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.

Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection.

Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10%. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 h after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1-5 µM at the alveolar surface. Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2-4 mg per inhalation in order to reach sufficient therapeutic levels at the alveolar epithelial cells. By using a low-dose non-systemic aerosol, adverse drug reactions will markedly be reduced compared with oral application. This increase in tolerability enables a broader use for prevention and after contact with an infected person, which would be an advantage especially for the high-risk, often multi-morbid and elderly patients. Empirical data on self-medication with a one-week aerosol application by two of the authors is presented. Inhalation was well tolerated without relevant side effects.

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.

Retrospective pilot study for analysis of antidepressant serum concentrations of citalopram and venlafaxine during inflammation.

INTRODUCTION: Inflammation-mediated changes in drug metabolism may increase drug levels in blood and lead to intoxications. The objective of this study was to find out whether elevated serum levels of C-reactive protein (CRP) are associated with increased serum concentrations of the antidepressants citalopram and venlafaxine. METHODS: Therapeutic drug monitoring request forms of psychiatric patients were screened retrospectively. The serum concentrations in relation to the daily doses [(C/D) (ng/ml/mg)] and the metabolic ratios (metabolite/drug) were compared intraindividually under normal (<5 mg/l) and pathological (>5 mg/l) condition by the Wilcoxon signed-rank test. RESULTS: Elevated levels of CRP were not associated with a significant (P>0.05) increase in C/D for citalopram (2.4 ng/ml/mg vs. 2.85 ng/ml/mg, N=15) or in C/D for the active moiety of venlafaxine (1.76 ng/ml/mg vs. 1.68 ng/ml/mg, N=39), compared with normal CRP serum levels. No significant difference in the metabolic ratio was observed in both groups. DISCUSSION: There was no major effect of inflammation on the metabolism of citalopram and venlafaxine. Because of the broad therapeutic indices of these 2 drugs, the drugs seem to be a good choice for the treatment of depression, even if an infection occurs.

Steady-state serum concentrations of venlafaxine in patients with late-life depression. Impact of age, sex and BMI.

Diagnosis of late-life depression is given when depressive symptoms emerge in persons older than 65 years. Great care is needed when elderly patients receive psychopharmacotherapy due to altered pharmacokinetic status. As a consequence, age is considered to have a significant effect on serum concentrations of antidepressant drugs. The magnitudes of age-dependent changes, however, are uncertain. By utilizing a large therapeutic drug monitoring (TDM) database, this cross-sectional study aimed to retrospectively assess pharmacotherapy in elderly patients in comparison with their younger counterparts, when treated with venlafaxine, which is widely used to treat late-life depression. In addition, the influence of sex and body mass index (BMI) was evaluated. Serum concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine requested during routine TDM in two University Medical Centers in Germany were analyzed. Patients with concomitant CYP2D6 inhibiting drugs as co-medication were excluded. In total, 1,417 samples were available for the analysis. Elderly patients had by average 42% higher dose-adjusted serum concentrations (ng/mL/mg) of the active moiety (venlafaxine plus O-desmethylvenlafaxine) than younger patients. In addition, our study demonstrated that the difference between age groups is independent of sex and BMI. However, age groups only explain 4.5% of the total dose-adjusted serum concentration variation of the venlafaxine active moiety. Dose adjustments for venlafaxine are recommended in patients aged 65 years or older, particularly in elderly female patients who are exceptionally vulnerable to high serum concentrations of venlafaxine. TDM is recommended during venlafaxine pharmacotherapy.

Cable-testing device fails to indicate that hypertension is artifactual.

A patient undergoing neurosurgical anesthesia was noted to have a mean systolic/intraarterial pressure of 190/135 mm Hg, whereas the mean systolic/noninvasive blood pressure was 110/77 mm Hg. The problem was traced to a short circuit between the contacts in two adjacent sockets at the transducer-end of the interface cable. The short circuit prevented sufficient attenuation of the excitation voltage from the bedside monitor to the pressure-sensitive bridge circuit of the transducer. A test device (Cable Checker, Viggo-Spectramed, Oxnard, CA) containing a resistance network that could be attached to the interface cable in place of the transducer incorrectly indicated that the cable was functioning properly. The malfunction was confirmed by exposing the transducer to known static pressures. The manufacturer modified the transducer end of its interface cable to reduce the likelihood of a similar problem recurring. Subtleties of the function of the disposable transducer, reasons for a disparity between systolic intraarterial pressures and noninvasive blood pressures, and methods for bedside testing of intraarterial pressure equipment are discussed.

Correlations between verbal memory performance and electrocorticographically determined suppression of electrical brain activity in intracarotid amobarbital tests.

As a part of presurgical evaluation, bilateral intracarotid amobarbital procedures (IAPs) were performed in 42 patients (84 tests) with long-standing, medically intractable complex-partial seizures. During the IAPs, electrocorticographic (ECoG) recording was carried out via bilaterally implanted subdural electrodes. Five distinct patterns of suppression of electrical brain activity were observed: (1) an isoelectric line; (2) a burst-suppression pattern; (3) polyphasic waves; (4) high-voltage beta; and (5) low-voltage beta activity. Further, two types of specific reactions of the epileptic focus were detectable: (1) spike-burst-suppression patterns (SBS; 11 left; 7 right; 6 in both IAPs) and amobarbital-induced spikes (7 left; 4 right). ECoG suppression patterns as well as SBS and spike induction showed great variability in duration and overall occurrence. To determine the influence of these amobarbital-induced ECoG changes on results of IAP memory testing, performance in a verbal learning task was analyzed according to the ECoG patterns predominant during encoding. In left IAPs, it was found that SBS at the beginning of or during encoding had a significant negative effect on verbal memory. In right IAPs, verbal memory performance improved significantly with the decline of ECoG suppression. Hence, verbal memory performance in IAPs is significantly affected by specific ECoG suppression patterns and activation of the epileptic focus.

Localization of the epileptic focus during methohexital-induced anesthesia.

A short anesthesia was provided by methohexital for painless percutaneous removal of subdural electrodes in 27 patients with medically intractable, complex partial seizures who had undergone invasive preoperative evaluation. Electrocorticographic(ECoG) recordings performed before and during the narcosis were submitted to visual (n = 27) and computerized (n = 3) analysis to obtain additional information about the location of the epileptic focus (or foci). The following observations were made: focal epileptiform potentials were induced in 24 of 27 patients (89%); (b) in 20 of these 24, the induced spikes appeared amid or were followed by isoelectric or subdelta activity. These spikes were characterized by high amplitude as well as rhythmic and synchronized appearance over a circumscribed focal area (or areas) known to be spontaneously epileptogenic. This phenomenon, termed spike-burst-suppression (SBS) pattern, allowed identification of the primary epileptic focus in many patients with temporal lobe epilepsy. Furthermore, it indicated a good outcome of epilepsy surgery. Computerized analysis of the induced synchronized spikes (n = 3) allowed further delineation of the primary site of epileptogenicity and quantitative comparison of multiple epileptic generators. ECoG recording during deep methohexital-induced narcosis is a valuable tool for lateralization and delineation of the primary epileptogenic focus.