The Italian version of the Brief Assessment of Cognition in Affective Disorders: performance of patients with bipolar disorder and healthy controls.

OBJECTIVES: Cognitive deficits in Bipolar Disorder (BD) are significant enough to have an impact on daily functioning. Therefore, appropriate tools must be used to improve our understanding of the nature and severity of cognitive deficits in BD. In this study, we aimed to compare the cognitive profiles of patients with BD and healthy controls (HC) applying the Italian version of the Brief Assessment of Cognition in Affective Disorders (BAC-A). METHODS: This cross-sectional study included 127 patients with BD and 134 HC. The participants' cognitive profiles were evaluated using the Italian version of the BAC-A, which assesses verbal memory, working memory, motor speed, verbal fluency, attention & processing speed, executive functions, and two new measures of affective processing. The BAC-A raw scores were corrected using the normative data for the Italian population. In addition, we explored whether intelligence quotient (IQ) and specific clinical variables would predict the BAC-A affective, non-affective, and total composite scores of patients with BD and HC. RESULTS: HC performed better than patients with BD in all BAC-A subtests (all p < .001), except for subtests of the Affective Interference Test. (p ≥ .05). The effect sizes varied in magnitude and ranged between d = 0.02 and d = 1.27. In patients with BD, lower BAC-A composite scores were predicted by a higher number of hospitalizations. There was a significant association between IQ and BAC-A composite scores in both bipolar patients and HC. CONCLUSIONS: The Italian BAC-A is sensitive to the cognitive impairments of patients with BD in both affective and non-affective cognitive domains.

Social withdrawal and neurocognitive correlates in schizophrenia.

Poor neurocognitive performance has been associated with poor functional outcome in schizophrenia (SCZ) in past studies. Nonetheless, the likely association between neurocognition and social withdrawal has never been investigated. The aim of our study was to investigate in a large and heterogeneous sample of SCZ patient cross-sectional associations between neurocognitive domains and social withdrawal. The sample included 761 SCZ patients who completed the baseline visit in the CATIE study. Neurocognition was assessed by a comprehensive battery of tests resulting in five domain scores and a composite score. Social withdrawal was measured by a specific item of the Heinrichs-Carpenter Quality of Life Scale. Social withdrawal was associated with a lower score in the neurocognitive composite score and in 'Verbal memory,' 'Processing speed' and 'Working memory' scores. 'Verbal memory' score showed the strongest association with social withdrawal. Eight percent of the total variance of social withdrawal was explained by these three cognitive domains and additional clinical and sociodemographic factors (education years, PANSS positive symptoms score, and employment). Our results confirmed the wide heterogeneity and specificity of the correlation between neurocognitive domains and indicators of functional outcome in SCZ, underlining the role of certain neurocognitive abilities in social withdrawal.

Venlafaxine and O-desmethylvenlafaxine serum levels are positively associated with antidepressant response in elder depressed out-patients.

BACKGROUND: Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still known regarding the relationship between clinical efficacy and serum concentration of venlafaxine (VEN). The aim of our study was to investigate the association between serum concentration of venlafaxine + O-desmethylvenlafaxine (SCVO) and antidepressant response (AR). METHODS: 52 depressed outpatients treated with VEN were recruited and followed in a naturalistic setting for three months. Hamilton Depression Rating Scale-21 was administered at baseline, at month 1 and at month 3 to assess AR. SCVO was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCVO and AR. RESULTS: Our results showed an association between AR and SCVO that follows a bell-shaped quadratic function with a progressive increase of AR within the therapeutic reference range of SCVO (i.e. 100-400 ng/mL) and a subsequent decrease of AR at higher serum levels. DISCUSSION: This study strongly suggests that TDM could represent a more appropriate tool than the oral dosage to optimise the treatment with VEN. Specifically, highest efficacy might be achieved by titrating patients at SCVO levels around 400 ng/mL.

The association of childhood trauma, lifetime stressful events and general psychopathological symptoms in euthymic bipolar patients and healthy subjects.

