Roger S. Mcintyre, MD, FRCPC

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."

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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.

 Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. 

 Raison CL, Borisov AS, Majer M, et al. Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. 

 Sundquist K, Li X, Hemminki K, Sundquist J. Subsequent risk of hospitalization for neuropsychiatric disorders in patients with rheumatic diseases: a nationwide study from Sweden. 

 Chen SJ, Chao YL, Chen CY, et al. Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study. 

 Eaton WW, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. 

 Dean B. Understanding the role of inflammatory-related pathways in the pathophysiology and treatment of psychiatric disorders: evidence from human peripheral studies and CNS studies. 

 Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. 

 Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. 

 Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. 

 Garver DL, Tamas RL, Holcomb JA. Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. 

 Levine J, Barak Y, Chengappa KN, et al. Cerebrospinal cytokine levels in patients with acute depression. 

 SÃ¶derlund J, Olsson SK, Samuelsson M, et al. Elevation of cerebrospinal fluid interleukin-1Ã in bipolar disorder. 

 Kim YK, Jung HG, Myint AM, et al. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. 

 Dhabhar FS, Burke HM, Epel ES, et al. Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression. 

 Kim YK, Myint AM, Lee BH, et al. Th1, Th2 and Th3 cytokine alteration in schizophrenia. 

Prog Neuropsychopharmacol Biol Psychiatry

 Goldstein BI, Collinger KA, Lotrich F, et al. Preliminary findings regarding proinflammatory markers and brain-derived neurotrophic factor among adolescents with bipolar spectrum disorders. 

 Padmos RC, Hillegers MH, Knijff EM, et al. A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. 

 Pandey GN, Rizavi HS, Ren X, et al. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. 

 Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. 

 van Os J, Selten JP. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. 

 Miller GE, Cole SW. Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. 

 Carroll JE, Cohen S, Marsland AL. Early childhood socioeconomic status is associated with circulating interleukin-6 among mid-life adults. 

 Uddin M, Koenen KC, Aiello AE, et al. Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. 

 Lucassen PJ, Meerlo P, Naylor AS, et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. 

 Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. 

Articles

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.


1. Bearden CE, Hoffman KM, Cannon TD. The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. 

. 2001;3:106-150.
2. Malhi GS, Ivanovski B, Hadzi-Pavlovic D. Neuropsychological deficits and functional impairment in bipolar depression, hypomania and euthymia. 

. 2007;9:114-125.
3. Martinez-Aran A, Vieta E, Colom F, et al. Cognitive dysfunctions in bipolar disorder: evidence of neuropsychological disturbances. 

. 2000;69:2-18.
4. Martinez-Aran A, Vieta E, Reinares M, et al. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. 

. 2004;161:262-270.
5. Wingo AP, Harvey PD, Baldessarini RJ. Neurocognitive impairment in bipolar disorder patients: functional implications. 

. 2009;11:113-125.
6. Friedman ES. Cognitive deficits in bipolar individuals: implications for clinical practice. 

. 2009;15:305-306.
7. McIntyre RS, Konarski JZ. Bipolar disorder: a national health concern. 

. 2004;9(Suppl 12):6-15.
8. Brook JS, Zhang C, Saar NS, Brook DW. Psychosocial predictors, higher body mass index, and aspects of neurocognitive dysfunction. 

. 2009;108:181-195.
9. Cohen RA. Obesity-associated cognitive decline: excess weight affects more than the waistline. Neuroepidemiol. 2010;34:230-231.
10. Cournot M, Marquie JC, Ansiau D, et al. Relation between body mass index and cognitive function in healthy middle-aged men and women. 

. 2006;67:1208-1214.
11. Elias MF, Elias PK, Sullivan LM, et al. Obesity, diabetes and cognitive deficit: The Framingham Heart Study. 

. 2005;26(Suppl 1):11-16.
12. Fergenbaum JH, Bruce S, Lou W, Hanley AJ, Greenwood C, Young TK. Obesity and lowered cognitive performance in a Canadian First Nations population. 

. 2009;17:1957-1963.
13. Gunstad J, Paul RH, Cohen RA, et al. Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. 

