Roger S. Mcintyre, MD, FRCPC

The unintended negative consequences of the coronavirus disease 2019 (COVID-19) pandemic continues to be a problem. Reduced social interaction and closure of public places, along with increased home confinement, has led to a sharp decrease in physical activity, a steady increase in food intake, and a 

 Stress has similarly impacted sleep, unhealthy eating, and even increased consumption of alcohol.

Public health and economic crises have been associated with serious, long-lasting negative impact on individual and population-based mental health outcomes. Indeed, a recent meta-analysis found higher rates of 

, depression, posttraumatic stress disorder, psychological distress, and stress during the COVID-19 pandemic.

 To further complicate matters, individuals are less likely to seek non-emergent health care, including care for mental disorders, during the pandemic.

Related health consequences of obesity such as hypertension and diabetes mellitus are a major source of morbidity.

 Stress, fatigue, physical inactivity, and a sedentary lifestyle can advance obesity and, subsequently contribute to a number of mental health disorders.

 Depression and obesity share a bidirectional relationship, where the presence of one disease increases the risk for developing the other (

 Increased carbohydrate consumption, a risk factor for obesity, is common in patients with depression. The presence of obesity often has a chronic course of illness and can result in poor treatment response in depression.

 are predominantly treated with antidepressants as a first-line treatment option, with 79% of primary care physicians prescribing antidepressants to these patients.

 Recent studies have shown that antidepressant medications can contribute to weight gain through various mechanisms, including increased food consumption and abnormal metabolic processes.

 Reductions in depressive symptoms and antidepressant usage may coincide with weight loss (as seen with bariatric surgery patients), and this underscores the importance of monitoring the increasing rates of obesity.

For the last 2 decades, depressive disorders have consistently ranked amongst the top 5 illnesses for years of life lived with a disability.

 Cognitive deficits is a core symptom of depression, and it often persist between affective episodes and beyond the remission of mood symptoms.

 Executive functioning, attention, memory, and learning can be affected.

 Obesity also contributes to impairments in cognition; individuals with obesity exhibit significantly impaired cognitive functioning and structural changes in brain regions associated with executive functioning.

 Moreover, in individuals with obesity, cognitive impairments 

 lower weight loss success, poor treatment adherence, and decreased physical functioning.

Individuals with a longer duration of illness and a higher frequency of depressive episodes are more likely to experience cognitive impairments. Persistent cognitive impairment contributes to consequences in occupational and social domains.

 In particular, evidence from adults with mood disorders implicates cognitive impairment as a mediator of workplace function and attendance, as well as patient-reported outcomes (eg, quality of life).

 Approximately 15% of patients with major depressive disorder attribute their unemployment to cognitive symptoms. Unfortunately, few treatments, including psychotropic medications, have proven effective in improving cognitive function in adults with mood disorders, especially in cases of treatment resistance.

Patients with comorbid depression and obesity often demonstrate higher levels of baseline inflammation, which is characterized by a higher level of inflammatory cytokines (a type of signaling molecule that promotes inflammation). Likewise, obesity involves a pro-inflammatory state. Conversely, findings have shown improved cognition is linked to a reduction in inflammation.

 Indeed, in a meta-analysis evaluating inflammation and treatment response, researchers found increased levels of inflammatory cytokines in patients with depression. In cases that successfully responded to treatment, the levels of inflammatory cytokines were decreased.

There are several proposed mechanisms that may mediate the relationship between chronic stress, inflammation, and mood disorders. Stressful experiences have been shown to increase production of cortisol. Glucocorticoids increase activities of the sympathetic system, such as heart rate and blood pressure, to reduce the stress response. However, if this system is dysregulated, chronic stress and cortisol production can lead to the desensitization of the glucocorticoid receptors. It can be conjectured that the dysregulation of the inflammatory pathway is also worsened by the presence of insulin resistance and increase in adipocytes. The bidirectional relationship between the 2 illnesses and the co-occurrence of an inflammatory state underscores the involvement of inflammation in the pathophysiology of depression and obesity.