BACKGROUND: Psychopathological symptoms during euthymia in Bipolar Disorder (BD) affect quality of life and predispose to the occurrence of new acute episodes, however only few studies investigated potential risk-factors. This study aims to explore the association between childhood trauma (CT), lifetime stressful events (SLEs) and psychopathological symptoms in BD patients during euthymia and controls (HC). METHODS: A total of 261 participants (93 euthymic patients with BD, 168 HC) were enrolled. Generalized linear models and multiple logistic models were used to assess the association among the Symptom Check List-90-R (SCL-90-R), the Infancy Trauma Interview, the Paykel Life Events Scale. RESULTS: The rate of participants reporting CT was higher in BD (n=47; 53%) than HC (n=43; 30%) (p=0.001). The experience of neglect was strongly related to BD (OR 6.5; p=0.003). CT was associated to higher scores on the SCL-90-R subscales (all the subscales except Phobia). No effects of the interaction between CT and diagnosis were found on SCL-90-R. Finally, there was a main effect of CT on lifetime SLEs (p<.001), that was not associated with diagnosis (p=0.833), nor with the interaction between CT and diagnosis (p=0.624). LIMITATIONS: The cross-sectional design does not allow causal inferences; the exclusion of subjects reporting medical or psychiatric comorbidity limits generalizability. CONCLUSIONS: CT was associated both to psychopathological symptoms during euthymia and the lifetime SLEs, thus it may represent a vulnerability factor influencing the course of BD. Overall, these data contribute to overcome the limited evidences documenting the influence of environmental factors on euthymic phase in BD.

Correction to: Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer's disease.

The following authors have double affiliations: Stefania Boccia, Marco Di Nicola and they should read.

Genetic variants associated with psychotic symptoms across psychiatric disorders.

BACKGROUND: Recent evidence suggests that psychiatric symptoms share a common genetic liability across diagnostic categories. The present study investigated the effects of variants within previously identified relevant genes on specific symptom clusters, independently from the diagnosis. METHODS: 1550 subjects affected by Schizophrenia (SCZ), Major Depressive Disorder or Bipolar Disorder were included. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HDRS). Principal component analysis and a further clinical refinement were used to define symptom clusters. Clusters scores were tested for association with 46 genetic variants within nine genes previously linked to one or more major psychiatric disorders by large genome wide association studies (ANK3, CACNA1C, CACNB2, FKBP5, FZD3, GRM7, ITIH3, SYNE1, TCF4). Exploratory analyses were performed in each disorder separately to further elucidate the SNPs effects. RESULTS: five PANSS clusters (Negative; Impulsiveness; Cognitive; Psychotic; Depressive) and four HDRS clusters (Core Depressive; Somatic; Psychotic-like; Insomnia) were identified. CACNA1C rs11615998 was associated with HDRS Psychotic cluster in the whole sample. In the SCZ sample, CACNA1C rs11062296 was associated with PANSS Impulsiveness cluster and CACNA1C rs2238062 was associated with PANSS negative cluster. DISCUSSION: CACNA1C rs11615998 was associated with psychotic symptoms (C-allele carriers have decreased psychotic-risk) independently from the diagnosis, in line with the evidence of a cross disorder effect of many risk variants. This gene was previously associated with SCZ and cross-disorder liability to psychiatric disorders. Our findings confirmed that deep phenotyping is pivotal to clarify the role of genetic variants on symptoms patterns.

Social dysfunction in mood disorders and schizophrenia: Clinical modulators in four independent samples.

