INTRODUCTION Psychiatric disorders and general medical conditions share a bidirectional relationship. Patients with severe mental illness have a higher prevalence of concurrent medical conditions, and chronic medical illness also increases the risk of developing mental illness. Psychotropic agents are commonly used in the management of psychiatric disorders in the medically ill. Comorbid medical illness poses many challenges when prescribing psychotropic drugs; important considerations include disease-induced changes in pharmacokinetics and pharmacodynamics while one must also consider drug–drug interactions and increased vulnerability to adverse effects. Most drugs and substances that we ingest are metabolized by the liver. Impaired hepatic function can critically alter many aspects of pharmacokinetics. Knowledge of these processes and changes are essential to understanding changes in systemic drug concentrations and prescribing appropriately to avoid drug toxicity. Similarly, the use of psychotropic medications in gastrointestinal (GI) conditions is complicated by issues such as interaction between GI medications and psychotropic drugs, risk of gastric bleed, and alteration in pharmacokinetics produced by conditions such as short bowel syndrome. The present article will review the considerations when prescribing psychotropic drugs to patients with hepatic and GI disorders. We summarize the pharmacokinetic changes and provide evidence-based dosing suggestions whenever available for individual agents of concern. The guideline first covers prescribing in hepatic disease, followed by GI disorders. PHARMACOKINETIC CHANGES IN HEPATIC DISEASE Hepatic impairment affects many critical aspects of pharmacokinetics (e.g., absorption, first-pass metabolism, hepatic biotransformation, the synthesis of drug-binding proteins, and fluid balance which determines the volume available for drug distribution).[1] The reduced first-pass metabolism and hepatic biotransformation lead to an increase in oral bioavailability and prolonged drug effects. If serum albumin is reduced, then it will affect the highly protein-bound drugs.[2] In presence of ascites, the increased volume of distribution will affect the water-soluble drugs. Figure 1 depicts the pharmacokinetic changes in liver disease.Figure 1: Pharmacokinetic changes in hepatic diseaseThere are two phases of drug metabolism in the liver; phase I reactions constitute hydrolysis, reduction, or oxidation and usually reduce the pharmacological activity of the molecule (except in cases where drugs are converted to their active metabolites). Phase II reactions involve drug conjugation with endogenous compounds such as glucuronic acid, amino acids, glutathione, and sulfate. This further reduces the pharmacological activity of the agent and makes it more water soluble. In chronic liver disease (CLD), more of the drug passes into the systemic circulation bypassing the liver; this is through the portosystemic shunts in these patients. Resultantly, there is a rise in drug levels which is more pronounced for drugs that undergo extensive first-pass metabolism. On the other hand, this is not seen for drugs that are mainly metabolized by phase II biotransformation reactions which are largely preserved in liver disease (such as lorazepam), and those with relatively little affinity for liver enzymes (such as paroxetine). Normally, phase II reactions are preserved in aging and liver disease. Hence, it is advisable to prefer agents that do not need phase I reactions in end-stage liver disease; examples of such agents are lorazepam and oxazepam. Further, the free (unbound) fractions of drugs that are extensively protein bound undergoes a change because of decreased synthesis of albumin and glycoproteins in end-stage liver disease. Many psychotropic drugs are highly protein bound; this includes tricyclic antidepressants (TCAs), fluoxetine, sertraline, aripiprazole, and diazepam. A rise in serum levels of the free fractions of these agents may imply an increased risk of adverse drug reactions. Most of the psychotropic agents that are currently used are lipophilic, implying that they need to be metabolized in the liver and made more soluble for them to get excreted in the urine or bile. Only a few drugs such as lithium and topiramate are hydrophilic, which are directly eliminated through the urine or bile. PREVALENCE OF LIVER DISEASE IN PSYCHIATRIC DISORDERS Growing literature suggests that prevalence of hepatitis B and C is higher among psychiatric populations compared to the general public. In a recent meta-analysis, the pooled prevalence of hepatitis B in severe mental illness varied from 2.2% in South America to 9.7% in Asia; the same authors also reported pooled prevalence rates of hepatitis C that ranged from 3.0% in South America to 17.4% in North America.[3] More specifically, population-based cohort studies have shown that patients with schizophrenia had a higher prevalence (7.0%) of CLD compared to general population (6.1%).