Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases

Abstract

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 assessment these should be and the of this will the of to cognitive of assessment that have been used in this population include the Assessment Scale, and Other that may be in CLD are which may have a by an hepatic and a as are with of liver from may be to and a of such as and IN HEPATIC DISEASE Depression depression and chronic liver disease studies have shown high prevalence of depression in medications used to depression such as are studies on patients have shown that depression such as high levels of systemic and increased levels have also been to the between and depression. in liver disease This of antidepressants is to be for use in has been with liver in with a risk of liver include fluoxetine, and when in patients with liver disease is with GI and the of risk of in those with liver disease. evidence from suggests that an increased risk of events with in liver disease when with this with in pharmacokinetic changes seen in CLD the and reduces drug The is to the at of that used for change is for the is evidence for of in treating symptoms of depression in chronic hepatitis C at for was found to be in the of depression among patients with depression. Similarly, in a the of in at from at and adverse were in of in hepatitis C patients. suggestions for antidepressants in liver disease are shown in 1: for antidepressants in patients with chronic liver and liver liver can be on the of liver or The following of liver have been and are on the of of liver is with levels of serum with little to increase in levels liver a of serum with in in liver and are on liver can be into common and or and on drug liver can either be of the or or the former is by a with symptoms of and and a short for onset the is by a to 1 and not have a in the for a psychotropic agent to liver are the of of multiple psychotropic agents and presence of medical it to and the short and small in the and have been with severe in has been with and liver and of have been with and have been for these antidepressants of agents are for their and such as and and of these agents is reduced in patients with Hence, there may be an increased for adverse at the for is shown to have increased in a with of the liver. is little on the of other such as and on the other hand, there are few of with of these suggestions in CLD are shown in must be when prescribing to patients with hepatic due to increased risk of and of the first to be was from the the due to of severe in patients. Most of these events in the first of and rates were high to is available on the metabolism of other in liver disease, studies on patients have shown prolonged and systemic for and most the use of in liver disease, if there is a need to use the may be as compared to the as there is less risk for Other antidepressants The pharmacokinetics of agents such as and are to be in patients with has been with adverse reactions such as and as should be when it in patients with hepatic On a is also with and a is with has been reported at has also been with to prolonged Furthermore, there are of when is with other drugs of antidepressants in liver patients of on the use of antidepressants among to a in the literature that antidepressants in this more on adverse and drug interactions with agents than on in pharmacokinetic seen in CLD patients. to their effect and are and among liver there are drug and enzymes which are in the metabolism of medications such as and there may be a rise in systemic levels of these agents when with these Other and sertraline, as as such as on enzymes which are to be the evidence on of on serum levels of a of for issues is use of has been to mental in must be made to the use of among depressed Anxiety including in metabolism, and metabolism in and and and personality factors and high have been to this anxiety disorders are with agents that are also used for treating may to for issues and considerations the suggestions in 1 for antidepressants also for anxiety disorders in dosing suggestions for other such as in hepatic suggestions for in patients with chronic liver disorders patients with CLD due to hepatitis disease, or CLD due to such as extensive portosystemic schizophrenia is not an Several may be to this drugs used to schizophrenia such as may liver and may be with including that increases the risk of medical comorbidity and liver common and such as increased central and systemic levels of and decreased levels of amino seen in conditions may this have been with the of (e.g., and (e.g., have been with liver and in the of is and to the two have been more in liver compared to A of severe with use of has been of agents in compared to in liver disease. of may lead to and in can lead to in hepatic and may also when these Hence, it is to liver function and at In patients are on as as those are of or other more may be a it is to if there is a of hepatic or of more than times the of liver should be among patients with liver disease or those are these agents are relatively there is a of on prevalence and risk factors for with In a review of studies and found a of for liver function while the for significant liver was Most such reactions were in the first and were The most common with liver was the changes in metabolism and prescribing suggestions for commonly used in liver suggestions for in patients with chronic liver disorders described the prevalence of hepatic illness in bipolar disorder is increased compared to the general of medical in bipolar disorder increases the risk of factors including and other and common (such as systemic are factors that may this the mood agents that are used to symptoms of bipolar lithium is metabolized in the liver and not protein is that lithium is to use in hepatic a few must be in when lithium in patients with with liver can also have impairment which to fluid this serum levels of lithium is important to serum