INTRODUCTION: Social dysfunction is a common symptom of several neuropsychiatric disorders. However, only in the last few years research began to systematically investigate clinical aspects of this relevant outcome. Interestingly, its distribution and link with other clinical variables is still unclear. This study investigated social dysfunction in 4 different cohorts of patients affected by mood disorders and schizophrenia to evaluate 1) the degree of social dysfunction in these populations; 2) the associations among social dysfunction and socio-demographic and psychopathological features. METHODS: Data from 4 independent studies (CATIE, GSRD ES1, ES2 and ES3, STAR*D, STEP-BD) were investigated. Behavioural and affective indicators of social dysfunction were derived and operationalized from scales or questionnaire items related to the interaction with relatives, friends and significant people in patients affected by schizophrenia (N = 765) and mood disorders (N = 2278 + 1954 + 1829). In particular the social dysfunction indicator was derived from Sheehan Disability Scale (SDS) for GSRD sample, from the Work and Social Adjustment Scale (WSAS) for STAR*D sample, from the Life-Range of Impaired Functioning Tool (LRIFT) for STEP-BD sample, and from the Quality of Life Scale (QOLS) for CATIE sample. The distribution of social dysfunction was described and association with socio-demographic and psychopathological characteristics were analysed. RESULTS: Social dysfunction indicators showed a broad distribution in all samples investigated. Consistently across studies, social dysfunction was associated with higher psychopathological severity (all samples except CATIE) and suicide risk (GSRD ES1 and ES2, STAR*D, and STEP-BD) that explain up to 47% of the variance, but also to lower education level (GSRD ES2, STAR*D, CATIE, and STEP-BD), poorer professional/work status (GSRD ES2 and ES3, STAR*D, CATIE, and STEP-BD), marital status (STAR*D and CATIE), age (younger age in GSRD ES1 and STAR*D, older age in CATIE), higher BMI (GSRD ES2 and ES3, and STEP-BD), and smoking (GSRD ES2 and ES3). CONCLUSION: Our results demonstrated that a significant percentage of patients affected by both mood disorders and schizophrenia shows relevant social dysfunction. Social dysfunction is related, but not completely explained by psychopathological severity. In several patients, it tends to persist also during remission state. Socio-demographic and lifestyle factors were also found to play a role and should therefore be taken into consideration in further studies investigating social dysfunction.

Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer's disease.

Serotoninergic system is one of the most important neurotransmission systems investigated in the field of psychiatry. Extensive evidence reveals how alterations of this system, and especially of the SLC6A4 gene, may be associated with psychiatric disorders. In this study we aimed to evaluate the pleiotropic nature of SLC6A4 alterations and their association with the overall risk of brain diseases rather than disorder-specific. SLC6A4 variants, namely 5HTTLPR, STin2, rs2066713, rs25531, rs4251417, rs6354 and rs7224199 were investigated in 4 independent cohorts of subjects with specific psychiatric disorders, including Alcohol dependence disorder (ALC), Alzheimer disease (ALZ), Schizophrenia (SCZ) and Bipolar disorder (BPD). Other variables (biochemical parameters and Psychiatric scales scores) were also tested for association. SLC6A4 polymorphisms are not associated with the risk of developing major psychiatric disorders (SCZ and BPD); however some signals were detected in ALC (HTTLPR pd = 9.25 × 10-03, pr = 7.24 × 10-03; rs2066713 pd = 6.35 × 10-08; rs25531 pd = 2.95 × 10-02; rs4251417 pd = 2.46 × 10-03), and ALZ (rs6354 pr = 1.22 × 10-02; rs7224199 pd = 1.00 × 10-08, pr = 2.65 × 10-02) cohorts. Some associations were also observed on exploratory analyses. Our findings did not reveal any major influence on SCZ and BPD development; On the other hand, some alteration of the SLC6A4 sequence were associated with an increased risk of ALC and ALZ disorders, suggesting common pathways. The results of this study should be carefully interpreted since it suffers of some inherent limitations (e.g. cohort size, slight ethnic heterogeneity). Further analyses may provide better detail on the molecular processes behind SLC6A4 alterations.

Alzheimer's Disease and Neurotransmission Gene Variants: Focus on Their Effects on Psychiatric Comorbidities and Inflammatory Parameters.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder accounting for 60-70% of dementia cases. Genetic origin accounts for 49-79% of disease risk. This paper aims to investigate the association of 17 polymorphisms within 7 genes involved in neurotransmission (COMT, HTR2A, PPP3CC, RORA, SIGMAR1, SIRT1, and SORBS3) and AD. METHODS: A Greek and an Italian sample were investigated, for a total of 156 AD subjects and 301 healthy controls. Exploratory analyses on psychosis and depression comorbidities were performed, as well as on other available clinical and serological parameters. RESULTS: AD was associated with rs4680 within the COMT gene in the total sample. Trends of association were found in the 2 subsamples. Some nominal associations were found for the depressive phenotype. rs10997871 and rs10997875 within SIRT1 were nominally associated with depression in the total sample and in the Greek subsample. rs174696 within COMT was associated with depression comorbidity in the Italian subsample. DISCUSSION: Our data support the role of COMT, and particularly of rs4680, in the pathogenesis of AD. Furthermore, the SIRT1 gene seems to modulate depressive symptomatology in the AD population.