[4] Similarly, the prevalence of CLD in bipolar disorder was 13.9%; this was 2.7 times higher than the general population, in whom the prevalence of CLD was 5.8%.[5] Further, the current and lifetime prevalence of hepatic illness in bipolar disorder were 17% and 21%, respectively.[6] Higher rates of anxiety disorders too have been found in patients with CLD.[7] Furthermore, presence of anxiety negatively correlates with health-related quality of life in this group. Several community-based studies have described a high prevalence and morbidity of depression in nonalcoholic fatty liver disease (NAFLD). For instance, a population-based study found that 23.6% of CLD patients fulfilled criteria for a diagnosis of depression;[8] another small case–control study[9] found that among patients with nonalcoholic steato-hepatitis, the odds of having lifetime depression was 3.8 times compared to controls without liver disease. ASSESSMENT OF PSYCHIATRIC DISORDERS IN CHRONIC LIVER DISEASE Psychiatric comorbidity is common in patients with CLD; this has a significant negative effect on quality of life. Apart from depression and anxiety, patients with CLD also experience neurocognitive impairment, such as deficits in attention, concentration, and memory. This may be either due to the direct consequences of the disease on the central nervous system (CNS) or as a result of anti-viral therapy with interferon-a.[10] The treating physician should have a high index of suspicion for depression if the following symptoms are present: depressed mood or loss of pleasure/interest in most activities, pain at multiple sites, feelings of helplessness or hopelessness, irritability, and anxiety. Additionally, risk factors including family history of depression and recent onset of stressful life events should prompt a detailed assessment for depression. The use of screening questionnaires for depression and anxiety such as the Hospital Anxiety and Depression Scale, Beck Depression Inventory, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 are supported by evidence in this group.[[111213] Further, there must be an attempt to formulate the depression/anxiety, if elicited, from a biopsychosocial perspective; this would inform management and prevention. An important complication here is suicide and clinicians must screen for suicidal risk periodically, particularly if depressive symptoms are endorsed. Other less common behavioural manifestations in CLD include psychosis and personality changes; the former may be assessed by the presence of delusions and/or hallucinations. Assessment of cognitive functioning in CLD can be done using validated neuropsychological assessment tools; these assessments should ideally be done before starting therapy, and prospectively monitored during the course of therapy; this will help determine the contribution of treatment to cognitive impairment. Examples of neuropsychological assessment tools that have been used in this population include the Mini–Mental State Examination, Memory Assessment Scale, and Wechsler Adult Intelligence Scale.[1415] Other special investigations that may be considered in CLD are electroencephalogram (EEG) which may have both a diagnostic role, by pointing toward an underlying hepatic encephalopathy, and a prognostic significance, as EEG abnormalities are often correlated with severity of liver disease.[16] Findings from neuroimaging may be useful to correctly diagnose and treat a range of alcohol-related encephalopathies such as Wernicke’s encephalopathy and Marchiafava–Bignami Disease.[17] PRESCRIBING PSYCHOTROPIC DRUGS IN HEPATIC DISEASE Depression Mechanisms linking depression and chronic liver disease Population-based studies have shown high prevalence of depression in NAFLD. Certain antiviral medications used to treat depression such as IFN-g are “depressogenic.” Indeed, studies on HCV-infected patients have shown that about 30%–70% develop depression during IFN therapy. Finally, shared biological pathways such as high levels of systemic inflammation and increased cortisol levels have also been postulated to underlie the links between NAFLD and depression. Antidepressants in liver disease Selective serotonin reuptake inhibitors This class of antidepressants is generally believed to be safe for use in CLD. However, sertraline has been associated with fatal liver injury in uncontrolled observations. Selective serotonin reuptake inhibitors (SSRIs) with a lower risk of liver injury include fluoxetine, paroxetine, citalopram, and escitalopram. One concern when using SSRI in patients with liver disease is its association with GI bleeding, and the extent of risk of bleeding in those with liver disease. Encouragingly, evidence from published reviews suggests that an increased risk of bleeding events with SSRIs in liver disease occurs only when co-prescribed with antiplatelet agents; this aligns well with recommendations in routine practice. Typical pharmacokinetic changes seen in CLD