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Issue 107, Mar 2021
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Clinical drug-drug interactions and elevated serum lithium levels in daily practice

Wilting I et al. Bipolar Disord. 2005. Jun; 7;(3):274-80. doi:10.1111/J.1399-5618.2005.00199.x

PMID:158988965

Background

Lithium is a drug with a narrow therapeutic window. Concomitantly used medication can alter lithium levels. This study aimed to investigate the lithium-related drug interactions resulting in the elevation of lithium levels in clinical practice.

Methods

This is a Dutch multicenter retrospective study involving 12 hospitals. The cases included were patients with an increase of at least 50% in lithium serum concentrations resulting in an elevated serum lithium level of at least 1.3 mmol/L, and who were not suspected of a suicide attempt. The date of the elevated lithium level was called the index date and the prior lithium level had to be within six months prior to the index date. Controls were patients who showed stable lithium serum levels within the therapeutic range. The use and start of non-steroidal anti-inflammatory drugs, diuretics, renin-angiotensin inhibitors, theophylline, and antibiotics were investigated as potential determinants of elevated lithium serum levels. Irregularity in lithium dispensing pattern, change in lithium dosing regimen, age, gender, prescribing physician, and laboratory parameters were investigated as potential confounders.

Results

There were N= 51 cases and 51 controls. Five (9.8%) controls and 15 (29.4%) cases used potentially interacting co-medication. The start of potentially interacting co-medication was observed in eight (15.7%) cases and zero (0%) controls which is a significant difference. After adjustment for co-medication, irregularity in lithium dispensing pattern, change in lithium dosing regimen, and age, the statistically significant association was lost. The prescription of antibiotic agents and the irregular dispensing pattern of lithium contributed to significantly elevated lithium levels in the cases.

Conclusions

The use of co-medication, especially antibiotics, tends to be associated with elevated lithium serum levels. It is important to check lithium levels.

Clinical Commentary

This is a unique study published in 2005 but extremely relevant to current clinical practice. It assesses elevated serum levels of lithium related to comedication treatments. The elevation threshold is 50% above the previous lithium level done within the last six months. The strengths include the evaluation of drug-drug interaction concerning serum lithium levels in a clinical setting. The limitations are the small sample size and retrospective design.

Clinical insights

  • The start of a potentially interactive medication is associated with elevated serum lithium levels. No specific drug seemed to be more associated with elevated serum levels.
  • Irregularity in lithium dispensing is statistically significantly associated with elevated serum lithium levels.
  • The use of antibiotics was significantly associated with increased serum lithium levels, which was not related to any particular antibiotic but more to the drug-disease state. The levels may be increased as a result of fever, underlying infection, or poor fluid intake.

Review of mechanisms of elevated serum lithium level

  • NSAIDs: decrease glomerular filtration rate (GFR) by inhibiting prostaglandin synthesis thereby elevating the serum lithium concentration
  • Diuretics: cause sodium depletion and thereby lithium retention via reduced renal clearance.
  • RAS inhibitors: volume depletion leading to reduced GFR and hence reduced lithium clearance
  • Antibiotics: no direct mechanism but via fever, diarrhea, reduced water and food intake, and as a result of the infection

Theophylline reduces lithium level by inducing lithium clearance via unknown mechanisms

Lithium-induced hypercalcemia and hyperparathyroidism are more common than we expect. The prevalence of hypercalcemia may vary from 5-25% in various studies. Even normal or high-normal parathyroid hormone level indicates hyperparathyroidism in the face of increased calcium levels.

Summary

In my professional opinion any patient on lithium who is prescribed an antibiotic, a lithium level should be checked. We should also look for irregularities in lithium dispensing patterns.

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Lithium-related medication problems on nonpsychiatric inpatient medical units

Alastanos JM et al. Am J Health Syst Pharm. 2019 Nov 13;76 (Supplement 4):S96-S101 (5) doi: 10.1093/ajhp/zxz212

PMID:31557277

Background

Lithium is a medication with a narrow therapeutic and safety index. This study investigated medication-related problems (MRPs) associated with lithium use on medical inpatient units.

Methods

This is a single site retrospective study.  The records of all patients hospitalized over a 21-month period who received lithium or had a documented serum lithium concentration during hospitalization were evaluated. The primary objective was to identify patient-specific factors associated with lithium MRPs on nonpsychiatric inpatient medical units. Secondary objectives included the characterization of lithium MRPs. Identified MRP occurrences were further evaluated to determine if an intervention was necessary to resolve the MRP and whether or not an intervention was made.