The brief assessment of cognition in affective disorders: Normative data for the Italian population.

BACKGROUND: To date there are no validated tests in Italian to assess cognitive functions in Bipolar Disorder. Therefore, this study aimed to provide normative data for the Italian version of the Brief Assessment of Cognition in Affective Disorders (BAC-A), a battery targeting neuro- and affective-cognition in affective disorders. METHODS: Data were collected from 228 healthy participants (age range: 18-67; mean age: 34.68 ± 12.15 years) across eight recruiting sites. The influence of age, sex and education was measured and adjusted for using multivariate stepwise regression models. Normative values were established by means of the Equivalent Score approach. RESULTS: Most of the BAC-A subtests showed patterns of association with age (inversely associated with overall cognitive performance), education (positively associated with Verbal Memory and Fluency, Digit Sequencing and Affective Processing subtests) and sex (females performed better than males in the Affective Interference Test but worse in the Emotion Inhibition Task, Digit Sequencing and Tower of London). LIMITATIONS: The sample size was not sufficiently large for developing stratified norms, using 10-years ranges. Moreover, the participants included in the study were, on average, highly educated. CONCLUSIONS: The normative data of the BAC-A provided in this study can serve as a cognitive functioning reference for Italian-speaking participants within the age range of the study sample. This can increase the applicability of this test in both clinical and research settings. The reliability and validity of the Italian BAC-A need to be further investigated.

Temperament and character influence on depression treatment outcome.

BACKGROUND: personality features have been repeatedly associated with depression treatment outcome in Major Depressive Disorder (MDD), however conclusive results are still lacking. Moreover, as for Bipolar Disorder (BD), results are only few and preliminary. AIM: the aim of the present study was to perform an exploratory investigation of the influence of personality traits as assessed by the Temperament and Character Inventory (TCI), on principal depression treatment outcomes (non remission, non response and resistance). METHODS: 743 mood disorders patients (455 MDD (61.24%) and 288 BD (38.76%)) were recruited in the context of 6 European studies. Generalized logit models were performed to test the effects of TCI dimensions on treatment outcomes, considering possible confounders such as age, gender and education. Positive results were controlled for comorbidities (anxiety and substance use disorders) as well. RESULTS: MDD Non-Remitters showed high Harm Avoidance (HA) and Self Transcendence (ST) (p = 0.0004, d = 0.40; p = 0.007, d = 0.36 respectively) and low Persistence (P) and Self Directedness (SD) (p = 0.05; d = 0.18; p = 0.002, d = 0.40, respectively); MDD Non-Responders showed a slightly different profile with high HA and low Reward Dependence (RD) and SD; finally, MDD Resistants showed low RD, P and Cooperativeness (C). In BD patients, only higher HA in non response was observed. LIMITATIONS: the retrospective cross-sectional design, the TCI assessment regardless of the mood state and the small number of bipolar patients represent the main limitations. CONCLUSION: specific TCI personality traits are associated with depression treatment outcome in MDD patients. The inclusion of such personality traits, together with other socio-demographic and clinical predictors, could ameliorate the accuracy of the prediction models available to date.

Psychotic Features in Patients With Major Depressive Disorder: A Report From the European Group for the Study of Resistant Depression.