Evidence suggests that physical activity aids in alleviating mild to moderate symptoms of depression in patients and may promote clinically significant antidepressant effects. For more severe cases of depression, 

 in conjunction with other treatments (ie, pharmacological).

 Exercise may also help improve cognition in individuals with depression. In a study investigating the dose-dependent effects of 

 on cognition in patients with depression, high-intensity exercise was associated with improvements in executive function and working memory tasks. Meanwhile, other cognitive domains, such as attention, visual memory, and spatial planning, improved regardless of dose.

 Therefore, it is importan that adequate social and physical activities are integrated into treatment plans to promote well-being.

is a researcher at the Canadian Rapid Treatment Center of Excellence and the Institute of Medical Science at the University of Toronto. 

is a professor of psychiatry and pharmacology at the University of Toronto, and Head of the Mood Disorders Psychopharmacology Unit for the University Health Network, Toronto, Canada.

Effect of obesity and body mass index on coronavirus disease 2019 severity: A systematic review and meta‐analysis

2 .Xiong J, Lipsitz O, Nasri F, et al. Impact of COVID-19 pandemic on mental health in the general population: A systematic review.

3. Alosco ML, Spitznagel MB, Strain G, et al. Improved serum leptin and ghrelin following bariatric surgery predict better postoperative cognitive function.

4. Sarris J, O’Neil A, Coulson, et al. Lifestyle medicine for depression.

5. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies.

Collaborative care for depression in primary care: how psychiatry could “troubleshoot” current treatments and practices.

7. Gill H, Gill B, El-Halabi S, et al. Antidepressant Medications and Weight Change: A Narrative Review. (Silver Spring)

8. Collaborators G 2016 ORF, GBD 2016 Occupational Risk Factors Collaborators. Global and regional burden of disease and injury in 2016 arising from occupational exposures: a systematic analysis for the Global Burden of Disease Study 2016.

9. McIntyre RS, Lee Y. Cognition in major depressive disorder: a “Systemically Important Functional Index” (SIFI).

10. Motter JN, Pimontel MA, Rindskopf D, Devanand DP, Doraiswamy PM, Sneed JR. Computerized cognitive training and functional recovery in major depressive disorder: A meta-analysis.

11. Spitznagel MB, Garcia S, Miller LA, et al. Cognitive function predicts weight loss after bariatric surgery.

12. Rasmussen LJH, Caspi A, Ambler A, et al. 

Association of Neurocognitive and Physical Function With Gait Speed in Midlife

13. Baune BT, Air T. Clinical, Functional, and Biological Correlates of Cognitive Dimensions in Major Depressive Disorder – Rationale, Design, and Characteristics of the Cognitive Function and Mood Study (CoFaM-Study).

14. McIntyre RS, Lee Y, Mansur RB. Treating to target in major depressive disorder: response to remission to functional recovery.

15. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. 

16. Schuch FB, Vancampfort D, Richards J, et al. 

Exercise as a treatment for depression: A meta-analysis adjusting for publication bias

17. Greer TL, Grannemann BD, Chansard M, et al. Dose-dependent changes in cognitive function with exercise augmentation for major depression : results from the TREAD study. 

Articles

Evidence suggests that physical activity aids in alleviating mild to moderate symptoms of depression in patients and may promote clinically significant antidepressant effects.

A Recipe for Homemade Obesity: The Association Between Depression, Obesity, and Cognitive Deficits

In the clinical ecosystem, there are very important suggestions offered by the collection of data sets (discussed in 

The first is that it is absolutely essential that every person who has bipolar disorder be screened for risk factors related to metabolic syndrome and diabetes and traditional risk factors like overweight and eating habits. We are also beginning to consider emerging risk factors like co-inflammation and behavior that promotes inflammation.

Here to talk about these issues is Roger McIntyre, MD, Professor of Psychiatry and Pharmacology and Head of the Mood Disorders Psychopharmacology Unit at the University of Toronto. He is a speaker at this year's PsychCongress in a presentation titled "Bipolar Disorder and Medical Comorbidity: Research and Treatment Implications."

Podcasts

It is absolutely essential that every person who has bipolar disorder be screened for risk factors related to metabolic syndrome and diabetes and traditional risk factors like overweight and eating habits. More in this podcast.

