Mental Health & Neurological

Drug & Alcohol Testing, Mental Health & Neurological

Amitriptyline is a tricyclic antidepressant that blocks the reuptake of serotonin at nerve endings and possesses high anticholinergic activity and cardiovascular toxicity. The drug is extensively metabolized to many polar compounds, the chief of which is nortriptyline. It is also an antidepressant. Both drugs are prescribed for depression and a range of other disorders.Amitriptyline has a peak serum concentration two to six hours postoral dose, and steady-state is achieved after three to eight days of chronic oral dosing. The half-life is 17 to 40 hours and the usual therapeutic range (predose sample at steady-state) includes nortriptyline and is 80−200 ng/mL. Nortriptyline is administered orally, has a half-life of 15 to 90 hours, and peak serum values two to six hours postoral dose. Steady-state is achieved after 4 to 20 days of chronic dosing. Therapeutic levels of nortriptyline alone are 50−150 ng/mL.All the tricyclic antidepressants have significantdrug interactions. Being potent inducers of hepatic drug-metabolizing enzymes, particularly CYP3A4, CYP1A2, and CYP2C9, the antiepileptic drugs, carbamazepine, phenytoin, phenobarbital, and primidone stimulate the oxidative transformation of concurrently prescribed antidepressants.1This results in decreased drug levels of the antidepressant. To a lesser extent, co-administration of oxcarbazepine, topiramate, and felbamate can also result in decreased antidepressant levels.Other tricyclic antidepressant drug interactions:hydrocortisone, methylphenidate, and phenothiazines increase tricyclic levels; tricyclics impair the antihypertensive effectiveness of clonidine and guanethidine; tricyclics and alcohol produce additive sedative effects, tricyclics and antiparkinsonism agents have potent anticholinergic side effects, and tricyclics and MAO inhibitors should not be co-administered because of the potential for antihypertensive and CNS crises.Tricyclics should be avoided in pregnant and lactating women because these drugs have not been established as safe. Geriatric patients are especially prone to postural hypotension, urinary retention, and sedation.2In general, it has been reported that, “Therapeutic drug monitoring of antidepressants allows us to take into account the influence of factors such as co-medications, diet, smoking habit, impaired organ function, and compliance. Therapeutic drug monitoring and genotyping are thus complementary, and their combined use contributes to improve pharmacotherapy with antidepressants and other drugs.”3

Drug & Alcohol Testing, Mental Health & Neurological

Topiramate is an anticonvulsant drug used as an adjunctive therapy in the treatment of patients with partial and secondary generalized epilepsy. Topiramate is a sulfamate-substituted monosaccharide, derived from D-fructose. The animal models suggest that topiramate exerts its anticonvulsant effect primarily by blocking the spread of seizures, rather than by elevating the seizure threshold. Pharmacokinetic studies in humans have shown that topiramate is absorbed rapidly, excreted largely unchanged in the urine.1Carbamazepine and phenytoin can significantly induce the metabolism of topiramate, whereas valproic acid has only a slight influence on topiramate concentrations.2The elimination half-life of topiramate is 18 to 23 hours and is dose-dependent; however, children, as differentiated from adults, can require at least a twofold increase in dose to achieve a comparable plasma level.3The drug is approximately 15% protein bound. Although carbamazepine and phenytoin induce the metabolism of topiramate and shorten its half-life, topiramate has no significant effect on the plasma concentrations of these drugs or valproic acid. Maintenance doses of topiramate, given twice daily, range from 300−600 mg/day. Side effects include dizziness, reduced cognitive function, weight loss, and headache. As observed with many therapeutic agents, the interpatient variability in clinical response at similar topiramate plasma concentration can be appreciable. Differences in plasma levels between responders, nonresponders, and seizure-free patients can be indiscernible.

Mental Health & Neurological

Approximately 1 in every 2500 individuals has inherited defective or deficiency of the enzyme (pseudocholinesterase) that metabolizes succinylcholine (an anesthetic agent). With "normal" dosage, these individuals have prolonged apnea. Such individuals are responsive at much smaller concentrations of this anesthetic agent than the general population. Low concentrations of pseudocholinesterase are observed in individuals exposed to organophosphorous insecticides and patients with hepatic dysfunction.

