by vertical banded gastroplasty in morbidly vs super obese individuals.

BACKGROUND: The amount of excess weight which must be lost in order to cure or to improve disorders associated with obesity remains unknown. This study was designed to compare super obese and morbidly obese patients in terms of weight reduction following VBG and to investigate the effects of postoperative weight changes to preexisting co-morbidities. METHODS: 125 patients underwent VBG. Group A consisted of 80 morbidly obese patients (64%) and group B consisted of 45 super obese patients (36%). Preoperative examination was planned to identify and determine the severity of any disorders associated with obesity, that the patients may have had. Following VBG, all patients were followed-up at regular time periods, for at least 2 and up to 4 years. The progress of preexisting co-morbidities was evaluated and carefully recorded. RESULTS: Among the 80 patients of Group A, there were 240 total co-morbidities (3 per patient), and in group B there were 196 co-morbidities (4.35 per patient) preoperatively. Dyspnea during fatigue and arthritis were found at statistically higher incidence in the super obese category. At the end of the second postoperative year, greater weight loss in terms of number kilograms was seen in patients in group B, but these patients did not reach a BMI lower than 35, while patients in group A had mean BMI below 30. In group A, 66% of the co-morbidities completely resolved, 19% significantly diminished and 15% remain unchanged. In group B, the respective percentages were 53%, 27.5% and 19.5%. However, after weight reduction by VBG a significant number of co-morbidities remain in the super obese patients (92 or 2.044 per/patient), and this is believed to be due to the greater remaining excess weight. CONCLUSION: Reduction of body weight by VBG is associated with resolution or improvement of a significant number of the obesity-associated disorders. However, super obese patients remain obese after surgery, and this results in two-fold higher remaining morbidity.

Disorders associated with clinically severe obesity: significant improvement after surgical weight reduction.

BACKGROUND: Surgical treatment for patients with clinically severe obesity mainly aims to reduce morbidity. METHODS: Sixty-two patients were examined for disorders associated with morbid obesity before and after surgical weight reduction by vertical banded gastroplasty. All patients were followed-up for 12 to 48 months. RESULTS: At the end of the first postoperative year, 84% of the patients had lost at least 50% of their excess weight. Of the 218 weight-related pathologic conditions existing before the operation, 131 (60%) were completely cured, 50 (23%) showed significant improvement, and only 37 (17%) remained unchanged. The same percentages were obtained for patients followed tip for 24, 36, and 48 postoperative months. CONCLUSIONS: Surgical treatment of clinically severe obesity has a significant effect on the health of the patients by eliminating the associated disorders.

Splenic abscess: a diagnostic and therapeutic challenge.

The records of five patients treated in our department for splenic abscess are analysed and the literature is reviewed. Computed tomography revealed the correct diagnosis in all patients, while clinical presentation was often nonspecific. Spleen-preserving management was possible in two patients (40%). Outcome was uneventful for four patients. One patient with a splenic abscess caused by Mycobacterium tuberculosis and acquired immunodeficiency syndrome, died 4 months after splenectomy from sepsis. We discuss the clinical presentation of splenic abscess, its diagnostic approach, and treatment. Additionally, we studied whether spleen-preserving management is feasible or not.

Cysts of the adrenal gland: diagnosis and management.

OBJECTIVE: Cysts of the adrenal gland are rare, but with the wider application of sonography and computed tomography more adrenal cysts are detected incidentally. To gain more insight into this entity, five such cases are reported and their diagnostic approach and management are discussed. PATIENTS AND METHODS: The records of five patients with six cysts of the adrenal glands seen at our department from 1987 till 1995 are reviewed. There were four males and one female and their age ranged from 24 to 72 years, with a mean age of 43 years. One patient had a primary hydatid cyst of the right adrenal gland, which was preoperatively thought to arise from the liver or the right kidney. A second patient had a very large pseudocyst of the left adrenal gland, which is the largest ever reported in the literature. The other four cysts in three patients were found incidentally during sonography or computed tomography. RESULTS: The hydatid cyst with a rim of normal adrenal tissue was excised. The large pseudocyst was removed together with the adrenal gland. In the cases of the incidentally found cysts, observation of the patient with regular follow-up was decided upon. All patients are in good condition and without symptoms 2 to 10 years after the initial diagnosis. CONCLUSIONS: Adrenal cysts are rare and their diagnosis may pose problems. Symptomatic adrenal cysts should be operated, but small, asymptomatic, non-functional cysts with benign characteristics may be treated conservatively with regular follow-up by sonography or computed tomography and hormonal evaluation.

