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 fur 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.

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

Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

Parkinson's Disease: From Pathogenesis to Pharmacogenomics

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients - psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the "behavioral toxicity" conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis.

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Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

Anticholinergic and sedative medications are commonly used in older adults and are associated with adverse clinical outcomes. The Drug Burden Index was developed to measure the cumulative exposure to these medications in older adults and its impact on physical and cognitive function. This narrative review discusses the research and clinical applications of the Drug Burden Index, and its advantages and limitations, compared with other pharmacologically developed measures of high-risk prescribing.

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Drug Burden Index in older adults: theoretical and practical issues

Aim
In 2005, the Japan Geriatrics Society published a list of potentially inappropriate medication that was an extract from the “Guidelines for medical treatment and its safety in the elderly 2005.” The 2005 guidelines are due for a revision, and a new comprehensive list of potentially inappropriate medications is required.

Methods
A total of 15 diseases, conditions and special areas related to their clinical care were selected. We originated clinical questions and keywords for these 15 areas, carried out a systematic review using these search criteria, and formulated guidelines applying the Grading of Recommendations Assessment, Development and Evaluation system advocated by Minds2014. If we did not find good evidence despite the drug being clinically important, we looked for evidence of efficacy and for disease-specific guidelines, and incorporated them into our guidelines.

Results
We selected 2098 articles (140 articles per area), and extracted another 186 articles through a manual search. We further added guidelines based on disease entity and made two lists, one of “drugs to be prescribed with special caution” and the other of “drugs to consider starting,” primarily considering individuals aged 75 years or older or those who are frail or in need of special care.

Conclusions
New lists of potentially inappropriate medications and potential prescribing omissions called “Screening Tool for Older Person's Appropriate Prescriptions for Japanese” were constructed. We anticipate that future studies will highlight more evidence regarding the safety of high-quality drugs, further improving the provision of appropriate medical care for the elderly. Geriatr Gerontol Int 2016: 16: 983–1001.

Screening Tool for Older Persons' Appropriate Prescriptions for Japanese: Report of the Japan Geriatrics Society Working Group on "Guidelines for medical treatment and its safety in the elderly".

Background: Scoring scales such as the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS), and the Anticholinergic Cognitive Burden Scale (ACB) provide an estimation of total anticholinergic burden. Not all the lists include the same drugs, and the points given for certain drugs differ among them. Whether these discrepancies present important differences in the estimation of anticholinergic burden for an individual patient is unknown. Therefore, the aim of this study is to assess agreement among the three scales.



Method:  Anticholinergic burden was measured with the three scales in 83 patients aged ≥65 years in a medium- and long-stay psychiatric hospital. Subsequently, patients were categorized into three risk categories: low risk (0 points), medium risk (1–2 points) or high risk (3 or more points). The chance-corrected measures of agreement for the different scores were determined with the k-statistic (kappa).



Results:  Values for kappa were: 0.19 for Anticholinergic Risk Scale-Anticholinergic Drug Scale, 0.21 for ACB-Anticholinergic Drug Scale and 0.25 for Anticholinergic Risk Scale-ACB. The mean anticholinergic burden measured with ACB was 3.28.



Conclusions:  There is poor agreement among the three scales. These lists cannot be directly applied to different settings in which drug availability differs substantially, and they require periodic updates. Anticholinergic burden in our setting (psychogeriatric inpatients) was particularly high.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1479-8301.2012.00418.x

Expert-based drug lists to measure anticholinergic burden: similar names, different results.

Purpose Almost all antipsychotics have been associated with a risk of epileptic seizure provocation. Among the first-generation antipsychotics (FGA) chlorpromazine appears to be associated with the greatest risk of seizures among the second-generation antipsychotics (SGA) clozapine is thought to be most likely to cause convulsions. This information is largely based on studies that are not sufficiently controlled. Besides, information about the seizure risk associated with newer antipsychotics is scarce. Method The Pharmacovigilance Unit of the Basque Country (network of centers of the Spanish Pharmacovigilance System, SEFV) provided reporting data for adverse reactions (AR) from the whole SEFV to estimate the reporting odds ratio (ROR) for antipsychotics and seizures ("convulsions" as Single MedDra Query). Data was obtained from SEFV database from 1984 to the June 2011. Results The total number of convulsions reported for SGA was 169 (total reported AR 3.204). The number of convulsions reported for FGA was 35 (total reported AR 2.051). 94 convulsions were reported in association with clozapine (total AR 1.052). The ROR for SGA versus FGA was 3.2 (CI 95%: 2.21–4.63). The ROR for SGA excluding clozapine versus FGA was 2.08 (CI 95%: 1.39–3.12). Conclusion Our results show that SGA may pose a higher risk of seizures than FGA, mainly, but not only due to clozapine. This is line with recent studies suggesting that some SGA carried a higher average risk of electroencephalographic abnormalities than many FGA. Nonetheless, It is well known that spontaneous reports do not allow strong inferences about adverse drug effects, because differences in reporting fractions by time, drug or type of event are difficult or even impossible to distinguish from differences in the occurrence rates of adverse events. Still, we consider that the possibility of SGA carrying a higher risk of seizure induction than FGA warrants further research.