Screening for Metabolic Syndrome in Bipolar Disorder

We know there is extensive overlap between bipolar disorder and medical morbidity-including obesity, diabetes, and metabolic syndrome. The real question is why.

Here to talk about the implications of concurrent metabolic problems on the clinical course of bipolar disorder in this first of a 2-part podcast is Roger McIntyre, MD, Professor of Psychiatry and Pharmacology and Head of the Mood Disorders Psychopharmacology Unit at the University of Toronto.

Dr McIntyre is a speaker at this year's PsychCongress in a presentation titled "Bipolar Disorder and Medical Comorbidity: Research and Treatment Implications." (For Part 2 of this podcast series, 

 Sex differences in rates of obesity in bipolar disorder: postulated mechanisms

2014;16:83-92.

Reininghaus EZ, McIntyre RS, Reininghaus B, et al. 

Tryptophan breakdown is increased in euthymic overweight individuals with bipolar disorder: a preliminary report

 2014;16:432-440.

McIntyre RS, Soczynska JK, Liauw SS, et al. 

The association between childhood adversity and components of metabolic syndrome in adults with mood disorders: results from the international mood disorders collaborative project

We know there is extensive overlap between bipolar disorder and medical morbidity-including obesity, diabetes, and metabolic syndrome. The real question is why.  More in this podcast.

Bipolar Disorder: A Brain-Body Disease

Psychiatric disorders are heterogeneous and of multifactorial origin.

 The illness course is often chronic and associated with high rates of nonrecovery, episode recurrence, interepisodic dysfunction, and morbidity as well as premature mortality.

It is therefore not surprising that MDD, bipolar disorder, and schizophrenia are among the primary leading causes of disability and economic burden worldwide. One major contributor to the economic burden associated with these conditions is the limited capability of available treatment options to effectively modify the disease process, fully restore function, halt illness progression, and treat cognitive deficits.

Since the original description of lithium’s efficacy for mania in 1948, followed by chlorpromazine and iproniazid shortly thereafter, no substantial pharmacological advances have been made in the field of psychiatry. Although advances in safety, tolerability, and simplicity of use have been made, the long-term outcomes for most patients with MDD, bipolar disorder, or schizophrenia remain largely the same as they did several decades ago, ie, many of these patients do not achieve symptomatic, syndromal, and functional recovery with conventional pharmacotherapy. This underscores the need for restructuring the current disease model.

The prevailing theory for the past 50 years has been that affective and psychotic disorders are subserved by disturbances in monoamines. Yet, despite intensified research efforts, monoamines have not proved to be reliable biomarkers of psychiatric disorders and no disease-modifying agents have been discovered on the basis of this model. A more comprehensive disease model that encompasses other physiological systems may accelerate progress toward novel treatment development.

Results from preclinical and clinical translational research indicate that disturbances in inflammation may play a role in the pathophysiology of psychiatric disorders, including MDD, bipolar disorder, and schizophrenia. Hence, it could be hypothesized that inflammatory mediators may constitute novel targets for drug development.

Cytokines are pleiotropic and often redundant soluble proteins that regulate survival, differentiation, proliferation, and effector functions of tissues and cells. While these proteins are well-known mediators of innate and adaptive immunity, more recently they have been implicated in a variety of other systems. For example, inflammatory cytokines have been shown to interact with neurotransmitter metabolism, neuroendocrine function, and neural as well as glial plasticity. Peripherally and centrally derived inflammatory cytokines exert a bidirectional influence across the blood-brain barrier or via peripheral afferent nerve fibers (ie, vagus nerve).

The increased incidence of inflammatory diseases in individuals with psychiatric disorders (eg, cardiovascular disease, obesity, autoimmune diseases) provides conjectural evidence that inflammatory mediators may be involved in the pathophysiology of these conditions. The obverse association is also reported, wherein in individuals with rheumatic diseases, the incidence of subsequent psychiatric disorders is higher.

In a population-based study that evaluated the entire Swedish population, the standardized incidence ratio of subsequent psychiatric disorders was highest for individuals with systemic lupus erythematosus followed by ankylosing spondylitis and rheumatoid arthritis.