prolong the half-life and reduces drug elimination. The usual recommendation is to keep the maintenance dosage at 50% of that used for healthy individuals. However, no change is needed for the starting/initial doses. There is evidence for efficacy of SSRIs in treating symptoms of depression in chronic hepatitis C infection. Paroxetine, dosed at 20 mg/day for 4 weeks, was found to be effective in the reduction of depression scores among patients with IFN-induced depression. Similarly, in a randomized controlled trial comparing the efficacy of citalopram versus placebo in IFN-induced depression, citalopram dosed at 20 mg daily, separated from placebo at 2 and 4 weeks. Also, no major adverse effects were noted in therapeutic open-label trials of SSRIs in hepatitis C patients. Dosing suggestions for major antidepressants in liver disease are shown in Table 1.Table 1: Dosing preferences for antidepressants in patients with chronic liver diseaseSelective serotonin reuptake inhibitors and liver injury Broadly, drug-induced liver injury (DILI) can be subtyped based on the pattern of liver injury or pathophysiological mechanism. The following three main categories of liver injury have been described: hepatocellular, cholestatic, and mixed. These sub-types are distinguished based on the pattern of elevation of liver enzymes, i.e., hepatocellular injury is associated with elevated levels of serum alanine aminotransferase (ALT) with little to no increase in alkaline phosphatase levels (ALP), cholestatic liver injury shows a pattern of elevated serum ALP titres along with minimal elevation in ALT, whereas, in mixed liver injury, both ALP and ALT titres are pathologically high. Based on pathophysiology, liver injury can be divided into idiosyncratic (more common and dose independent) or intrinsic type (dose dependent and based on drug accumulation). Idiosyncratic liver injury can either be of the immune mediated or allergic type, or metabolic type; the former is characterized by a hypersensitivity syndrome with symptoms of fever, eosinophilia, and rash, and a short latency period for onset (1–6 weeks), the latter is characterized by a longer latency period (1 month to 1 year) and does not have a hypersensitivity reaction. Challenges involved in assessing the potential for a psychotropic agent to induce liver injury are the lack of incidence studies, co-prescription of multiple psychotropic agents and presence of medical co-morbidities (which make it difficult to ascertain causality), and the short duration and small numbers in the premarketing trials. Serotonin norepinephrine reuptake inhibitors Venlafaxine and duloxetine have been associated with severe DILI in uncontrolled observations. Whereas venlafaxine has been associated with hepatocellular and cholestatic liver injury, all three types (hepatocellular, cholestatic, and mixed) of DILI have been noted with duloxetine. Both immunoallergic and metabolic mechanisms have been implicated for both these agents. Tricyclic antidepressants These group of agents are well known for their anticholinergic side effects (dry mouth, constipation, and urinary retention), arrhythmogenic effects, CNS effects such as seizures and sedation, and orthostatic hypotension. Clearance of these agents is generally reduced in patients with CLD. Hence, there may be an increased propensity for adverse effects at the regular dosage; for example, amitriptyline is shown to have increased sedating effects in a patient with cirrhosis of the liver. There is little data on the safety of other TCAs such as nortriptyline, imipramine, and clomipramine; on the other hand, there are few reports of DILI associated with some of these agents. Dosing suggestions in CLD are shown in Table 1. Caution must be exercised when prescribing TCAs to patients with hepatic encephalopathy due to increased risk of sedation and worsening of sensorium. Monoamine oxidase inhibitors Iproniazid, the first monoamine oxidase inhibitors (MAOI) to be developed, was later withdrawn from the market during the late 70s due to reports of severe DILI even in apparently healthy patients. Most of these events occurred in the first 3 months of treatment, and mortality rates were high (up to 20%). Little data is available on the metabolism of other MAOIs in liver disease, though studies done on cirrhotic patients have shown prolonged half-lives and systemic clearance for tranylcypromine and moclobemide. While most authorities discourage the use of MAOIs in liver disease, if there is a need to use one, the reversible MAOI moclobemide may be preferred as compared to the irreversible MAOIs, as there is less risk for DILI. Other antidepressants The pharmacokinetics of agents such as bupropion and reboxetine are likely to be altered in patients with CLD. Particularly, bupropion has been linked with adverse reactions such as nausea, vomiting, and seizures; as such, caution should be exercised when using it in patients with hepatic encephalopathy. On a similar note, trazodone is also associated with sedation and therefore, a similar caution is warranted. DILI with trazodone has been reported at normal therapeutic dosages.