Results

150 patients were included in the study. One or more lithium MRPs were identified in 85% of the patients, with a total of 255 lithium MRPs identified. None of the patient-specific factors analyzed were significantly associated with MRP occurrence. Of the 128 patients in whom a lithium MRP occurred, 92.2% (n = 118) were judged to be appropriate candidates for interventions as defined per the study definitions; among those 118 patients, such interventions were documented for only 40.7% (n = 48).

Conclusions

Lithium MRPs were found to have occurred frequently on nonpsychiatric inpatient medical units. Laboratory test-related MRPs and drug-drug interactions were the most commonly identified types of MRPs. Interventions to address MRPs were not made in the majority of patients; however, interventions were more frequently made when psychiatry consultation was involved.

Clinical Commentary

Despite being a retrospective study, this paper provides useful clinical insights. The limitations of this study included the retrospective study design, single site, and electronic medical record review. Not all adverse events of lithium were included. Recent medication changes that may have occurred in the outpatient setting were not recorded.

Medications prescribed with lithium that may increase serum lithium concentrations: Nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors (ACE), Angiotensin receptor blockers (ARBs), thiazide, loop, and potassium-sparing diuretics. Medications that decrease lithium concentrations:  carbonic anhydrase inhibitors, osmotic diuretics, methylxanthines, and sodium bicarbonate.

Calcium channel blockers (CCB) may increase intracellular concentrations of lithium and carbamazepine may increase the risk of neurotoxicity when combined with lithium.

Clinical Insights:

  • Lithium related MRPs are common on non-psychiatric inpatient units
  • Lithium levels were not done at medical admission and when obtained were at the suboptimal time. Ideally, the lithium level should be done 10-12 hours post-dose to get a trough level.
  • No pregnancy test was performed before administration of lithium.
  • Approximately 16 % of lithium levels were therapeutic while 32% were subtherapeutic and about 10 % were supratherapeutic.
  • The most common interacting medications prescribed were NSAIDs, loop diuretics, ACE inhibitors, potassium-sparing diuretics, thiazide diuretics, and ARBs.
  • 60% of individuals received a new medication that would increase lithium concentration and 7% had a new interacting medication in addition to a home interacting home medication. Only 4% had subsequent lithium levels to check for changes in lithium concentration.
  • A psychiatric consult was ordered in 1/3 of these patients on the medical service and when ordered an intervention was necessary for 70% of the individuals. In those patients where a psychiatric consult was not ordered 83% needed an intervention.
  • The MRPs were not just elevated lithium levels but also drug-disease issues such as kidney injury, non-optimal dosing, and non-optimal drug including formulation.

Summary

In my professional opinion, lithium is an excellent drug but needs careful monitoring due to its narrow therapeutic index. Before starting lithium, a pre lithium work-up including CBC with diff, TSH, electrolytes, renal function, and pregnancy testing in women of childbearing age. The lithium levels need to be done 5-7 days post-dose adjustment or when a medication that could alter the level is added. Periodic monitoring of stable patient should include levels with TSH and renal function every 3-6 months or as clinically determined. The patient must be educated regarding these issues. We should also periodically educate our medical colleagues regarding lithium related issues in the medical inpatient units. Specifically, if a medically hospitalized patient is on lithium please obtain a full list of discharge medications, check for drug interactions, and order a serum lithium level 10-12 hours post-dose.

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Pharmacokinetic drug-drug interactions of mood stabilizers and risperidone in patients under combined treatment

Schoretsanitis G et al. J Clin Psychopharmacol 2016 Dec; 36 (6):554-561. doi: 10.1097/JCP.000000000000601

PMID:27811552

Background

The combination of anticonvulsant mood stabilizers with antipsychotic drugs may lead to clinically relevant drug-drug interactions. This study aimed to identify pharmacokinetic interactions of various mood stabilizers on the metabolism of risperidone (RIS).

Methods

This is a retrospective study conducted in Germany. A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxy-RIS (9-OH-RIS) of 1,584 adult patients was analyzed. Four groups (n = 1,072) were compared: a control group without a potentially cytochrome interacting comedication (R0, n = 852), a group co-medicated with valproate (VPA) (RVPA, n = 153), a group co-medicated with lamotrigine (LMT) (RLMT, n = 46), and a group under concomitant medication with carbamazepine (CBZ) (RCBZ, n = 21). Dose-adjusted plasma concentrations (C/D ratio) for RIS, 9-OH-RIS, and active moiety (AM) (RIS + 9-OH-RIS), as well as metabolic ratios (RIS/9-OH-RIS), were computed.