 Further analysis revealed a higher incidence of subsequent affective, psychotic, and personality disorders, as well as dementia and delirium, although the risk of psychotic disorders was significant only in women with rheumatoid arthritis and systemic lupus erythematosus.

Other population-based studies, however, have reported a lower incidence of schizophrenia in individuals with rheumatoid arthritis.

Higher rates of depression are also evident with various other medical conditions, including obesity and cardiovascular disease.

 The bidirectional co-occurrence of psychiatric and autoimmune or inflammatory diseases suggests the involvement of common networks central to the pathophysiology of these conditions.


Triggers of inflammation in psychiatric disorders

The hypothesis that inflammatory cytokines play a role in the pathophysiology of psychiatric disorders stems from the observation that sickness behavior is characterized by signs and symptoms that are common to major depression. Sickness behavior is a nonspecific reaction to inflammation that is mediated by proinflammatory cytokines (eg, interleukin (IL)-1, IL-6, tumor necrosis factor Î± [TNF-Î±], and interferon-Î³ [IFN-Î³]) and is characterized by decreased appetite, amotivation, cognitive impairment, and neurovegetative symptoms.

During the past 2 decades, numerous studies have documented abnormal inflammatory cytokine concentrations in patients with MDD, bipolar disorder, or schizophrenia.

 Most replicated and common to all 3 conditions are elevated concentrations of circulating TNF-Î±, IL-6, and IL-1Î². Preliminary evidence also documents abnormalities in concentrations of proinflammatory cytokines in the cerebrospinal fluid of patients with MDD, bipolar disorder, or schizophrenia.

 It has been hypothesized that inflammation in mood disorders may arise from an imbalance between proinflammatory and anti-inflammatory cytokines. This is supported by evidence of increased proinflammatory to anti-inflammatory cytokine ratios in these populations.

There is a pressing need for studies of inflammatory markers in children and adolescents at risk for or in the early stages of a psychiatric disorder. At this point, it is not known if inflammatory cytokine abnormalities are a cause or consequence of the illness. Preliminary evidence suggests that manic but not depressive symptom severity in adolescents with bipolar disorder is significantly associated with high-sensitivity C-reactive protein (CRP) levels, an acute phase reactant that is elevated in response to inflammation, but not with IL-6 levels.

 A preliminary proinflammatory gene expression signature has been reported in offspring of individuals with bipolar disorder, and elevated messenger RNA (mRNA) levels as well as protein expression levels of IL-1Î², IL-6, and TNF-Î± have been reported in the prefrontal cortex of adolescent suicide victims.

 Longitudinal studies in children at genetic risk for major psychiatric disorders may aid identification of biomarkers that allow for earlier detection of candidates for prophylactic treatment.

Although the triggers of inflammation in psychiatric disorders are unknown, they are likely multifactorial in origin and encompass environmental and genetic factors (

). For example, maternal infections as well as maternal stress have been reported to pose a risk for the onset of schizophrenia later in life.

 Early childhood stress has also been shown to trigger an inflammatory response and may render individuals more vulnerable to psychiatric disorders.

Among female adolescents at high risk for depression, transition to depression was associated with increases in CRP and IL-6 levels; the magnitude of these changes was greater among females with multiple types of childhood adversity.

 Lower socioeconomic status in early childhood (1 to 2 years of age) has also been associated with elevated circulating IL-6 levels in adulthood.

 Environmental factors during the prenatal period or early childhood may activate the inflammatory response, which in combination with a genetic susceptibility or epigenetic modification, may increase the risk of psychiatric disorders.

Inflammation is highly interconnected with oxidative stress and results in a widespread influence on protein expression and cell survival. Oxidative stress exerts effects on DNA methylation patterns and produces unique epigenetic profiles that may increase vulnerability to psychiatric disorders. For example, decreased IL-6 CpG methylation is associated with elevated serum IL-6 and CRP levels in individuals with lifetime depression.

 Moreover, inflammation and oxidative stress are associated with increased apoptosis and decreased neural and glial plasticity.