[19] Mirtazapine has also been associated with DILI related to prolonged jaundice, albeit rarely. Furthermore, there are reports of serotonin syndrome when mirtazapine is co-administered with other serotonergic drugs (i.e. SSRIs/serotonin norepinephrine reuptake inhibitors [SNRIs]). Use of antidepressants in liver transplant patients Limited availability of controlled data on the use of antidepressants among organ transplant recipients points to a lacuna in the literature that prevents drawing firm conclusions. Concerns about using antidepressants in this group center more on safety, adverse effects, and possible drug interactions with immunosuppressant agents than on potential differences in pharmacokinetic profiles seen in CLD patients. Due to their favorable side effect profile, SSRIs and SNRIs are preferred over MAOIs and TCAs among liver transplant recipients. However, there are concerns about drug interactions; fluoxetine and paroxetine inhibit cytochrome P450 3A4 enzymes which are involved in the metabolism of immunosuppressant medications such as cyclosporine and tacrolimus. Therefore, there may be a rise in systemic levels of these agents when co-administered with these SSRIs. Other SSRIs, namely escitalopram and sertraline, as well as SNRIs such as venlafaxine, exert only minor effects on cytochrome P450 enzymes which are unlikely to be clinically significant. However, given the mixed evidence on effects of SSRIs on serum levels of cyclosporine, a close monitoring of transplant recipients for tolerability issues is indicated. Interestingly, use of high-dose corticosteroids has been linked to worse mental health outcomes in post-liver transplant recipients; hence, efforts must be made to minimize the use of corticosteroids among depressed graft recipients. Anxiety Common pathophysiology including metabolic (impairment in mitochondrial metabolism, inflammation, and oxidative stress), genetic (lipid metabolism genes, genes involved in inflammation and oxidative stress), lifestyle (unhealthy diet and lifestyle), and personality factors (low conscientiousness and high neuroticism) have been proposed to explain this association.[20] As anxiety disorders are generally managed with agents that are also used for treating depression, readers may refer to preceding section for issues and considerations during the treatment. Dosing suggestions given in Table 1 for antidepressants also apply for anxiety disorders in CLD. Table 2 presents dosing suggestions for other antianxiety agents, such as benzodiazepines, in hepatic insufficiency.Table 2: Dosage suggestions for anxiolytics in patients with chronic liver diseasePsychotic disorders Among patients with CLD due to hepatitis A, Wilson’s disease, or CLD due to nonhepatocellular causes such as extensive portosystemic collateral circulation, schizophrenia is not an uncommon occurrence. Several reasons may be proposed to explain this association; first, drugs used to treat schizophrenia such as antipsychotics may cause liver injury and dysfunction. Schizophrenia may be associated with unhealthy lifestyle practices including substance use, that itself increases the risk of medical comorbidity and liver disease.[4] Finally, common biological and biochemical perturbations such as increased central and systemic levels of certain biogenic amines and decreased levels of gamma amino butyric acid (GABA) seen in both conditions may explain this association.[23] First-generation antipsychotics Neuroleptics have been frequently associated with the development of steatosis. Phenothiazines (e.g., chlorpromazine) and butyrophenones (e.g., haloperidol) have been associated with elevated liver enzymes, and rarely, hepatocellular failure; in both cases, the type of lesion is cholestatic and related to immuno-allergic mechanisms. Of the two agents, phenothiazines have been more frequently implicated in liver damage compared to butyrophenones. A large case series of severe DILI associated with use of first-generation antipsychotics (FGAs) has been published.[2425] Second-generation antipsychotics These group of agents are, in general, safer compared to FGAs in liver disease. Nevertheless, usage of second-generation antipsychotics (SGA) may lead to metabolic syndrome and this, in turn, can lead to NAFLD. Asymptomatic elevation in hepatic transaminases and bilirubin may also occur when using these agents. Hence, it is good practice to obtain baseline liver function tests before initiating SGAs, and subsequently monitor at regular intervals (every year). In patients who are on clozapine as well as those who are regular users of alcohol or other substances, more frequent monitoring may be warranted. As a rule, it is recommended to stop antipsychotics if there is a symptomatic elevation of hepatic transaminases or asymptomatic elevation of more than three times the normal upper limit of liver enzymes. Extra caution should be exercised among patients with preexisting liver disease or those who are concurrently receiving potentially hepatotoxic medications. Because these agents are relatively new, there is a paucity of controlled data on prevalence and risk factors for DILI associated with SGAs. In a review of 10 group studies and 91 case reports/series, Marwick et al. found a median of 32% for any abnormal liver function test while the median for clinically significant liver enzyme elevation was 4%.