Results

The groups did not differ with regard to the daily dosage. Statistically significant differences were detected for the distributions of the C/D ratios for RIS, 9-OH-RIS, and AM. Differences remained significant after conducting a Bonferroni correction. Pairwise comparisons of the concomitant medication groups with the control group revealed significant differences; RIS C/D ratios were statistically significantly higher in the VPA and the LMT group than in the control group. However, these differences did not remain significant after the Bonferroni correction. In contrast, CBZ-treated patients showed lower dose-adjusted plasma concentrations of 9-OH-RIS as well as the AM than the control group; this difference survived the Bonferroni correction.

Conclusions

The data provide evidence for pharmacokinetic interactions between RIS and different anticonvulsant mood stabilizers. Carbamazepine decreased serum concentrations of 9-OH-RIS and the AM when compared with the control group. In the case of VPA and LMT, findings were less significant; hints for a weak RIS metabolism inhibition by LMT of unclear clinical significance were found.

Clinical Commentary

This study is of high value for clinicians. Guidelines worldwide recommend co-prescribing of second-generation antipsychotics as augmentation therapy to mood stabilizers or vice-versa in the treatment of bipolar disorder, especially for manic episodes. Risperidone is a commonly used atypical antipsychotic hence the importance of this study. The strengths include recognizing these important interactions and limitations include the retrospective nature of the study. The Bonferroni correction is a statistical procedure used to correct for multiple comparisons.

Clinical insights:

  • CYP2D6 inhibition and CYP3A4 induction and inhibition play an important role concerning risperidone interactions with mood stabilizers.
  • Risperidone is metabolized to 9-OH-Risperidone (paliperidone/ brand name Invega). The active moiety includes a combination of both drugs.
  • There can be clinically relevant changes in risperidone levels with comedication with mood stabilizers For example valproic acid and lamotrigine increase risperidone levels, while carbamazepine causes a substantial decrease. This interaction is of high significance and clinical importance.
  • Be cautious with carbamazepine as autoinduction can occur because this drug induces CYP3A4 inducing its metabolism into carbamazepine epoxide which is an anticonvulsant also. The autoinduction can begin within 30 days of starting therapy.

Summary

In my professional opinion, these combinations using risperidone are clinically sound but we need to monitor plasma levels. Monitoring needs to be performed after dosage changes and periodically every 3-6 months. In the case of carbamazepine and valproic acid, I also suggest checking CBC with diff and liver profile.   

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Drug interactions of psychiatric and COVID-19 medications

Mohebbi N. et al.  Basic Clin Neurosci. Mar 2020;11 (12):185-200. doi:10.32598/bcn.11.covid19. [Epub 2020 Apr27]

Background

Coronavirus disease 2019 (COVID-19) has resulted in a pandemic leading to morbidity, mortality, and economic losses worldwide. The co-prescription of psychotropics with COVID-19 medication is not uncommon. Healthcare providers should be familiar with many potential Drug-Drug Interactions (DDIs) between COVID-19 therapeutic agents and psychotropic drugs based on cytochrome P450 metabolism. This review comprehensively summarizes the current literature.

Methods

Medical databases, including Google Scholar, PubMed, Web of Science, and Scopus were searched to identify studies in English with keywords related to psychiatric disorders, medications used in the treatment of psychiatric disorders, and COVID-19 medications.

Results

There is a great potential for DDIs between psychiatric and COVID-19 medications ranging from interactions that are not clinically apparent (minor) to those that produce life-threatening adverse drug reactions, or loss of treatment efficacy. The majority of interactions are pharmacokinetic interactions via the cytochrome P450 enzyme system.

Conclusions

DDIs are a major concern in the comorbidity of psychiatric disorders and COVID-19 infection resulting in the alteration of expected therapeutic outcomes. The risk of toxicity or lack of efficacy may occur due to a higher or lower plasma concentration of medications. However, psychiatric medication can be safely used in combination with COVID-19 pharmacotherapy with either a wise selection of medication with the least possibility of interaction or careful patient monitoring and management.