 Abnormalities in these processes have also been reported in persons with MDD, bipolar disorder, and schizophrenia.

Anti-inflammatory agents have been shown to mitigate psychiatric symptoms. For example, adjunctive celecoxib has been shown to exert antidepressant effects in MDD and bipolar disorder as well as ameliorate symptoms of schizophrenia.

 Minocycline, a tetracycline antibiotic with anti-inflammatory properties, has also been shown to mitigate negative symptoms and improve cognitive function in patients with schizophrenia.

 Moreover, evidence from animal studies and a pilot open-label clinical trial in patients who had MDD with psychotic symptoms suggests that minocycline exerts antidepressant effects.

 TNF antagonists may also have antidepressant effects, as suggested by improvements in secondary measures of depression and quality of life in individuals with inflammatory disorders.

Conventional antidepressants, mood stabilizers, and antipsychotics, in varying capacities, down-regulate proinflammatory cytokine mRNA and protein levels. Moreover, for patients who are candidates for IFN-Î± therapy, antidepressant pretreatment has been shown to reduce the risk of cytokine-induced depression.

 Interestingly, preliminary preclinical evidence suggests that SSRIs and antipsychotics suppress inflammatory cytokine production and inhibit disease progression in an animal model of rheumatoid arthritis.

A plethora of studies support the hypothesis that inflammation plays a role in the pathophysiology of major psychiatric disorders. A unique inflammatory signature capable of distinguishing between each condition, however, remains to be elucidated. Although differences between the psychiatric disorders have been reported, no consistent disorder-specific profiles have emerged from these efforts. The heterogeneous presentation of each psychiatric disorder and the pleiotropic nature of inflammatory cytokines support the hypothesis that a combination of biomarkers along with genetic and environmental risk factors may prove to be a more reliable predictor of disease.

Considering that not all individuals will manifest inflammatory abnormalities, identifying subtypes of mood disorders (perhaps informed by biomarkers) may help identify a subgroup of individuals with mood disorders wherein inflammatory disturbances are a critical component of the pathoetiology and/or treatment. With technological advancement, it is now possible to conduct microarrays and evaluate over 1000 analytes simultaneously. Preliminary studies using this method have begun to delineate common and distinct biological processes in MDD, bipolar disorder, and schizophrenia, bringing us one step closer to a more comprehensive model of disease and pharmacological revolution.

Acknowledgment-The authors would like to thank Marena Manierka for her invaluable input and comments during the writing of this article.

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A plethora of studies support the hypothesis that inflammation plays a role in the pathophysiology of major psychiatric disorders.

Are Psychiatric Disorders Inflammatory-Based Conditions?

Dr Roger McIntyre answers a reader's question below. How would you answer? Take the quiz-

for the answer and discussion, go to the next page

Bipolar disorder (BD) has been highly associated with disparate cognitive deficits, including attention, psychomotor performance, executive function, verbal fluency, learning, memory, and global neurocognitive functioning.

 The pertinacity of cognitive deficits in BD is underscored by reports that document an association between cognitive deficits and psychosocial functioning, workforce performance, and interpersonal adjustment.

Emerging evidence also indicate that obesity is associated with reduced cognitive function in otherwise healthy individuals.

 The association between anthropometrics and cognitive deficits is detectable in individuals without obesity-associated comorbidities (eg, type 2 diabetes mellitus, hypertension) known to independently affect brain function.

 Most cognitive domains are reported to be adversely affected by excess weight with replicated abnormalities in measures of learning, memory, and executive function.

It has been amply documented that individuals with BD are differentially associated with overweight/obesity and abdominal obesity and excess weight adversely effects illness presentation, course, and outcome. Available evidence is beginning to suggest that excess weight is negatively associated with cognitive function in BD.

It is well established that impairments in executive function are apparent in mixed populations of individuals with BD as well as obese individuals without psychiatric disorders.

 It could be hypothesized that obesity and BD are associated with common CNS structural and/or functional changes in brain regions that subserve cognitive functioning. For example, frontal cortical regions that mediate executive function are hypometabolic in depressed individuals; similarly, overweight/obese individuals manifest reduced metabolic activity, as well as atrophy, in several cortical and subcortical structures.