[26] Most such reactions were asymptomatic, arose in the first 6 weeks, and were self-limiting. The most common antipsychotic associated with acute liver injury was chlorpromazine. Table 3 shows the changes in metabolism and prescribing suggestions for commonly used antipsychotics in liver disease.Table 3: Prescribing suggestions for anti-psychotics in patients with chronic liver diseaseBipolar disorders As described earlier, the prevalence of hepatic illness in bipolar disorder is increased compared to the general population. Increased incidence of medical co-morbidities in bipolar disorder (which increases the risk of NAFLD), unhealthy lifestyle factors including alcohol and other substance use, and common underlying pathological mechanisms (such as raised systemic inflammation) are factors that may explain this association. Among the mood stabilizing agents that are used to control symptoms of bipolar disorder, lithium is minimally metabolized in the liver and not protein bound. It is generally believed that lithium is safe to use in hepatic dysfunction. However, a few things must be kept in mind when using lithium in patients with CLD. First, people with liver dysfunction can also have renal impairment which leads to precarious fluid balance. Given this scenario, maintaining therapeutic serum levels of lithium becomes challenging. It is important to closely monitor serum lithium levels in such a scenario. Second, long term lithium therapy has been associated with deranged liver function tests. Though most of these changes are reversible with time and do not necessitate change of drug, episodes of lithium toxicity can cause more marked changes in liver function tests. Commonly used antiepileptic mood-stabilizing agents are valproate, carbamazepine, topiramate, gabapentin, and lamotrigine. Of these, valproate and carbamazepine are associated with maximum risk of hepatotoxicity, while gabapentin is considered safe as it is minimally metabolized by the liver,[27] though there are case reports of gabapentin-induced hepatotoxicity.[28] Asymptomatic elevations in hepatic transaminases can be seen in 10%–15% of patients on valproate, while hyperbilirubinemia can be seen in up to 44% cases. As long as these elevations are within three times the upper limit of normal range, valproate may be continued. Valproate-induced liver injury is more common among infants and children and is an idiosyncratic metabolic phenomenon.[1] Valproate-induced hyperammonemic encephalopathy is a serious adverse reaction that can result uncommonly from acute DILI due to valproate and consequently raised liver enzymes,[29] though the more common cause is inhibited activity of key enzymes involved in urea cycle such as carbamoyl phosphate synthetase-1 and ornithine transcarbamylase.[30] Concurrent use of topiramate and other antiepileptics is a risk factor for hyperammonemia due to valproate. About 10% of patients initiated on carbamazepine experience hypersensitivity reactions, of which ~10% report hepatic adverse events leading to a 1% incidence rate of carbamazepine-induced DILI. Common symptoms of carbamazepine-induced hypersensitivity and liver damage are fever, skin rash, facial edema, enlarged lymph nodes, and leukocytosis, which typically begin 1–8 weeks after initiation of the drug.[31] Lamotrigine and topiramate are infrequently associated with liver enzyme elevation and idiosyncratic hepatotoxicity. Prescribing suggestions for common mood stabilizers in liver disease are shown in Table 4.Table 4: Prescribing suggestions for mood stabilizers in patients with chronic liver diseaseSubstance use disorders Substance use, in particular chronic use of alcohol, is an important cause of liver disease. Many such patients may present with alcohol withdrawal of varying severity ranging from simple withdrawal to severe cases with seizures and delirium tremens. Benzodiazepines are the drugs of choice in management of alcohol withdrawal as they mitigate the risk of withdrawal-related seizures and delirium tremens. Among the benzodiazepines, lorazepam or oxazepam are preferred for detoxification in alcohol withdrawal as they only undergo glucuronidation (phase II metabolism) in the liver and do not require to undergo phase I biotransformation. As discussed in section 1, phase II reactions are largely preserved in liver disease. Following detoxification, among pharmacological agents used to promote abstinence and prevent relapse in alcohol use disorders, naltrexone and acamprosate have more evidence for efficacy than disulfiram.