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). 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. In presence of ascites, the increased volume of distribution will affect the water-soluble drugs. Figure 1 depicts the pharmacokinetic changes in liver disease.
There 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.
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%). 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%. Further, the current and lifetime prevalence of hepatic illness in bipolar disorder were 17% and 21%, respectively.
Higher rates of anxiety disorders too have been found in patients with CLD. 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; another small case–control study 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.
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.[ 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.
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. 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.
PRESCRIBING PSYCHOTROPIC DRUGS IN HEPATIC DISEASE
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.
Selective 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.
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.
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. 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.
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.
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.
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. 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.
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.
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%. 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.
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, though there are case reports of gabapentin-induced hepatotoxicity.
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. Valproate-induced hyperammonemic encephalopathy is a serious adverse reaction that can result uncommonly from acute DILI due to valproate and consequently raised liver enzymes, though the more common cause is inhibited activity of key enzymes involved in urea cycle such as carbamoyl phosphate synthetase-1 and ornithine transcarbamylase. 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. 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.
Substance 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. 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.
Another 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%. 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. However, liver disease may be a risk factor for methadone overdose, as methadone clearance is impaired in CLD.
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. 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.
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. 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.
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. 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.
Management 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 hepatitis C who are on IFN therapy because hematological abnormalities are common in this population. Antidepressants with prominent anticholinergic effect (such as tricyclic agents) must be avoided too, as they can further worsen cognitive impairment in these patients. SSRIs are the drugs of choice in IFN-induced depression in hepatitis C, and are in general well tolerated, though concerns have been raised about the risk of gastric bleed. These agents have evidence for efficacy in both acute phase and prophylactic management aimed at reducing the frequency and intensity of IFN-induced depression.
Severity of hepatic disease
Elevated liver enzymes (AST and ALT) may reflect inflammatory hepatic disease, though not diagnostically specific. Of them, ALT is liver specific, and a normal ALT level excludes hepatic disease with 90% probability. The AST/ALT ratio (De Ritis quotient) is a rough measure of the extent and progression of disease and damage; <1 suggest minor liver injury, and values more than 1–2 occurs in severe inflammatory liver pathologies. The Child-Turcotte-Pugh (CTP) has been validated for rating the severity of hepatic disease. The CTP scoring involves five parameters, i.e., serum albumin, serum bilirubin, encephalopathy, ascites, and prothrombin time to generate three stages, “A,” “B,” or “C.” Scores of 5–6 constitute stage A (understood as well-compensated disease), 7–9 constitute stage B (with significant compromise in functioning), and 10–15 is classified as stage C (decompensated liver disease).
HEPATIC MONITORING PREFERENCES WHEN INITIATING PSYCHOTROPIC AGENTS
It is not necessary to measure hepatic functions before starting all psychotropic medication. Some psychotropic medications may require dosage adjustment in those with hepatic disease, for which baseline hepatic function measurement is essential. In the absence of any prior studies, a baseline liver function test is considered useful. However, the treatment can be initiated in urgent situations if there is no clinical evidence of hepatic disease.
Also, few of the psychotropic drugs are hepatotoxic [Table 7], that require monitoring at periodic intervals (e.g. valproate, carbamazepine, and disulfiram). For other drugs, liver function tests should be checked if there are clinical symptoms of hepatic disease such as fatigue, right upper quadrant abdominal pain, jaundice etc. The most common type of hepatotoxicity seen in more than 90% is elevated serum ALT levels, with little change in ALP levels. Sometimes, a cholestatic pattern is seen with high ALP levels with slightly raised ALT levels. High serum bilirubin along with these changes suggests severe hepatocellular damage and poorer prognosis. Occasionally steatosis or steatohepatitis is seen with psychotropic drugs, which is usually reversible.