Mental Health & Neurological, Hormone Testing

Measurement of dopamine levels in urine or blood in addition to urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels may aid in the biochemical diagnosis and monitoring of neuroblastomas [1]. This test may also be useful in evaluating dopamine-secreting pheochromocytomas and paragangliomas (PPGLs) [2].Neuroblastomas occur predominantly in children and are the most common malignancy under 1 year old. Neuroblastomas are catecholamine-metabolizing tumors, and thus catecholamine metabolites (including VMA and HVA) are more reliable than catecholamines as biochemical markers for neuroblastomas [1]. However, urinary VMA and HVA levels may have limited accuracy for diagnosis of neuroblastomas with high-risk metastatic biology [1]. Because poor prognosis is associated with immaturity of catecholamine metabolism, dopamine levels in urine or blood have been proposed as an additional marker to aid in diagnosis and monitoring of neuroblastomas [3].Most PPGLs secrete catecholamines, but the relative amount of dopamine, norepinephrine, and epinephrine varies widely. Measurements of plasma free or urinary fractionated metanephrines (ie, the O-methylated catecholamine metabolites) are recommended by the Endocrine Society for the initial biochemical testing of PPGLs [4]. In patients with high clinical suspicion but normal blood pressure and normal levels of metanephrines, measurement of dopamine and its metabolites (HVA and methoxytyramine) may help diagnose PPGLs that predominantly secrete dopamine [2].The results of this test should be interpreted in the context of pertinent clinical and family history and physical examination findings.References1. Eisenhofer G. Monoamine-producing tumors. In: Rifai R, et al. eds.Tietz Textbook of Laboratory Medicine. 7th ed. Elsevier Inc; 2022.2. Jain A, et al.Pediatr Nephrol. 2020;35(4):581-594.3. Brodeur GM, et al.J Clin Oncol. 1993;11(8):1466-1477.4. Lenders JW, et al.J Clin Endocrinol Metab. 2014;99(6):1915-1942

Drug & Alcohol Testing, Mental Health & Neurological

Levetiracetam (LTA), a piracetam analogue, is an antiepileptic drug (AED) structurally unrelated to other AEDs. The exact mechanism by which LTA acts has not been determined at this time; however, binding sites for the drug have been identified in synaptic plasma membranes of CNS neurons. Secondary alteration in GABA-related enzymes may result from binding to neurons in specific regions of the CNS.1While approximately one-fourth of LTA is converted by enzymatic hydrolysis to a carboxylic acid metabolite, the drug has no effect on UDP glucuronyltransferase, epoxide hydrolase, or enzymes in the CYP system,1,2resulting in minimal interactions with other AEDs in a polypharmacy regimen. LTA has minimal protein binding (<10%), an elimination half-life of six to eight hours in healthy adults, six hours in children, and 10-11 hours in the elderly. In healthy adults, approximately 95% of LTA and metabolites are excreted in the urine. Renal impairment can, therefore, decrease clearance from 35% to 60%.3,4A single 1000 mg dose or 1000 mg twice daily doses produced peak levels of 31 μg/mL and 43 μg/mL, respectively.3Neuropsychiatric adverse events of aggression, anger, and irritability, as well as adverse reactions of leukopenia, neutropenia, pancytopenia, and thrombocytopenia have been reported.5

Mental Health & Neurological, Hormone Testing

Serotonin concentrations are greatly increased in patients with carcinoid syndrome. Carcinoid tumors are associated with Multiple Endocrine Neoplasia (MEN) Types I and II. These tumors are associated with flushing, diarrhea, pain, and other symptoms.