. 2007;48:57-61.
14. Jeong SK, Nam HS, Son MH, et al. Interactive effect of obesity indexes on cognition. 

. 2005;19:91-96.
15. Nilsson LG, Nilsson E. Overweight and cognition. 

. 2009;50:660-667.
16. Gunstad J, Spitznagel MB, Paul RH, et al. Body mass index and neuropsychological function in healthy children and adolescents. 

. 2008;50:246-251.
17. Yim CY, Soczynska JK, Kennedy SH, Woldeyohannes HO, Brietzke E, McIntyre RS. The effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder. 

. 2011 May 11 (Epub ahead of print].
18. Bruce-Keller AJ, Keller JN, Morrison CD. Obesity and vulnerability of the CNS. 

. 2009;1792:395-400.
19. Jamrozinski K. Do euthymic bipolar patients have normal cognitive functioning? 

. 2010;23:255-260.
20. Martinez-Aran A, Vieta E, Colom F, et al. Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome. Bipolar Disord. 2004;6:224-232.
21. Robinson LJ, Thompson JM, Gallagher P, et al. A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. 

. 2006;93:105-115.
22. Walther K, Birdsill AC, Glisky EL, Ryan L. Structural brain differences and cognitive functioning related to body mass index in older females. 

. 2010;31:1052-1064.
23. Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. 

. 2008;213:93-118.
24. Volkow ND, Wang GJ, Telang F, et al. Inverse association between BMI and prefrontal metabolic activity in healthy adults. 

. 2009;17:60-65.
25. Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. 

. 2004;56:819-824.
26. Thompson JM, Gallagher P, Hughes JH, et al. Neurocognitive impairment in euthymic patients with bipolar affective disorder. 

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.

Lithium is the only known psychotropic medication in which long-term use is associated with nephrotoxicity, renal insufficiency, and even ESRD. Although renal function will often improve if the drug is stopped, some patients require maintenance dialysis or kidney transplant. Attempts should be made to transition to the classic anticonvulsant medications divalproex and carbamazepine, but they may be inadequate mood stabilizers.

For the minority of bipolar patients with ESRD who continue to require lithium, treatment involves administration of a single dose (usually 600 mg) after each dialysis session. Because lithium is a readily dialyzable, small molecule, it is entirely eliminated by dialysis, and a single post-dialysis dose will result in a steady serum level. Serum lithium levels should be measured immediately before dialysis. If lithium is used to augment the therapeutic effects of antidepressants in treatment-resistant unipolar depression, a smaller dose (eg, 300 mg) may be given after dialysis sessions.

The ultimate goal for children with ESRD is kidney transplant. However, many will live years before transplant occurs, and many may need psychiatric care before and after the transplant. With the exception of recommended dosing of anticonvulsants, 2 treatment reviews do not list any psychotropic medications in their Tables of dosing considerations for children with significant renal impairment.

 predates the dramatic increase in use of psychoactive medications for children with a variety of internalizing and externalizing behavioral conditions.

Pediatric ESRD differs from the adult version in which diabetes mellitus and hypertension are more frequent long-standing comorbid disorders.

 Pediatric psychopharmacology ideally determines dosing on the basis of body surface area instead of body weight, but minimal information is available concerning either application with psychotropic medications.

 For children on dialysis and in need of psychiatric management, rely on the pediatric axiom for dosing: “start low and go slow.”

Many of the psychotropic medications-with the exception of the typical neuroleptics and somnolent tranquilizers-are used in pediatric psychiatry. In this population, some are relied on more often than others (eg, fluoxetine is preferred over paroxetine because of its longer half-life and research data that support its indication and use). Conservative initial dosing for pediatric indications would frequently be a 50% to 75% lower dose than the typical adult dose, with allowances to increase dosing during subsequent care, depending on tolerability, response, and changes in clinical status. This is especially the case for stimulant compounds such as amphetamine and methylphenidate, which have a higher proportion of elimination through the kidneys than many other medications.

Because there are no available data, even the package inserts for the stimulant medications do not specify any dosing adjustments to be made for children with ESRD. It appears that methylphenidate or the clearance of its inactive hepatic metabolite, ritalinic acid, is not as sensitive to the alkalinization of urine as amphetamine products.