Acute intestinal obstruction caused by endometriosis mimicking sigmoid carcinoma.

Endometriosis is a relatively frequent disease in fertile women. The intestine is involved in 12-37% of cases. Intestinal endometriosis is usually asymptomatic and complete obstruction of the bowel lumen occurs in less than 1% of cases. We report a case of endometriosis of the sigmoid, which caused complete intestinal obstruction and mimicked carcinoma of the sigmoid colon. This case demonstrates the difficulty of establishing an accurate pre- and peroperative diagnosis and the propensity of intestinal endometriosis to mimic colon cancer.

Does draining the neck affect morbidity following thyroid surgery?

A prospective randomized study questioning the benefit of neck drainage in thyroid surgery is presented. Two hundred consecutive patients, candidates for elective thyroid surgery, were randomized into Group A (no drain) and Group B (drain). Reoperation for bleeding was necessary for two patients of Group A and for one patient in Group B. Minor hematomas occurred in seven patients from Group A and five patients from Group B; wound infection occurred in two and four patients in Groups A and B, respectively; and lymphatic discharge occurred in two patients from Group B. These differences were not statistically different. The present study failed to demonstrate any protective value from the use of drains. However, the hospital stay was shorter and pain scores were smaller in the non-drain Group A.

Staple-line disruption following vertical banded gastroplasty.

BACKGROUND: The purpose of this study was to determine the frequency with which staple-line disruption occurs following vertical banded gastroplasty (VBG) in morbidly obese patients, to investigate the effect of this complication on weight loss, and to identify any clinical symptoms that might be associated with staple-line disruption. METHODS: From April of 1992 to June of 1994, 60 patients with morbid obesity underwent VBG. Double-contrast radiographic examination of the upper gastrointestinal tract was performed on all patients at 6, 12, 24, and 36 months postoperation to assess the integrity of the staple line. At these same times, the weight of each patient was measured, so that the patients found to have staple-line disruption could be compared to those without disruption in terms of weight loss. RESULTS: Over the duration of the study, staple-line disruption was found in 12 patients (20%). All of these patients demonstrated satisfactory weight loss. Between the group of patients with staple-line disruption versus the group without disruption, weight loss did not differ significantly at any time up to 3 years postoperation. In addition, in the patients with staple-line disruption, no clear symptomatology that might be associated with this complication was discovered. CONCLUSIONS: Our results lead to the conclusion that small disruptions in the staple line lack clinical importance and do not significantly affect weight loss for at least the first 3 postoperative years. Furthermore, staple-line disruption does not seem to be associated with any specific clinical symptoms. Follow-up of all patients via barium meal is the correct approach for discovering the exact incidence of this complication.

Primary hydatid cyst of the adrenal gland.

An extremely rare case of primary hydatid cyst of the adrenal gland is reported. Adrenal hydatid cysts are usually a manifestation of generalized echinococcosis. Only nine primary cases have so far been reported in the literature. The presentation is insidious. Correct preoperative diagnosis is difficult. Clinical and investigative findings are non-specific and ambiguous. Surgery is the treatment of choice.

Intramural haematoma of the duodenum: a rare cause of duodenal obstruction.

Intramural haematoma is a rare cause of duodenal obstruction. Its most common cause is abdominal trauma. Diagnostic difficulty arises if the patient or the child's parents fail to mention the episode of trauma, regarding it as an unrelated or insignificant event, as in the presented case. Computed tomography is the imaging modality of choice. Intramural duodenal haematoma is best treated conservatively, since operative treatment is associated with a high complication rate and longer hospitalization.