OBJECTIVE: To elucidate the impact of the presence of psychotic features in patients diagnosed with major depressive disorder (MDD) on sociodemographic, psychosocial, clinical, and response characteristics. METHODS: A total of 1,410 DSM-IV-TR MDD patients were included in the present European multicenter study, which was conducted between 2011 and 2016. Analyses of covariance, χ² tests, and binary logistic regression analyses were performed to explore differences in sociodemographic and clinical variables between MDD patients with and without psychotic symptoms. RESULTS: A prevalence rate of 10.92% for psychotic features was found in MDD. Compared to nonpsychotic MDD patients, those with psychotic features were characterized by a higher likelihood for melancholic characteristics (73.38% vs 59.16%, P = .0006), a higher rate of current suicide risk (60.39% vs 44.27%, P = .0002), greater likelihood of receiving inpatient treatment (55.84% vs 32.01%, P < .0001), greater depressive symptom severity (measured by various rating scales), and more often receiving augmentation/combination treatment strategies in general (81.17% vs 58.12%, P < .0001) and add-on therapy with antipsychotics (50.00% vs 22.69%, P < .0001) and benzodiazepines (47.40% vs 31.29%, P = .0001) in particular. Moreover, psychotic symptoms in MDD were highly predictive of treatment resistance, expressed by a more than 2.2-fold higher likelihood for resistance compared to nonpsychotic MDD patients (79.87% vs 35.75%, P < .0001). Only 3.25% of the patients with psychotic MDD achieved treatment response (vs 27.15% of those with nonpsychotic MDD, P < .0001). CONCLUSIONS: These findings suggest that adequate diagnosis of psychotic features in MDD should be ensured in routine clinical care. As a combination of antipsychotics and antidepressants represents the first-line treatment option in psychotic MDD, the finding of a 2-fold higher prescription rate for antipsychotic drugs in psychotic versus nonpsychotic MDD patients reflects the current evidence.

Duloxetine plasma level and antidepressant response.

BACKGROUND: Major Depressive Disorder (MDD) is associated with a high rate of inadequate treatment response, which is mainly due to the large inter-individual genetic variability in pharmacokinetic and pharmacodynamic targets of antidepressant drugs. Little is still known about the exact association between plasma level of first-line antidepressants and clinical response. This is particularly true for duloxetine, a dual serotonin and norepinephrine reuptake inhibitor recommended as first-line treatment for MDD. The aim of this study was to investigate the association between serum concentration of duloxetine (SCD) and antidepressant response (AR). METHODS: 66 MDD patients treated with duloxetine 60 mg/day monotherapy were recruited in an outpatient setting and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, at month 1, and at month 3 to assess AR. SCD was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCD and AR. RESULTS: SCD showed a high inter-individual variability in our sample, despite the duloxetine fixed oral dosage. We found a strong association between SCD and AR following a bell-shaped function at month 1 and at month 3. Nonetheless, within the recommended SCD range of 30-120 ng/mL a more linear correlation between SCD and AR was observed. DISCUSSION: Our results suggest that for duloxetine the association between SCD and AR likely follows a bell-shaped quadratic function with poor AR at subtherapeutic SCD and progressive decrease of AR at higher SCD. The maximum antidepressant efficacy seems to require SCD values next to the highest recommended SCD (30-120 ng/mL), probably because of the optimal saturation of both serotonin and norepinephrine transporters. Thus, taking into account the observed high interindividual variability of SCD, our findings suggest that for MDD patients treated with duloxetine, SCD could be a useful tool to guide the treatment by optimizing the oral dosage in order to increase the AR rate.

Opinion paper: poor response to treatment of depression in people in high occupational levels.

The working environment may have a significant effect on response to treatment of depression and this issue has not yet been sufficiently addressed in the scientific literature. There is evidence showing that being engaged in high-level positions can be an obstacle to the success of treatment. This article discusses the few evidence in the literature and some of the possible mechanisms involved. Specific personality attributes and difficulties in adapting to depression may delay access to care and may also reduce treatment compliance. The presence of stress in jobs that require high cognitive function and lack of social support may be elements that hinder the recovery process. Residual symptoms that impact on cognitive functions may undermine adherence to treatment and adversely affect the response. The implications of these issues are potentially relevant for clinical practice in the treatment of depression and for future research.

Relating constructs of attention and working memory to social withdrawal in Alzheimer's disease and schizophrenia: issues regarding paradigm selection.