Clinical Commentary

Patients suffering from COVID19 have significant morbidity. This disease has been reported to cause neuropsychiatric complications including depression, anxiety, cognitive issues as well as psychosis. Psychotropic medications may be used to treat these manifestations during the illness or patients on these medications may develop COVID19. Hence, we should be aware of the importance of these DDIs.  Most patients who contract COVID are home with supportive measures. The DDIs become relevant in hospitalized patients as well as those in long-term care facilities.

Pharmacokinetic DDIs: One drug alters the disposition of a co-administered agent.  Cytochrome P450 plays a key role.

Antidepressants: Selective serotonin reuptake inhibitors (SSRIs) for example fluoxetine and its active metabolite nor-fluoxetine are inhibitors of CYP2D6 (strong), CYP2C9 (moderate), and CYP2C19 (weak). Thus, fluoxetine and its metabolites increase the area under the curve (AUC) of ritonavir by 19% via inhibition of CYP2D6 and CYP3A4. This is not a high-level interaction needing dose adjustment. However, there is a real possibility of serotonin syndrome with SSRIs and ritonavir.

Fluoxetine being a CYP2D6 inhibitor may decrease the metabolism of CYP2D6 substrates like chloroquine and hydroxychloroquine. Cardiac monitoring is necessary to assess the QTc interval. In the case of Paroxetine co-prescribed with fosamprenavir/ritonavir combination paroxetine levels dropped by 55% due to protein binding displacement.

Sertraline has low CYP2D6 inhibition but can potentiate hypoglycemic effects of chloroquine/hydroxychloroquine.

Serotonin-Norepinephrine reuptake inhibitors (SNRIs): Venlafaxine is metabolized mainly by the CYP2D6 and CYP3A4 and partially by CVP2C19. It does not inhibit or induce CYP450 microsomes. Ritonavir has a strong inhibitory effect on CYP3A4 leading to increase venlafaxine levels. There is a need for QTc monitoring with chloroquine/hydroxychloroquine.  Chloroquine may affect the concentration of duloxetine by inhibiting CYP2D6. Despite the inhibitory effect of CYP2D6 and induction of CYP1A2 by ritonavir, concomitant use of duloxetine and ritonavir is permittable.

Trazodone: A commonly used medication at the present times for sleep does not affect the CYP isoenzymes. The trazodone peak plasma concentration and AUC increased 34% and 137% respectively with ritonavir (CYP3A4 inhibitor). This would lead to increased sedation and performance impairment.

Mirtazapine: The lowest effective dose should be used with CYP3A4 inhibitors such as ritonavir.

Bupropion levels can be reduced by ritonavir due to the induction of CYP2B6. Being an inhibitor of CYP2D6 which metabolizes hydroxychloroquine, bupropion can increase levels of hydroxychloroquine. Interaction can similarly be predicted for tricyclic antidepressants and Monoamine oxidase inhibitors.

Mood stabilizers: Lopinavir/ritonavir may reduce lamotrigine levels by inducing Uridine Diphosphate Glucuronosyltransferases (UGTs) which metabolize lamotrigine. These agents can also decrease the concentration of valproic acid by a similar mechanism. Similarly, close monitoring of carbamazepine is needed with these drugs. Carbamazepine can reduce chloroquine levels.

Lithium has no significant interactions with antiretroviral agents. No significant interactions have been observed between mood stabilizers and hydroxychloroquine.

Atypical antipsychotics: In the case of aripiprazole, quetiapine, ziprasidone, and risperidone the levels can be increased by antiretroviral agents like ritonavir. In the case of olanzapine, the levels are decreased by ritonavir which induces CYP1A2 the enzyme that metabolizes olanzapine.

Antianxiety agents: The levels of buspirone are increased (inhibition of CYP3A4). In the case of benzodiazepines levels of diazepam and alprazolam can be increased, and triazolam can be decreased.

Zolpidem levels are increased based on the CYP3A4 interactions.

Please note the FDA-approved drug remdesivir (Velklury) for COVID-19 another retroviral agent is a substrate for CYP3A4, OATP1B1, and P-gp substrate. Though studies are not available the interaction can be predicted based on this information. This agent can elevate LFTs which can increase when combined with Valproic acid. The antiviral activity of this drug is reduced when co-administered with chloroquine or hydroxychloroquine.

Summary

In my professional opinion, the DDIs apply to severely ill COVID-19 patients prescribed agents like remdesivir, ritonavir, chloroquine/hydroxychloroquine, and azithromycin. This particularly applies to hospitalized patients being treated by intensivists, hospitalists, internists, and psychiatrists on the consultation service. DDIs need to be borne in mind when COVID-19 comes into play. We should step back and think about the DDIs when seeing these patients, especially if they are not being treated with symptomatic measures alone.