Mental Health & Neurological, Drug & Alcohol Testing

This test may be used to detect exposure to or poisoning from organophosphate-based pesticides; to assess baseline levels before exposure to organophosphates; or to monitor cholinesterase levels in individuals who work with pesticides. This test is also used in the diagnosis of inherited pseudocholinesterase deficiency, for individuals with a family history who will be receiving the muscle relaxant succinylcholine during surgery.The Cholinesterase, Serum assay is often used as part of the diagnostic evaluation for individuals who present with symptoms of pesticide poisoning. Symptoms of organophosphate poisoning can range from mild to severe and may include sweating, salivation, miosis, hypotension, urinary incontinence, mental confusion, gastrointestinal spasms, anxiety, insomnia, tremors, convulsions, respiratory depression, and circulatory collapse, among others [1].This test is also used in the diagnosis of inherited pseudocholinesterase deficiency, an enzyme deficiency characterized by impaired metabolism of succinylcholine, a muscle relaxant for surgical anesthesia. Individuals with this disorder who receive succinylcholine are at risk for prolonged postsurgical apnea and paralysis lasting 2 or more hours [2]. Thus, testing may be helpful to evaluate individuals who present with these symptoms postsurgically, as well as those with a family history of pseudocholinesterase deficiency who are scheduled for surgery.References1. Lessenger JE, Reese BE.J Am Board Fam Pract. 1999;12:307-314.2. Soliday FK, et al.AANA J. 2010;78:313-320.

Mental Health & Neurological, Drug & Alcohol Testing

True cholinesterase (RBC and plasma) activity is decreased in individuals with exposure to organophosphorous insecticides. True cholinesterase, found in erythrocytes and nerve tissue, is responsible for inactivating acetylcholinesterase at nerve endings. With decreased enzyme activity, patients may display a range of nervous system dysfunction. Analysis of RBC and serum or plasma activity is useful in monitoring exposure and recovery.

Genetic Testing, Mental Health & Neurological

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Mental Health & Neurological

This panel may aid in evaluating catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). However, measurements of plasma free or urinary fractionated metanephrines (ie, the O-methylated catecholamine metabolites) are preferred for the initial biochemical evaluation of PPGLs because of their overall high diagnostic sensitivity [1]. To adjust for the concentration differences in random urine specimens, results are expressed as catecholamine to creatinine ratios.Most PPGLs secrete catecholamines and can cause catecholamine excess, resulting in hypertension, arrhythmia, and hyperglycemia. Left untreated, PPGLs often lead to life-threatening cardiovascular complications. The estimated prevalence of PPGLs is 0.05% to 0.1% in adults with hypertension and 1.7% in children with hypertension [2]. Recognizing the possibility of a PPGL and performing appropriate biochemical testing are crucial for the diagnosis [1]. Plasma or urine catecholamine levels may be used, in addition to metanephrine levels, to provide additional information during the initial biochemical evaluation of PPGLs (eg, when detecting dopamine-secreting paragangliomas) [2].Intermittent or insignificant secretion of catecholamines by some PPGLs may not increase catecholamine measurements. Physiological stress and certain medications (eg, acetaminophen, labetalol, and sotalol) may increase catecholamine measurements [1].The results of this test should be interpreted in the context of pertinent clinical and family history and physical examination findings.References1. Lenders JW, et al.J Clin Endocrinol Metab. 2014;99(6):1915-1942.2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Neuroendocrine and Adrenal Tumors. V1.2022. Accessed June 28, 2022.http://www.nccn.org

Drug & Alcohol Testing, Mental Health & Neurological

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Mental Health & Neurological