Moreover, the interrelationship between obesity and mood disorders may be due to a pathophysiological nexus that includes abnormalities in hypothalamus-pituitary-adrenal axis function, inflammatory and metabolic systems, disruption of brain circuitry, all of which are potential mediators of cognitive function.

 Further structural and functional investigations, as well as the establishment of mechanisms that mediate cognitive deficits in obesity and BD, are required before a firm conclusion can be drawn.


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Dr Roger McIntyre answers a reader's question. How would you answer? Take the quiz.

Obesity and Bipolar Disorder

Psychiatrists are often asked to medicate patients with chronic kidney disease (CKD). Currently, there are 350,000 Americans who receive maintenance dialysis for renal failure, and this predominantly elderly population with multiple comorbidities is growing. In selecting psychotropic medications, psychiatrists need to be aware of the effects of renal dysfunction on medication absorption (ie, bioavailability), volume of distribution, metabolism, and excretion of the parent drug and the respective metabolites.

A few psychotropic medications, such as lithium, are primarily excreted by the kidneys, whereas most others are fat-soluble and are metabolized by the liver. Although the 

routinely recommends the use of partial dosages of psychotropic medications for renal patients, the data that support these recommendations are limited. There are even fewer empirical data available about psychotropic medication use for children. Thus, the clinician will find it necessary to engage in medication trials that are influenced by individual patient tolerability, response, and changes in clinical status.

In 2005, more than 106,000 patients with newly diagnosed end-stage renal disease (ESRD) began dialysis therapy, joining a dialysis population of 341,000 people and a transplant population of 144,000.

 Kidney disease involves people of all ages, including children, but most individuals fall into the adult and geriatric categories.

, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative has divided chronic kidney disease into 5 stages. This article emphasizes the management of persons who fall into stages 4 and 5, in which renal function is greatly compromised, necessitating renal replacement therapy. In the nephrology literature, they have traditionally been labeled as having ESRD (the stages of CKD are a more recent taxonomy)-the term we will use throughout this article.

Although the psychiatric epidemiological literature has glaring limitations, clinicians need to familiarize themselves with the prevalence and hazards posed by psychiatric disorders in renal patients.

 For example, precisely quantifying the rate of depression in dialysis patients is limited by heterogeneity in study design, assessment procedures, and sample composition. Reported rates of depression have ranged from 0% to 100%. This variation underscores the need for a more refined and systematic approach to evaluating depression in renal patients. Furthermore, medication-related problems are extraordinarily frequent and were identified in 98% of a sample of 133 hemodialysis patients.

 In this study, patients had a mean of 6 ± 2.3 comorbid illnesses; 11 ± 4.2 different drugs were prescribed per patient, and a total of 475 medication-related problems were detected.

Patients with renal failure may evince alterations in any pharmacokinetic parameter-absorption, volume of distribution, metabolism, or excretion (

 Consequently, medication-related problems are frequent occurrences. Two other factors may be of equal or even greater importance, and both influence pharmacokinetics: Many ESRD patients are elderly, and the prevalence of associated severe comorbid disorders (eg, diabetes, hypertension) is high.

Bioavailability is the extent to which a dose of drug enters the systemic circulation. An oral dose is first absorbed from the GI tract; it subsequently passes through the liver, where metabolism and biliary excretion may occur. A decrease in bioavailability for some agents occurs at the level of drug absorption from the GI tract. Alterations in gastric alkalinity (caused by excessive urea generation by the internal urea-ammonia cycle) result in alterations in gastric pH that affect the absorption of psychotropic drugs.

What is already known about psychiatric treatment for patients with renal failure? 
? Clinical research and pharmacokinetic data about the psychiatric management of patients with renal failure are lacking. However, experience suggests that in this patient population, competent care may be delivered when the unique physiological, pharmacokinetic, dynamic, and risk/benefit factors are considered.

What new information does this article provide? 
? This article reviews the indications and dosing considerations for the most commonly used psychotropic medications. Clinical pearls and practical tips are offered to provide guidance and to assist clinicians as they initiate medication interventions for renal patients with comorbid psychiatric disorders.