Antipsychotics and seizures: higher risk with atypicals?

Purpose. A literature evaluation of antidopaminergic therapies in patients with Parkinson’s disease (PD) who have developed psychosis, nausea, vomiting, and hiccups was conducted.

Summary. Complications associated with the use of antiparkinsonian drugs make PD management more difficult given the need for antidopaminergic therapy, which worsens motor functioning in patients with PD. For psychosis, clozapine is the only atypical antipsychotic that has proven effective without worsening motor function in PD patients. However, its use requires the monitoring of agranulocytosis. Newer atypical antipsychotics such as quetiapine have been claimed to be safe in terms of motor functioning, but evidence about their effectiveness is not compelling. The emergency treatment of psychosis in PD would require parenteral administration, only available for olanzapine and ziprasidone. However, no randomized controlled trials have been conducted to establish the efficacy and safety in this setting. For nausea and vomiting, very little domperidone crosses the blood–brain barrier. As a result, the risk of developing extrapyramidal adverse effects is minimal. Metoclopramide blocks central dopamine receptors and worsens motor parkinsonian symptoms. Chlorpromazine, the first-line treatment of intractable hiccups, is contraindicated in PD. Baclofen could be considered as a first-line alternative.

Conclusion. Although clozapine can be used to treat psychosis in patients with PD, managing nausea, vomiting, hiccups, and emergent psychotic symptoms in these patients remains a challenge due to a lack of evidence for currently available options.

Antidopaminergic therapy for managing comorbidities in patients with Parkinson's disease.

Anticholinergic toxicity can arise as a result of the cumulative burden of multiple medications and metabolites rather than be caused by a single compound. In this sense, prescribing drugs with anticholinergic properties to Parkinson’s disease (PD) patients could contribute to aggravate some frequent problems of the disease, like dementia, urinary retention, falls, or constipation, among others. The main purpose of this article is to measure the total anticholinergic burden in a group of PD inpatients. We analyzed information from different administrative Basque Country’s healthcare databases using encrypted unique identifiers in order to detect PD patients admitted to public acute care hospital during 2011–2012. Subsequently, anticholinergic burden was measured using Duran et al.’s list. Secondarily, total anticholinergic load was assessed with the Anticholinergic Drug Scale, the Anticholinergic Risk Score, and the Anticholinergic Burden Scale. A logistic regression model was performed to study association of predictive variables with anticholinergic use. A high proportion of PD patients were prescribed anticholinergic drugs, with 53.6 % of admissions receiving at least one drug from Duran et al.’s “low-risk” and 10 % at least “high-risk” drug. Drugs used for non-motor symptoms and other comorbidities other than PD itself contributed significantly to anticholinergic burden, namely antidepressants, antipsychotics, urological drugs, analgesics, and antihistamines, among others. The total number of drugs and cholinesterase inhibitors were independently associated with anticholinergic drug use. Anticholinergic burden in PD patients is significant, and is caused mostly by drugs not used for PD motor symptoms. Polypharmacy and cholinesterase inhibitors were independently associated with anticholinergic drug prescriptions.

Anticholinergic burden in Parkinson's disease inpatients.

Purpose Although antipsychotics are well known for causing a plethora of adverse drug reactions (ADRs), the main concern when used to treat psychosis in Parkinson disease (PD) has traditionally been motor function worsening. The limited number of patients included in clinical trials contributes to underreport less common ADR. The aims of this study were to describe ADR to antipsychotics occurring in patients with PD notified to the Spanish Pharmacovigilance System and to contrast them with published reports. Methods All notifications from the Spanish Pharmacovigilance System for the last 30 years (1984-2014) where an antipsychotic was considered suspicious of the ADR in patients who were also on dopaminergic therapy were reviewed. In addition, a systematic search of MEDLINE (1966-2014) was conducted with the following Medical Subject Headings (MeSH) terms: "Parkinson disease" and "antipsychotic agents" or "psychotic disorders" and "drug-related side effects" or "adverse reactions." Results Forty-four notifications were selected for evaluation. Quetiapine was the most frequently implicated drug since 2002, and previously clozapine was the drug implied in higher number of notifications. The most severe ADR was neuroleptic malignant syndrome, which was described in 5 patients (3 cases related to quetiapine, one to haloperidol, and another to olanzapine). Conclusions Some previously unreported ADRs caused by antipsychotic drugs in patients with PD have been described for the first time in this study, although there are in general well-known antipsychotic adverse effects. It is remarkable that some notifications involve the use of drugs not recommended in these patients.

Saioa Domingo-Echaburu

Papers

Expert-based drug lists to measure anticholinergic burden: similar names, different results.

Antipsychotics and seizures: higher risk with atypicals?

Antidopaminergic therapy for managing comorbidities in patients with Parkinson's disease.

Anticholinergic burden in Parkinson's disease inpatients.

Adverse reactions to antipsychotics in Parkinson disease: an analysis of the Spanish pharmacovigilance database