Definitive diagnosis of Alzheimer disease (AD) is established by autopsy confirmation of two major pathological hallmarks: extracellular amyloid plaques consisting of aggregated amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles containing abnormally phosphorylated tau (pTau).3Up to a third of living individuals diagnosed with AD exclusively on the basis of clinical symptoms do not have AD neuropathological changes post-mortem.4A biological definition of AD was recently proposed by the National Institute on Aging and the Alzheimer's Association (NIA-AA).5According the AT(N) system that they proposed, AD is biologically defined by biomarker evidence determined by either CSF biomarker concentrations or via Positron Emission Tomography (PET) of Aβ or tau, regardless of the accompanying clinical syndrome.5In this framework, neurodegeneration (N) is defined by MRI-based identification of hippocampal atrophy or glucose hypometabolism (fluorodeoxyglucose PET), elevation of CSF total tau or elevation of CSF NfL.5In living individuals, AD-related pathophysiological changes can be accurately detected with PET imaging of the intensity and distribution of Aβ plaques and tau neurofibrillary tangles, structural MRI of brain atrophy,6and/or the evaluation of alterations in CSF levels of Aβ1–42 (or the Aβ1–42 to Aβ1–40 ratio), phosphorylated tau (pTau) and total tau (or neurofilament light (NfL).7-9These established biomarkers are predictive of autopsy findings,10,11and are thus included in research and clinical criteria for the definition and staging of AD.5,12-14The mid-region of tau protein has several threonine and serine residues that can be phosphorylation by specific kinases.15-18This phosphorylation can occur at numerous locations, including amino acids 181, 199, 202, 205, 217, 231, 235 and 396. pTau has known physiological functions, including maintenance of microtubule assembly and stability.19However, excessive phosphorylation has pathophysiological consequences.20,21In patients with AD, some fractions of the phosphorylated tau pool in the brain progressively aggregate into insoluble filamentous deposits that can be detected in neuropathology and PET investigations.16,22Concomitantly, some soluble pTau fractions accumulate in the CSF, where they can be detected and quantified to provide indirect evidence of disease state.9,23-27The accumulation of pTau in the CSF seems to be specifically induced by Aβ pathology (plaques) and does not occur to a significant extent in individuals with Aβ-negative non-AD tauopathies.28As a consequence, CSF pTau is used as an indirect marker of AD-type brain tau pathology and increases with disease progression and is associated with incremental neurofibrillary tangle formation.28-32A fraction of the pTau protein in the CSF diffuses into the blood where it too can be measured in the assessment of AD status.28,33The clinical application of plasma p-tau biomarkers in AD has been reviewed extensively.34-38The measurement of plasma of pTau phosphorylated and amino acid 181 (pTau-181) for the assessment of AD clinical status has been investigated in numerous clinical settings.15,25,37,39-67Plasma pTau-181 concentrations have been shown to correlate with tau PET in patients suspected of having AD.49,55,62,64,68Plasma pTau-181 levels have been shown to be higher in Aβ-positive, tau-negative individuals than in Aβ-negative, tau negative individuals.15,55pTau-181 levels are generally higher in patients with preclinical AD (i.e., early stage disease where individuals do not have overt symptoms but are positive for CSF or PET biomarkers; these individuals are often Aβ-positive but tau-negative) than in patients otherwise healthy individuals.15,25,41,42,53,57,65,68A relative elevation of pTau-181 has also been observed in patients with prodromal AD (i.e., individuals with mild cognitive impairment who are positive for CSF or PET biomarkers).2,15,41,54,57Evidence from multiple studies has shown that plasma pTau-181 levels increase as patients with AD progress to dementia.49,55-57,60-62,64,68Other studies have found that plasma pTau-181 concentration differentiated individuals with autopsy-verified AD dementia from Aβ-negative control participants.15,37,44,52,69In familial AD, plasma levels of pTau-181 were higher in symptomatic mutation carriers than in cognitively healthy non-carriers.57Plasma pTau-181 accurately differentiated individuals with Down syndrome dementia from individuals with Down syndrome and no dementia and age-matched control participants.54,67A number of studies have found that plasma pTau-181 concentrations increase with AD disease progression and worsening of cognition, brain Aβ burden, brain tau burden and brain atrophy.7,15,40,41,44,51,55-58,62,68,70-72Numerous studies have reported that measurement of plasma pTau-181 can predict the extent of brain amyloid and tau as measured by PET.9,15,29,39-62In general, these studies have included patients with limited clinical pathologies other than those associated with AD. As a consequence, it has been suggested that the results of these studies may not be completely generalizable to the population as a whole.2In a recent study, Mielke and coworkers2evaluated factors that could affect the interpretation of the plasma pTau-181 at the population level. Their study of the concentration of plasma pTau-181 in a community-based cohort allowed them to discern the effect of coexisting comorbidities on the measured concentrations of plasma pTau-181. Consistent with previously published studies,49Mielke found that plasma pTau-181 increased with age starting between the ages of 65 and 70 years. However, they found that this increase was most pronounced among those with elevated brain amyloid. A diagnosis of chronic kidney disease (CKD) or a history of myocardial infarction (MI) or clinical stroke also had an effect on the population distribution of plasma pTau-181 concentrations.2By testing a reference population consisting of amyloid negative individuals with no history of CKD, MI or stroke, Mielke went on to define a single, fixed clinical threshold for plasma pTau-181 for all ages.2Using this single threshold, they reported that plasma pTau-181 proved to be an excellent predictor of elevated brain amyloid and tau PET in the entorhinal cortex.2Based on this finding, Labcorp has defined a single clinical threshold for pTau-181 using a ostensibly normal, chemically screened population of individuals between 20 and 55 years of age. This clinical threshold is applied as a “reference Interval” for all patient reports.