If liver function tests show mild transaminase elevations, the drug can be continued with regular monitoring at more frequent intervals. Transaminase levels of three to four times of the upper value (i.e. 120–160) is an indication to discontinue the offending drug. If it is clinically indicated to continue the drug, a dose reduction may be attempted, however, there is no evidence that such strategy is helpful. If there is a history of such hepatic inflammation with a drug, it is likely to appear with rechallenge, hence better avoided if an alternative treatment option is available. An opinion from hepatologist may be helpful if hepatic functions are found to be deranged before initiating medications or any changes in laboratory parameters while on psychotropic medications.
Valproate therapy is associated with hyperammonemia, specifically in those with other risk factors such as lower carnitine levels. It is not mandatory to routinely check serum ammonia levels before initiating treatment on valproate. If a patient develops clinical signs associated with hyperammonemia such as drowsiness, lethargy, altered mental status, serum ammonia levels may be monitored and valproate should be stopped. Sometimes, levocarnitine can be given for resolution of the hyperammonemia. Dose reduction of valproate may help in some patients. The differential diagnosis of valproate-induced nonhepatic hyperammonemic encephalopathy (VNHE) include other reasons such as urea cycle disorders (late onset ornithine transcarbamylase deficiency), or organic acidemias such as methylmalonic acidemia, proprionic acidemia, and multiple carboxylase deficiency. Risk factors for VNHE include those for secondary carnitine deficiency such as malnutrition, chronic renal failure, ketogenic diet, strict vegetarianism, and concurrent treatment with certain antiepileptics that can lower carnitine levels (e.g. topiramate, phenytoin, carbamazepine, and phenobarbitone).
DRUGS THAT ESCAPE HEPATIC METABOLISM
There are some drugs that escape hepatic metabolism, a knowledge of which will be helpful for clinical considerations in those with hepatic diseases. Some of the drugs are not metabolized at all by liver, and are predominantly excreted through kidneys [Table 8]. Some other drugs are only minimally metabolized by liver, i.e., there are no phase 1 oxidation reactions that occur through cytochrome P450 system, but only phase 2 conjugation reactions which are relatively preserved in hepatic cirrhosis [Table 9]. Also, the proportion of drug that is metabolized by the liver in contrast to the proportion that is excreted unchanged is relevant while deciding on the psychotropic and their dose (e.g. paliperidone and milnacipran).
It is known that those with cirrhosis have lower glomerular filtration rates, and lower creatinine levels because of reduced hepatic synthesis of creatine. Therefore, in patients with cirrhosis, medications with predominantly renal elimination and with narrow therapeutic index, such as lithium, should be used with caution. Also, serum creatinine levels are not good measure of glomerular filtration rates in those with cirrhosis and tend to overestimate it. Similarly, acamprosate is not metabolized by liver and is considered safe in liver disease though its safety is not established in those with Child-Pugh class C cirrhosis. Some medications do not require any dose adjustments in cirrhosis (e.g. gabapentin and pregabalin), and should be the preferred drugs if clinically indicated.
Drugs that are only minimally metabolized and undergo only conjugation reactions are considered relatively safe and are preferred over those that involves cytochrome P450 metabolism (e.g. lorazepam over diazepam for alcohol withdrawal in alcoholic liver disease). However, it is known that conjugation reactions are also impaired in advanced liver disease such as cirrhosis. Therefore, in patients with cirrhosis it is prudent to make appropriate dose adjustments. A usual strategy is 50% of the usual dose in a Child-Pugh class A patient, and 25% in Child-Pugh class B patients, along with monitoring for signs of toxicity. For those with Child-Pugh class C patients, these medications are to be preferred only if clinical safety data is available.
ASSESSING PSYCHIATRIC DISORDERS IN PATIENTS WITH GI DISORDERS
A multidisciplinary team (e.g., Psychiatrist, Physician, and Psychologist) should be involved in management of psychiatric comorbidities in patients with GI disorders. The following stepwise approach can be used to assess these patients.