What are the implications for psychiatric practice? 
? Patients with chronic renal disease may receive timely and effective psychiatric care for their debilitating conditions with psychiatric consultation and the judicious use of psychoactive medications.


Rival mechanisms that affect absorption in patients with renal failure include nausea and vomiting as well as delayed gastric emptying (from diabetic gastroparesis). Diabetes mellitus is a common cause of ESRD and is an important factor to consider when prescribing because of the relationship between atypical neuroleptics and increased serum glucose levels.

Volume of distribution entails the effects of dilution or concentration of medications in the body. The 2 overarching factors that influence distribution are the volume of distribution and protein binding. It is not uncommon in ESRD for elderly patients to become cachectic. These patients have less fluid and less body mass and a decreased volume of distribution. Consequently, a given dose results in a greater concentration of medication in a cachectic patient than in a non-cachectic patient.

The issue of protein binding is especially significant in ESRD. The principle plasma protein responsible for binding to acidic drugs is albumin, while for alkaline drugs, it is α

 Proteinuria and hypoalbuminemia are frequently found in renal failure, and there is an accumulation of endogenous binding inhibitors (eg, organic acids, uremic toxins). Binding inhibitors compete with drugs for the carrier protein binding site, and albumin undergoes conformational changes with hypothesized changes in binding properties. The results are diminished protein binding and an increase in the bioactive free fraction of acidic drugs in plasma. All other factors remaining constant, the greater the protein binding of a medication, the lower the dose of the drug required in ESRD, since there is a greater risk of toxicity when increased amounts of the free, unbound forms of acidic drugs are in the plasma.

Another factor to consider is that the circulating concentration of α

-acid glycoprotein may increase in patients maintained with renal transplant or hemodialysis. The effect may be a decrease in the unbound circulating fraction and diminished biological activity of the drug.

The metabolism or degradation of a medication is probably the area of pharmacokinetics that is least familiar, particularly because the intermediate products of metabolism are difficult to isolate and identify. The rate of renal metabolism by the renal brush border is predicted to decrease as the glomerular filtration rate (GFR) declines. In addition, evidence suggests that metabolism by the liver is variably altered in ESRD. Both the expression and function of cytochrome P-450 (CYP) 2C9 and CYP3A4 are decreased in severe ESRD.

 Although the literature is sometimes contradictory, it appears that in renal failure there is a general slowing of chemical reduction and hydrolysis, but there are normal rates of glucuronidation, microsomal oxidation, and sulfate conjugation.

Excretion takes place through the GI tract and from the kidney to the bladder, and this latter avenue is obviously absent following renal failure. Glomerular filtration, active tubular secretion, and passive tubular reabsorption are the 3 distinct mechanisms of excretion by the kidney, and all of them are affected in ESRD. The artificial substitution by a dialysis machine results in intermittent excretion rather than the continual process performed by healthy kidneys. Drugs are only occasionally metabolized to pharmacologically active compounds that are then normally excreted in urine. Fortunately, most psychotropic medications are metabolized by the liver, eliminated in bile, and excreted in feces.

There is a paucity of data documenting the efficacy and pharmacokinetics of psychotropic agents in patients with renal impairment.

 Most research is based on a handful of subjects, and well-controlled trials in psychopharmacology are rare. There are very few in vivo studies of pharmacokinetics in persons without kidney disease or patients with ESRD. Accordingly, in the absence of empirical data, clinical experience suggests that the majority of psychotropic medications can be safely used in the ESRD population. Some important considerations and exceptions are noted below.

Most psychotropic medications are fat-soluble and have large volumes of distribution. They are metabolized in the liver and metabo-lites are eliminated in urine and bile. Most of these drugs easily pass the blood-brain barrier, and they are not dialyzable. Attention needs to be paid to medications that have active metabolites-those that are highly plasma protein–bound, and those that have altered pharmacokinetics or pharmacodynamics.

Currently, there are 350,000 Americans who receive maintenance dialysis for renal failure, and this predominantly elderly population with multiple comorbidities is growing.

Roger S. Mcintyre, MD, FRCPC

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