Mental Health & Neurological

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Genetic Testing, Mental Health & Neurological

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Mental Health & Neurological

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Genetic Testing, Mental Health & Neurological

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Mental Health & Neurological

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Mental Health & Neurological, Autoimmune & Inflammation

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Mental Health & Neurological

Current research indicates that plasma p-tau, including p-tau 217, is concordant with amyloid status defined by either CSF biomarker testing or PET scan analysis, and is able to differentiate between AD and non-AD neurodegenerative diseases and to predict progression to AD. Blood-based biomarkers, such as plasma p-tau, could potentially be used as inclusion criteria or to evaluate target engagement and treatment efficacy, and could further advance the development of disease-modifying treatments in the field of AD and related disorders. This assay is designed specifically for the quantitative measurement of tau phosphorylated at threonine 217 (p-tau 217) in human plasma.

Mental Health & Neurological, Autoimmune & Inflammation

Neuromyelitis optica (NMO), also known as Devic's disease, is an immune-mediated neurologic disorder that causes very severe, often bilateral, optic neuritis and longitudinally extensive spinal cord lesions.2,3Historically, NMO was thought to be a form of multiple sclerosis;3however, the nerve damage suffered by patients with NMO has been shown to be distinct from that found in patients with multiple sclerosis.2-4Patients with NMO can present with a variety of symptoms, including visual impairment, muscle weakness, reduced peripheral sensation, and loss of bladder and/or bowel control.5NMO typically follows a relapsing course without marked remission between flare-ups. Neural damage tends to be cumulative, resulting in rapid progression of disability and the development of irreversible deficits.6Recently, antibodies to the most abundant water channel in the central nervous system, aquaporin-4 (AQP4), have been found in patients with NMO.1These antibodies, referred to as AQP4-Ab or NMO-Ab, have been detected in 60% to 90% of patients with NMO and have been shown to correlate with NMO disease activity.1,3NMO-Ab have also been observed in some patients with limited forms of the disease (NMO spectrum disorders), including longitudinally extensive transverse myelitis (LETM) and isolated optic neuritis. Studies have demonstrated that injection of NMO-Ab-positive serum into animals or cultured cells expressing AQP4 produces a disruption of the blood-brain barrier, impairment of glutamate homeostasis, and induction of necrotic cell death.3These studies suggest a direct role of NMO-Ab in the pathogenesis of NMO.Immunoassays employing a variety of different immunological techniques for the detection of NMO-Ab in patients with NMO have been described.3Wingerchuk and associates have proposed a set of criteria for the diagnosis of neuromyelitis optica that incorporate the assessment of NMO-Ab status.7This guideline suggests that the diagnosis of NMO requires two absolute criteria (optic neuritis and acute myelitis) plus at least two of three supportive criteria, one of which is NMO-Ab seropositive status. Measurement of NMO-Ab can be of value in distinguishing NMO from MS when full clinical features may not be apparent and early intervention may prevent or delay disability. Early diagnosis of NMO is critical for avoiding the cumulative effects that result in progressive disability. A positive value is consistent with NMO or a related disorder and helps justify initiation of appropriate therapy.Four hundred thirty-three samples routinely submitted for NMO-Ab testing were tested by both the aquaporin-4 autoantibody ELISA and indirect immunofluorescence assay (IFA) performed at Mayo Clinic Laboratory.898.1% of results were in agreement with a positive result agreement of 78.6% and negative result agreement of 98.8% (IFA as reference method). These results are comparable to those observed in a previously published study comparing an ELISA to IFA for diagnosing NMO.9

