Influence of Pathogenic and Metabolic Genes on the Pharmacogenetics of Mood Disorders in Alzheimer’s Disease

Abstract

Background: Mood disorders represent a risk factor for dementia and are present in over 60% of cases with Alzheimer’s disease (AD). More than 80% variability in drug pharmacokinetics and pharmacodynamics is associated with pharmacogenetics. Methods: Anxiety and depression symptoms were assessed in 1006 patients with dementia (591 females, 415 males) and the influence of pathogenic (APOE) and metabolic (CYP2D6, CYP2C19, and CYP2C9) gene variants on the therapeutic outcome were analyzed after treatment with a multifactorial regime in a natural setting. Results and Conclusions: (i) Biochemical, hematological, and metabolic differences may contribute to changes in drug efficacy and safety; (ii) anxiety and depression are more frequent and severe in females than males; (iii) both females and males respond similarly to treatment, showing significant improvements in anxiety and depression; (iv) APOE-3 carriers are the best responders and APOE-4 carriers tend to be the worst responders to conventional treatments; and (v) among CYP2D6, CYP2C19, and CYP2C9 genophenotypes, normal metabolizers (NMs) and intermediate metabolizers (IMs) are significantly better responders than poor metabolizers (PMs) and ultra-rapid metabolizers (UMs) to therapeutic interventions that modify anxiety and depression phenotypes in dementia. APOE-4 carriers and CYP-related PMs and UMs deserve special attention for their vulnerability and poor response to current treatments.

Personalized Management and Treatment of Alzheimer’s Disease

“…Although the diagnostic criteria for AD are relatively well-established by different scientific entities and expert groups [ 18 , 19 , 20 ], there is still a high rate of misdiagnoses and possible overdiagnosis of AD [ 21 ]. In highly specialized centers and in the selection and follow-up of patients undergoing clinical trials for the study of the safety and efficacy of anti-dementia drugs, we recommend a protocol comprising the following items: (i) clinical assessment (general, psychiatric, and neurologic), (ii) blood (biochemistry, hematology, metabolism, hormones, and neurotransmitters) and other body fluids (urine, cerebrospinal fluid) analyses, (iii) neuropsychological and psychometric assessment (cognition, mood, behavior, and motor function) with psychometric tools adapted and validated in each country), (iv) cardiovascular evaluation (ECG), (v) structural neuroimaging, (vi) functional neuroimaging, (vii) genetic screening (gene clusters of AD and cerebrovascular pathogenic genes), and (viii) pharmacogenetic profiling [ 13 , 22 , 23 , 24 ] ( Table 1 , Table 2 , Table 3 and Table 4 ).…”

“…About 50% of men do not show anxiety, whereas only 30% of women with dementia are free of symptoms in early stages of the disease. Both anxiety and depression fluctuate with the clinical course of the disease [ 24 , 27 , 28 , 29 , 30 ]. Behavioral disorders and psychotic symptoms are also frequent (20–90%) in patients with AD along the clinical course of the disease [ 24 , 31 , 32 ].…”

“…Both anxiety and depression fluctuate with the clinical course of the disease [ 24 , 27 , 28 , 29 , 30 ]. Behavioral disorders and psychotic symptoms are also frequent (20–90%) in patients with AD along the clinical course of the disease [ 24 , 31 , 32 ].…”

“…Several pharmacogenetic studies agree that APOE-4 carriers respond poorly to conventional treatments, while APOE-3 carriers tend to respond better to different therapeutic regimens. Similarly, normal metabolizers (NMs) and intermediate metabolizers (IMs) associated with the different genotypes of the CYP2D6 , CYP2C9 , and CYP2C19 genes show a better therapeutic response than poor metabolizers (PMs) and ultra-rapid metabolizers (UMs) to treatments with anti-dementia drugs and psychotropic drugs to regulate aberrant behaviors [ 24 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].…”

“…When analyzing the pharmacogenetics of multifactorial treatments based on CYP variants ( CYP2D6 , CYP2C9 , CYP2C19 , and CYP3A4/5 ), in most cases, in Caucasian patients (with large variations in other ethnic groups), it is observed that carriers of CYP2D6 -NM geno-phenotypes are the best responders, while CYP2D6 -PMs tend to be poor responders to common treatments. Carriers of CYP2D6 -IM and CYP2D6 -UM geno-phenotypes show intermediate responses between those observed in NMs and PMs [ 11 , 12 , 13 , 15 , 24 , 44 , 60 , 66 , 67 , 100 ].…”