Central nervous system diseases are not currently diagnosed based on knowledge of biological mechanisms underlying their symptoms. Greater understanding may be offered through an agnostic approach to traditional disease categories, where learning more about shared biological mechanisms across conditions could potentially reclassify sub-groups of patients to allow realisation of more effective treatments. This review represents the output of the collaborative group "PRISM", tasked with considering assay choices for assessment of attention and working memory in a transdiagnostic cohort of Alzheimer's disease and schizophrenia patients exhibiting symptomatic spectra of social withdrawal. A multidimensional analysis of this nature has not been previously attempted. Nominated assays (continuous performance test III, attention network test, digit symbol substitution, N-back, complex span, spatial navigation in a virtual environment) reflected a necessary compromise between the need for broad assessment of the neuropsychological constructs in question with several pragmatic criteria: patient burden, compatibility with neurophysiologic measures and availability of preclinical homologues.

Working definitions, subjective and objective assessments and experimental paradigms in a study exploring social withdrawal in schizophrenia and Alzheimer's disease.

Social withdrawal is one of the first and common signs of early social dysfunction in a number of important neuropsychiatric disorders, likely because of the enormous amount and complexity of brain processes required to initiate and maintain social relationships (Adolphs, 2009). The Psychiatric Ratings using Intermediate Stratified Markers (PRISM) project focusses on the shared and unique neurobiological basis of social withdrawal in schizophrenia, Alzheimer and depression. In this paper, we discuss the working definition of social withdrawal for this study and the selection of objective and subjective rating scales to assess social withdrawal chosen or adapted for this project. We also discuss the MRI and EEG paradigms selected to study the systems and neural circuitry thought to underlie social functioning and more particularly to be involved in social withdrawal in humans, such as the social perception and the social affiliation networks. A number of behavioral paradigms were selected to assess complementary aspects of social cognition. Also, a digital phenotyping method (a smartphone application) was chosen to obtain real-life data.

Social brain, social dysfunction and social withdrawal.

The human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Unfortunately, such a high complexity may also be associated with a high susceptibility to several pathogenic interventions. Consistently, social deficits sometimes represent the first signs of a number of neuropsychiatric disorders including schizophrenia (SCZ), Alzheimer's disease (AD) and major depressive disorder (MDD) which leads to a progressive social dysfunction. In the present review we summarize present knowledge linking neurobiological substrates sustaining social functioning, social dysfunction and social withdrawal in major psychiatric disorders. Interestingly, AD, SCZ, and MDD affect the social brain in similar ways. Thus, social dysfunction and its most evident clinical expression (i.e., social withdrawal) may represent an innovative transdiagnostic domain, with the potential of being an independent entity in terms of biological roots, with the perspective of targeted interventions.

Clinical factors associated with augmentation treatment with second-generation antipsychotics and lithium in major depression - Results from a European multicenter study.

This cross-sectional European multicenter study with retrospective assessment of treatment response sought to determine variables associated with the administration of augmentation strategies with second-generation antipsychotics (SGAs) and lithium in the pharmacotherapy of major depressive disorder (MDD). In 349 DSM-IV-TR MDD patients, differences in socio-demographic, clinical, treatment, and pharmacological features between participants receiving add-on treatment of their antidepressants with either SGAs (n = 318) or lithium (n = 31) were investigated using analyses of covariance, chi-squared tests, and binary logistic regression analyses. As only significant between-group difference, we found SGA augmentation (compared with lithium augmentation) to be associated with high depressive symptom severity expressed by a higher mean Montgomery and Åsberg Depression Rating (MADRS) total score (27.19 ± 11.35 vs 18.87 ± 12.88, F = 14.82, p = < .0001) and a higher mean 21-item Hamilton Rating Scale for Depression (HAM-D) total score (21.27 ± 9.30 vs 13.74 ± 9.11, F = 18.60, p = < .0001). No significant differences for socio-demographic features, psychotic symptoms, suicidality, psychiatric and somatic comorbidities, antidepressant pharmacotherapy, and other add-on medications could be seen. Even if there was no significant superiority of one augmentation strategy with regard to treatment response pattern, a trend whereupon adjunctive SGAs were more likely dispensed in treatment-resistant and difficult-to-treat MDD conditions could be observed. In terms of the prescription pattern, we could demonstrate that lithium is less frequently used than SGAs in the clinical routine care which may reflect the need of continuous plasma level determinations and the anticipation of adverse effects.