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Anticholinergic burden, older adults, and falls: What is the risk?

Green AR et al.  Drugs Aging 2019 Mar;36(3) 289-297.doi: 10.1007/s40266-018-006378-z

PMID:30652263

Background

The additive anticholinergic side-effects can be problematic in older adults leading to complications including falls and impaired cognition. It is not known whether drugs with different anticholinergic ratings contribute proportionately to the overall anticholinergic score. This study aimed to assess the risk of falls or fall-related injuries as a function of the overall anticholinergic score resulting from drugs with different anticholinergic ratings among patients with impaired cognition.

Methods

This was a retrospective cohort study of adults aged ≥ 65 years with mild cognitive impairment (MCI) or dementia and two or more additional chronic conditions (N = 10,698). Electronic health record data, including pharmacy, fills, and diagnosis claims, were used to assess anticholinergic medication use, quantified using the anticholinergic cognitive burden (ACB) scale, falls, and fall-related injuries.

Results

During a median follow-up of 366 days, 63% of the cohort used one or more ACB drugs; in 2015 (18.8%) people experienced a fall or fall-related injury. Among patients with a daily ACB score of 5, the greatest increase in the risk of falls or fall-related injuries was seen when level 2 and level 3 drugs were used in combination. Multiple ACB level 1 drugs taken together also increased the hazard of a fall or fall-related injury. The risk of fall or fall-related injury as a function of exposure to ACB level 2 drugs was higher than that for ACB level 1 or 3 drugs.

Conclusions

The same daily ACB score was associated with a different degree of risk, depending on the ACB ratings of the individual drugs comprising the score. Combinations of level 2 and level 3 drugs had the greatest risk of fall or fall-related injury relative to other individuals with the same daily ACB score. Low-potency anticholinergic drugs taken together modestly increased the hazard of a fall or fall-related injury.

Clinical Commentary

This is the first study to examine the contribution of individual anticholinergic drug ratings to the risks associated with overall anticholinergic exposure. This study used the anticholinergic cognitive burden scale to assess the cumulative effect of individual drugs with anticholinergic properties. Each drug is rated from 1-3. A rating of 1 indicates the presence of anticholinergic activity but the impact is uncertain. Drugs rated 2 and 3 have established clinically relevant cognitive anticholinergic effects. The overall score is the sum of the ACB ratings of all medications taken by the person. The average ACB score ranged from 1.9 to 13.9 in this sample. The ACB ratings were calculated on the day before a fall or a fall-related injury. The ACB ratings were calculated only for prescribed medications but not for any supplements of herbals taken with these medications which is a limitation.

https://americandeliriumsociety.org/files/ACB_Handout_Version_03-09-10.pdf

http://www.acbcalc.com/  (ACB score calculator)

  • Individuals taking combinations of level 2 and level 3 drugs had the greatest risk of fall or fall-related injury relative to other individuals with the same daily ACB score.
  • Multiple low potency anticholinergic drugs taken together modestly increase the risk of fall or fall-related injury. This is important as multiple low potency anticholinergic drugs prescribed by most clinicians are not perceived as having anticholinergic properties. When prescribing to older adults with cognitive impairment each such medication takes a toll on the patients. Hence the risk and benefit must be reviewed.
  • Older adults have chronic diseases such as hypertension, heart failure, and atrial fibrillation. Patients may be prescribed an ACE inhibitor, digoxin, beta-blockers, loop diuretic, spironolactone, or warfarin which add to the anticholinergic burden. After the diagnosis of cognitive impairment, there may be a need to modify therapy due to the risk of falls.     

Summary

In my professional opinion all patients especially older adults need to have an accurate list of medications they are actually taking. We as clinicians should be doing medication reconciliation as a key feature of every visit. For the highest accuracy, the list should include prescribed medications, supplements, herbals, and over the counter medications. Drug-drug interactions should be assessed, and the anticholinergic burden should be estimated. The aim should always be to minimize the total number of medications. Orthostatic blood pressure and pulse should also be assessed to further evaluate fall risk.

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Sanjay Gupta, MD
Clinical Professor of Psychiatry, SUNY Buffalo

GME Research Review is a monthly newsletter edited by Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo. Dr. Gupta selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Gupta the citation at [email protected]

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