- The treating physician (General practitioner, gastroenterologist) may conduct a brief psychosocial evaluation of each patient with GI disorders. Such assessment should be aimed at engendering a physician-patient relationship, facilitate a diagnosis of the GI disorders and screening for psychiatric comorbidities, and screen for any “red flag” signs that immediate psychiatric referrals. The “red flag” indicators include severe depression, suicidal ideations, severe disability, maladaptive illness behavior, and other identifiable disorders (e.g., anxiety, substance use disorders)Subsequently, these patients should be educated about GI disorder and psychiatric comorbidities using bio-psycho-social model. GI disorders often do not fit in a parsimonious pathophysiologic model; instead, they stem from complex interactions between biological, psychological, and psychosocial factors. Therefore, the provision of information about the psychosocial aspects of the GI disorders is critical for understanding and effective management of these illnesses. Childhood experiences (e.g., child abuse), adult stressors (eg, marital separation), poor social support, and genetics influence both the physiologic and psychological responses of the individual, including emotional distress, psychiatric illnesses, cognitions, and coping mechanisms. The gut responds to these factors and also interacts directly with the brain thorough the “brain-gut” axis. The use of a bio-psycho-social approach improves the clinical outcome of patients with GI disorders.
- A psychiatrist should conduct an in-depth psychosocial assessment in patients with severe symptoms, red flag indicators, physician referral, prior episodes of treatment failure, sub-optimal treatment adherence, and evidence of inadequate illness coping. The assessment must include in-depth diagnostic interview and use of standardized screening tools for assessing the following domains (1) Screening for depression, somatization, and anxiety (e.g., Hospital Anxiety and Depression Scale, Patient Health Questionnaire, (2) health beliefs and coping (Visceral Sensitivity Index or Cognitive Strategies Questionnaire) (3) impact of illness and health-associated quality of life (irritable bowel syndrome [IBS]-Quality of Life) and (4) assessment of the sequential psychosocial factors as well as periods of symptom exacerbations and remissions.
- Then, in patients with mild to moderate psychiatric illness, medical therapies (e.g., laxatives, antidiarrheal agents) and/or simple lifestyle changes (e.g., yoga, relaxation classes, meditation) with or without psychopharmacologic medication can be used. In addition, appropriate psychopharmacologic agents or more specific psychological management based on patient choices and constraints related to time or cost (of medications and investigations) should be attempted in moderate to severe cases.
PRESCRIBING IN GASTROINTESTINAL DISEASE
Psychological stress and illness are prevalent among patients with GI disease. Psychological distress may be the cause of, exacerbate, or be a result of these disorders. Therefore, psychotropic medications are frequently required for the treatment of GI disorder symptoms and comorbid psychopathology. Prescription of psychotropic medications in these patients is frequently difficult due to potential interactions between GI medications and psychotropic agents, risks of prescription, and alterations in drug pharmacokinetics due to underlying GI disorders (e.g., hepatic failure, short bowel syndrome).
SSRIs may prolong upper GI bleeding in patients receiving nonsteroidal anti-inflammatory drugs, thrombocytopenic, or with other platelet dysfunction, such as von Willebrand disease. SSRIs do not appear to increase the risk of GI bleeding in patients receiving warfarin, but they may increase the risk for non-GI bleeding.
Interactions between over-the-counter (OTC) GI medications and psychotropic medications can affect drug absorption. Antacids and sucralfate reduce drug absorption by increasing the gastric pH and delaying gastric emptying. In such scenario, it is advised that antacids should be taken at least 2–3 h spaced from the other medications. Furthermore, antacids may augment renal lithium clearance by increasing sodium excretion.
Histamine receptor antagonist (e.g., cimetidine) inhibits the oxidative metabolism of most drugs including psychotropic medication. Therefore, reduction of psychotropic medications or avoidance of histamine receptor antagonists (e.g., cimetidine) is recommended. Some proton pump inhibitors (e, g, esomeprazole, lansoprazole) induces the CYP 1A2, which increases the elimination of clozapine and olanzapine. On other hand, some proton pump inhibitors (such as omeprazole) inhibit CYP 2C19 and thus increases the level and toxicity of diazepam, flunitrazepam, and phenytoin.