[33] Naltrexone has an FDA “black box” warning against use in patients with liver disease; therefore, it must be avoided in such cases. Although there are few controlled trials investigating the safety of acamprosate in alcoholic liver disease, considering that it does not undergo hepatic metabolism and there are few reports of DILI associated with acamprosate, it may be preferred option for pharmacoprophylaxis in alcoholic liver disease. Dosing in liver disease and safety considerations for commonly used medications in alcohol use disorders are shown in Table 5.Table 5: Medications for alcohol use disorder and their safety in alcoholic liver diseaseAnother category of substances with significant implications in liver disease is opioids. Most opioids are, at least to some extent, metabolized by the liver. Liver failure due to hepatitis C is one of the leading indications for liver transplant. Prevalence of this condition among drug users on methadone maintenance therapy ranges from 84% to 90%.[3536] Hence, it is important to know dosing considerations when using pharmacologic treatments for opioid dependence. Studies of methadone maintenance treatment have not found evidence for long term damage to liver.[37] However, liver disease may be a risk factor for methadone overdose, as methadone clearance is impaired in CLD.[38] Buprenorphine is metabolized by cytochrome P450 3A4 enzyme system but investigators who looked at interactions with HIV medications that inhibit this cytochrome enzyme did not find evidence for clinically significant drug interactions, except when buprenorphine was co-administered with atazanavir or ritonavir.[3940] As mentioned earlier, naltrexone, an FDA approved agent for use in opioid dependence, has a potential to impair liver function tests and must be avoided among those with a history of liver disease. Management pearls When initiating opioids for pain relief in liver disease patients, always initiate lower doses with longer interval between doses, and assess ability of patients to tolerate before administering higher dosages. Hydromorphone and fentanyl are preferred agents for pain relief in cirrhotic patients as they are least affected by ongoing hemodynamic disturbance.[41] Close monitoring is warranted and those who are showing signs of deteriorating liver function should be assessed for symptoms of opioid toxicity, and necessary dose reduction should be undertaken. Because all opioids are metabolized in the liver, at least partially, the potential for concurrently administered nonopioid medications to affect the metabolism of opioids by inducing or inhibiting the CYP family of enzymes must be borne in mind. Finally, because most patients with liver disease also have an increased likelihood of renal dysfunction (i.e. hepatorenal syndrome), and because renal impairment can impact opioid levels and elevate risk of toxicity, dose adjustments based on glomerular filtration rate may be a prudent approach.[42] Managing cognitive impairment and attention-deficit hyperactivity disorder (ADHD) in hepatic insufficiency Neurocognitive dysfunction has been noted in a range of liver diseases (chronic hepatitis C, Wilson’s disease, alcoholic liver disease, and primary biliary cirrhosis). Moreover, such impairment is associated with significant negative impact on activities of daily living and quality of life. Certain drugs used to manage attention-deficit hyperactivity disorder (ADHD) are linked to severe DILI.[43] While prescribing in such situations, the clinician must be cognizant of the balance between risk of serious adverse effects and clinical efficacy as well as the dosage adjustments necessary based on the severity of hepatic insufficiency. Table 6 below summarizes prescribing suggestions for key procognitive agents and psychostimulants in hepatic insufficiency.Table 6: Prescribing suggestions for cholinesterase inhibitors, memantine, and psychostimulants in patients with chronic liver diseaseManagement of neuropsychiatric adverse effects of interferon-alpha in hepatitis C Chronic Hepatitis C virus infection is a leading cause of liver transplantation worldwide. IFN-a is commonly used for the treatment of hepatitis C infection but is associated with a range of significant neuropsychiatric side effects. These include mood changes (commonly depression, but mania may also occur), neurovegetative symptoms (fatigue, malaise, and lethargy), cognitive impairment, suicide ideation, and rarely, delirium or psychosis. Up to 10%–50% of patients on therapy with IFN may develop depression. Psychotropic medications that have a known association with blood dyscrasia, such as carbamazepine, clozapine, mirtazapine, and valproate must be used with extreme caution in persons with hepatiti
Search from 250 M+ research papersSearch from 250 M+ research papers
Feb 1, 2023
Chirag Ambaliya + 2
Open Access