Mental Health & Neurological, Autoimmune & Inflammation

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Autoimmune & Inflammation, Mental Health & Neurological

Myasthenia gravis (MG) is a chronic, autoimmune disease of the motor system characterized by fatigable weakness with sensory and autonomic sparing.MG is caused by autoantibodies against proteins of the neuromuscular junction. Most cases of generalized MG are anti-acetylcholine receptor (AChR) antibodypositive; a sub-fraction of MG patients produce antibodies against Muscle Specific receptor tyrosine Kinase (MuSK).Of generalized MG patients who lack anti-AChR antibodies (AChR-seronegative), about 40% are positive for Muscle-Specific Kinase (MuSK) antibody.MuSK MG accounts for 5-8% of all MG and is characterized by prominent facial, bulbar and respiratory weakness, frequent respiratory crises, and atrophy of the tongue and masseter muscles.MuSK antibody levels have been shown to correlate with disease severity. Serial measurements may be useful to follow treatment.

Autoimmune & Inflammation, Mental Health & Neurological

Myasthenia gravis (MG) is a chronic, autoimmune disease of the motor system characterized by fatigable weakness with sensory and autonomic sparing.MG is caused by autoantibodies against proteins of the neuromuscular junction. Most cases of generalized MG are anti-acetylcholine receptor (AChR) antibodypositive; a sub-fraction of MG patients produce antibodies against Muscle Specific receptor tyrosine Kinase (MuSK).Of generalized MG patients who lack anti-AChR antibodies (AChR-seronegative), about 40% are positive for Muscle-Specific Kinase (MuSK) antibody.MuSK MG accounts for 5-8% of all MG and is characterized by prominent facial, bulbar and respiratory weakness, frequent respiratory crises, and atrophy of the tongue and masseter muscles.MuSK antibody levels have been shown to correlate with disease severity. Serial measurements may be useful to follow treatment.

Mental Health & Neurological, Autoimmune & Inflammation

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Mental Health & Neurological, Autoimmune & Inflammation

Neuromyelitis optica spectrum disorders (NMOSDs), classified as immune-mediated chronic and frequently recurring inflammatory conditions, primarily impact the optic nerve and spinal cord. While NMOSDs can occur in any demographic, they tend to be more prevalent in middle-aged and elderly women. Due to the presence of similar symptoms such as optic neuritis and transverse myelitis, NMOSDs are sometimes misdiagnosed as multiple sclerosis (MS). However, distinguishing factors between the two conditions include the clinical progression, the location and size of lesions in the brain and/or spinal cord, the occurence of optic neuritis, and the detection of specific autoantibodies like aquaporin-4 receptor (AQP4) or myelin oligodendrocyte glycoprotein (MOG) IgG. Once initial non-specific tests have been conducted to exclude infections, vasculitis and other conditions that may resemble NMOSDs in their presentation, it is recommended to assess the serum antibody status for AQP4 IgG and MOG IgG. The detection of AQP4 IgG antibodies in the appropriated clinical context confirms the presence of NMOSDs. In patients with MS, AQP4 IgG testing generally yields negative results, whereas around 75% of NMOSD patients show antibodies targeting the AQP4 receptor. Although a small percentage of individuals with clinical symptoms suggestive of NMOSDs may test negative for AQP4 IgG, they may still have detectable serum MOG IgG antibodies. It is important to note that the absence of both AQP4 IgG and MOG IgG antibodies does not exclude the diagnosis of NMOSD, and it is advisable to consider retesting before initiating antibody-targeted therapies.