Concurrent use of 5-HT3 antagonists (e.g., ondansetron) along with TCAs, typical/atypical antipsychotics, and lithium may augment the risk of arrhythmias and conduction disturbances such as QT prolongation. Co-administration of dimenhydrinate, diphenhydramine, and promethazine with psychotropic drugs with prominent anticholinergic effect can increase the risk of neurocognitive impairment and also result in delirium. In addition, these medications may reduce the therapeutic effect of cholinesterase inhibitors and memantine.
Domperidone and droperidol can cause extrapyramidal symptoms when combined with antipsychotics. In addition, these medications may increase the risk of QT prolongation when co-prescribed with other psychotropic drugs (such as TCAs, typical/atypical antipsychotics, and lithium). The use of metoclopramide in combination with antipsychotics can cause extrapyramidal symptoms. Glucocorticoids induce CYP 3A4 enzyme, which ultimately leads to increased metabolism and reduced level of oxidatively metabolized drugs (e.g., benzodiazepine, carbamazepine, quetiapine).
Dronabinol can produce effects such as additive tachycardia, hypertension, and cardiotoxicity (when administered with amphetamines or methylphenidate), additive hypertension, and drowsiness (when administered with TCAs), and drowsiness and CNS depression (with lithium, opioids, and benzodiazepines).
Antispasmodics (e.g., dicyclomine, glycopyrrolate) increases the risk of neurocognitive impairment and, more importantly, delirium when co-administered with psychotropic drugs with anticholinergic properties. In addition, these medications may reduce the therapeutic effect of cholinesterase inhibitors and memantine.
GUT MICROBIOTA AND EFFECT ON PSYCHOTROPIC DRUGS
A growing body of research supports the role of the gut microbiome in modifying the action of therapeutic drugs. Likewise, the relationship between psychiatric disorders and gut microbiota has been a major research focus in recent times. Specifically, alterations in gut microbial compositions have been reported in a range of psychiatric disorders including depression, bipolar disorder, schizophrenia, ADHD, and autism spectrum disorders. The interaction between gut microbiota and psychotropic drugs is bidirectional: Effect of gut microbiota on the pharmacokinetics and pharmacodynamics of psychotropic agents, and impact of psychotropic agents on gut microbiota compositions.
Preclinical studies have shown that depletion in gut microbiota, following use of antibiotics or probiotics, lead to an increase in bioavailability of olanzapine, but exerted no appreciable effects on bioavailability of risperidone. This suggests that the effect of gut microbiome depletion may be drug specific. On a similar note, antibiotic induced depletion of gut microbiome attenuated olanzapine-related metabolic changes among rats. In fact, a recent meta-analysis, that examined both human and animal studies, concluded that antipsychotic-induced alterations in gut microbiome may underlie drug-induced weight gain and metabolic disturbance noted during treatment.
The other key aspect in the relationship is changes in gut microbiome composition induced by psychotropic usage. Certain FGAs (e.g. thioridazine, fluphenazine, and chlorpromazine) have been shown to have antimicrobial properties in vitro. Cross-sectional studies on humans have shown significant differences between microbiota communities between antipsychotic treated and drug free people with bipolar disorder. Furthermore, evidence from in vitro as well as in vivo studies suggest that a range of antidepressants including TCA, SSRI, and ketamine may exert antimicrobial effect against different bacterial strains, though whether these effects mediate drug response and toxicity remain unclear. The implications of these findings are many and pertain to issues with drug selection, drug safety, and efficacy. In future, microbiome measures may be integrated into clinical practice to assess these issues and inform patient management.
IRRITABLE BOWEL SYNDROME AND OTHER FUNCTIONAL GASTROINTESTINAL DISORDERS (FGIDS)
Psychotropic medications can be used to treat IBS, other functional gastrointestinal disorders (FGIDs), and associated psychiatric comorbidities. It is necessary to consider potential interactions between GI and psychotropic medications and risks involved in prescribing psychotropic agents in various FGIDs. Table 10 summarizes specific prescribing suggestions that can be used in conjunction with the standard treatment.