lithium levels in such a lithium therapy has been with liver function most of these changes are with and do not change of of lithium can more changes in liver function used agents are and and are with risk of while is as it is metabolized by the there are of in hepatic can be seen in of patients on while can be seen in to as these are times the of may be liver is more common among and and is an is a adverse that can result from due to and liver the more common is activity of enzymes in such as and use of topiramate and other is a risk for due to of patients on experience of which hepatic adverse events to a of symptoms of and liver are and which of the and topiramate are with liver and suggestions for common mood in liver disease are shown in suggestions for mood in patients with chronic liver use disorders in chronic use of is an important of liver disease. Many such patients may present with of from to severe cases with and are the drugs of in management of as they the risk of and the lorazepam or are for in as they undergo II in the liver and do not to undergo phase I in phase II reactions are largely preserved in liver disease. among pharmacological agents used to and in use and have more evidence for than has an use in patients with liver disease; it must be in such there are few the of in liver disease, that it not undergo hepatic metabolism and there are few of with it may be for in liver disease. in liver disease and considerations for commonly used medications in use disorders are shown in for use disorder and their in liver of substances with significant in liver disease is Most at to metabolized by the liver. due to hepatitis C is one of the for liver of this among drug on therapy from to Hence, it is important to dosing considerations when for of have not found evidence for to liver disease may be a risk for as is in is metabolized by system at interactions with medications that this not evidence for significant drug when was with or an agent for use in has a to liver function and must be among those with a history of liver disease. for pain in liver disease with between and of patients to higher and are agents for pain in patients as they are by is and those are of liver function should be assessed for symptoms of and should be are metabolized in the at the for medications to affect the metabolism of by or the family of enzymes must be in because most patients with liver disease also have an increased of and because impairment can levels and risk of on may be a cognitive impairment and disorder in hepatic has been in a of liver hepatitis disease, liver disease, and such impairment is with significant negative on of and quality of life. drugs used to disorder are to severe prescribing in such the must be of the balance between risk of adverse and as as the on the of hepatic prescribing suggestions for agents and in hepatic suggestions for and in patients with chronic liver of adverse of in hepatitis C C is a of liver is commonly used for the of hepatitis C is with a of significant effects. include mood changes may also symptoms and cognitive impairment, suicide and or to of patients on therapy with may depression. Psychotropic medications that have a with such as and must be used with in with hepatitis C are on therapy because are common in this with effect (such as tricyclic must be as they can further cognitive impairment in these patients. are the drugs of in depression in hepatitis and are in general have been the risk of gastric agents have evidence for in phase and management at the and of HEPATIC of hepatic disease liver enzymes and may hepatic disease, not is liver and a hepatic disease with The is a of the and of disease and liver and more than in severe liver The has been for the of hepatic disease. The serum serum ascites, and to or of constitute A as constitute B significant in and is as C liver HEPATIC is not to hepatic psychotropic psychotropic medications may in those with hepatic disease, for which hepatic function is In the of a liver function is the can be in if there is evidence of hepatic disease. few of the psychotropic drugs are that at and For other drugs, liver function should be if there are symptoms of hepatic disease such as The most common of seen in more than is serum with little change in a is seen with high levels with serum with these changes suggests severe and or is seen with psychotropic drugs, which is usually psychotropic drugs and liver function the drug can be with at more levels of to times of the is an to the If it is to the a may be there is evidence that such is If there is a history of such hepatic with a it is to with if an is An from may be if hepatic are found to be medications or changes in while on psychotropic therapy is with in those with other risk factors such as is not to serum levels on If a with such as mental serum levels may be and should be can be for of the of may in patients. The diagnosis of include other such as disorders onset or such as and multiple factors for include those for such as chronic and concurrent with that can levels and HEPATIC are drugs that hepatic metabolism, a of which will be for considerations in those with hepatic of the drugs are not metabolized at by and are excreted through other drugs are metabolized by there are phase 1 oxidation reactions that through phase conjugation reactions which are relatively preserved in hepatic the of drug that is metabolized by the liver in to the that is excreted is while on the psychotropic and their and not metabolized by that are metabolized by is that those with have and levels because of reduced hepatic synthesis of in patients with medications with and with such as should be used with serum levels are not of rates in those with and to Similarly, is not metabolized by liver and is in liver disease is not in those with C medications do not in and and should be the drugs if that are metabolized and undergo conjugation reactions are relatively and are those that