CELIAC DISEASE, ABDOMINAL EPILEPSY, AND ACUTE INTERMENT PORPHYRIA
Celiac disease (CeD) is an autoimmune enteropathy caused by an abnormal immune response to gluten. As per the Indian Council of Medical Research diagnostic criteria, a diagnosis of CeD is based on a combination of clinical manifestations, antibodies to transglutaminase 2 (i.e. positive IgA anti-tTG antibody), and a deep duodenal biopsy demonstrating the presence of at least Marsh grade 2 villous abnormalities.
Individuals with CeD are more likely to develop GI and extra-intestinal disorders, including psychiatric disorders. Depression, anxiety, schizophrenia, bipolar disorder, other psychotic illnesses, ADHD, autism, sleep, and eating disorders are the most commonly reported psychiatric disorders among patients with CeD. Furthermore, neuropsychiatric disorders such as gluten ataxia, peripheral neuropathy, and gluten encephalopathy are commonly reported among these patients.
There is evidence to suggest that drug absorption may be increased (e.g. propranolol), delayed, reduced, or normal in CeD; this includes psychotropic medications too. There is little research on the pharmacokinetics of psychotropic medications among patients with CeD. Therefore, while treating psychiatric disorders among patients with CeD, drugs should be used with caution.
Gluten-free diet is the main stay of treatment among patients with CeD. Patients with CeD would benefit from dietary education: To avoid cereals derived from wheat or barley and gluten-contaminated cereals or foods derived from these. A gluten-free diet also improves depressive and behavioral symptoms in these patients and increases free L-tryptophan levels.
Abdominal epilepsy is an infrequent cause of recurring abdominal pain. Characteristic features include paroxysmal episodes of abdominal pain, a variety of abdominal complaints (e.g., vomiting, nausea), definite electroencephalograhic abnormalities, and a favourable response to anticonvulsants. The condition is commoner among young children. Patients who experience recurring abdominal pain are frequently referred for psychiatric evaluation to rule out functional disorders. Therefore, a clinician should assess these patients for the possibility of abdominal epilepsy.
Acute interment porphyria
Acute intermittent porphyria (AIP) is a disorder characterized by recurrent attacks of abdominal pain, autonomic nervous system disturbances, and GI symptoms where there is an abnormality in heme metabolism. Possible triggers of AIP attacks include starvation, pregnancy-related infections; certain drugs have also been implicated. Mood swings, psychosis, anxiety, and organic brain disorders are possible psychiatric manifestations. Most mood stabilisers or anticonvulsants (e.g., barbiturates, phenytoin, carbamazepine), agents with sedative properties (e.g. chlordiazepoxide), oral contraceptive pills, and alcohol are contraindicated in patients with AIP. Psychotropic medications such as chlorpromazine, trifluoperazine, diazepam, clonazepam, lorazepam, sertraline, venlafaxine, olanzapine, risperidone, clozapine, buspirone, trazodone, and morphine are considered safe for treatment of acute attack of porphyria and concurrent psychiatric disorders.
Psychopharmacology in patients with liver and GI disorders must be individualized based on the choice of psychotropic agent and severity of the underlying medical condition. In patients with liver disease, it is preferable to use psychotropic drugs that avoid or minimally undergo hepatic metabolism. Caution is required while prescribing any psychotropic drug in severe hepatic disease (Child-Pugh C), as safety data may be lacking. In GI disorders, there are few absolute contraindications, but conditions such as gastric bypass and coeliac disease may alter absorption of drugs and reduce therapeutic benefits. Every patient must be assessed for drug-drug interactions and adverse effects. Periodic monitoring of hepatic functions may be required for medications that have a propensity to cause hepatotoxicity. Proper awareness about challenges stemming from co-morbid medical illness can enable successful pharmacologic treatment of psychiatric disorders among the medically ill.
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