metabolism lorazepam for in liver it is that conjugation reactions are also in liver disease such as in patients with it is to A is of the in a A and in B with for of For those with C these medications are to be if is PSYCHIATRIC DISORDERS IN GI DISORDERS A (e.g., and should be in management of psychiatric in patients with GI disorders. The following can be used to these patients. The treating physician may a of with GI disorders. assessment should be at a a diagnosis of the GI disorders and screening for psychiatric and screen for that psychiatric The include severe suicidal severe illness and other disorders (e.g., anxiety, use these patients should be GI disorder and psychiatric GI disorders do not in a they from interactions between and the of the aspects of the GI disorders is critical for understanding and management of these (e.g., and the and of the including psychiatric and The to these factors and also directly with the the The use of a the of patients with GI should an assessment in patients with severe physician of and evidence of illness The assessment must include and use of screening for the following for and anxiety (e.g., Hospital Anxiety and Depression Scale, Patient Health and or of illness and quality of life bowel of and assessment of the factors as as of and in patients with to psychiatric medical (e.g., and/or changes (e.g., with or without can be In agents or more management on and to or medications and should be in to severe IN DISEASE and illness are among patients with GI disease. may be the or be a result of these disorders. psychotropic medications are for the of GI disorder symptoms and of psychotropic medications in these patients is due to interactions between GI medications and psychotropic of and in drug pharmacokinetics due to GI disorders (e.g., hepatic short bowel may GI in patients drugs, or with other such as do not to increase the risk of GI in patients they may increase the risk for between GI medications and psychotropic medications can affect drug and reduce drug by the gastric and gastric In such it is that should be at from the other Furthermore, may lithium by (e.g., the metabolism of most drugs including psychotropic of psychotropic medications or of (e.g., is the which increases the of and On other hand, (such as and increases the and of and use of (e.g., with and lithium may the risk of and such as of and with psychotropic drugs with effect can increase the risk of neurocognitive impairment and also result in In these medications may reduce the effect of and and can symptoms when with In these medications may increase the risk of when with other psychotropic drugs (such as and The use of in with can which to increased metabolism and reduced of metabolized drugs (e.g., can such as and with or and with and and depression and (e.g., increases the risk of neurocognitive impairment more when with psychotropic drugs with In these medications may reduce the effect of and A of the of the in the of drugs. the between psychiatric disorders and has been a in recent in have been reported in a of psychiatric disorders including bipolar and disorders. The interaction between and psychotropic drugs is of on the pharmacokinetics and pharmacodynamics of psychotropic and of psychotropic agents on studies have shown that in following use of or lead to an increase in bioavailability of on bioavailability of This suggests that the effect of may be drug On a of changes among In a recent that and that in may and The other in the is changes in by psychotropic and have been shown to have in studies on have shown significant between between and drug free with bipolar Furthermore, evidence from in as as in studies that a of antidepressants including and may effect these drug and The of these are many and to issues with drug drug and In may be into to these issues and inform DISORDERS Psychotropic medications can be used to other gastrointestinal disorders and psychiatric is to consider interactions between GI and psychotropic medications and in prescribing psychotropic agents in prescribing suggestions that can be used in with the suggestions in patients with bowel and other gastrointestinal disease disease is an by an to the of a diagnosis of is on a of to and a the presence of at with are more to GI and including psychiatric disorders. anxiety, bipolar other and disorders are the most commonly reported psychiatric disorders among patients with Furthermore, disorders such as and are commonly reported among these is evidence to that drug may be increased reduced, or in this includes psychotropic medications is little on the pharmacokinetics of psychotropic medications among patients with while treating psychiatric disorders among patients with drugs should be used with is the of among patients with Patients with would from avoid from or and or from A also depressive and symptoms in these patients and increases free is an of include of a of (e.g., and a to The is among Patients experience pain are for psychiatric to disorders. a should these patients for the of is a disorder by of nervous system and GI symptoms where there is an in metabolism. of include drugs have also been anxiety, and disorders are psychiatric Most mood or (e.g., agents with oral and are in patients with Psychotropic medications such as sertraline, and are for of of and concurrent psychiatric in patients with liver and GI disorders must be on the of psychotropic agent and of the medical In patients with liver disease, it is to use psychotropic drugs that avoid or undergo hepatic metabolism. is while prescribing psychotropic drug in severe hepatic disease as may be In GI there are few conditions such as gastric and disease may alter of drugs and reduce must be assessed for interactions and adverse effects. of hepatic may be for medications that have a to challenges from medical illness can of psychiatric disorders among the medically ill. and of are of

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