With renal dysfunction and ESRD, lower dosing and slower increases during the clinical use of mixed amphetamine salts and dextroamphetamine is prudent. The alkalinization of urine associated with renal disease reduces the clearance of amphetamine and its metabolites to as low as 1%, while acidification increases clearance and can there-fore reduce levels. Consulting psychiatrists, in coordination with the primary care team and nephrolo-gists, can be of assistance with assessing the indications for and judicious use of psychiatric medications in any child with ESRD and psychiatric comorbidities. Families need to be fully informed as to treatment shortcomings.

Psychopharmacological pearls and renal failure

There are no formal guidelines for the treatment of psychiatric disorders in patients with renal failure, so the following points are based on clinical experience.

• ESRD is defined as a GFR of less than 15 mL/min/1.73 m

, in most cases accompanied by signs and symptoms of uremia

• Individuals with ESRD are in need of dialysis/transplant; some patients may require dialysis or transplant at a GFR of 15 mL/min/1.73 m

 or greater because of symptoms of uremia

• Practitioners who prescribe psychotropic agents should consider obtaining postdialysis blood drug levels to inform decisions regarding dose titration when reference levels are known

• Drug dialyzability is determined by the physical and chemical characteristics of the agent (eg, molecular size, protein binding, water solubility, volume of distribution) and the dialysis procedure (eg, dialysis membrane and flow rates)

• Peritoneal dialysis is generally much less efficient at removing agents than hemodialysis

• An agent incapable of being removed by hemodialysis cannot be removed by peritoneal dialysis

• The predominant form of CKD associated with lithium therapy is chronic tubulointerstitial nephropathy, which often presents with insidious development of renal insufficiency with minimal proteinuria

• The prevalence of reduced GFR associated with long-term lithium therapy is approximately 15%; a much smaller number of lithium-treated patients eventually have renal insufficiency that leads to dialysis

• Patients with mild to moderate chronic renal insufficiency associated with lithium can expect gradual improvement in GFR after lithium discontinuation

• Uninterrupted lithium exposure decreases the kidney’s endogenous ability for cellular regeneration; although a consensus does not currently exist as to the discontinuation threshold for lithium treatment because of diminished kidney function, it is suggested that repeated serum cre-atinine concentrations exceeding 140 μmol/L (1.6 mg/dL) indi-cate the need for nephrologist consultation

• Individuals with serum creatinine concentrations of more than 2.5 mg/dL are at very high risk for progression to ESRD compared with individuals who have serum creatinine concentrations of less than 2.5 mg/dL. Moreover, in individuals with a creatinine clearance of 40 mL/min or less, there is a higher probability of continued renal deterioration at lithium discontinuation than in those who have a creatinine clearance of more than 40 mL/min

• In patients with ESRD, a reduction in the lithium dose is required to prevent further toxicity, and a single dose of lithium is recommended after dialysis sessions; serum lithium levels obtained before and after dialysis are used to established appropriate dosing

• In treating depression, SSRIs (eg, fluoxetine) appear to be generally safe and well-tolerated; venlafaxine levels markedly increase in patients with renal failure, which theoretically could intensify hypertension, a common morbidity in ESRD; tricyclic antidepressants are generally avoided because of concern for safety and tolerability; duloxetine levels increase markedly in patients who have ESRD compared with patients who have normal renal function, and this medication is not recommended

Sizable numbers of patients have compromised renal function, and it is highly likely that psychiatrists will need to collaborate with primary care providers and nephrologists when prescribing psychotropic medications. There are unfortunately few formal pharmacological research studies that have investigated this subject, and clinicians must rely on basic knowledge of the factors that influence the effects and metabolism of psychoactive substances. This requires an appreciation of pharmacokinetics, including absorption, volume of distribution, metabolism, and excretion of the parent drug and metabolites.

Most psychotropic medications are not metabolized or excreted by the kidneys. In the absence of systematic data, caution is always necessary, but most of these medications are well tolerated and produce their accustomed beneficial effects. Renal dysfunction should not theoretically be associated with any unusual drug interactions.

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

Psychiatric Issues for Patients With Renal Disease

Bipolar disorders are heterogeneous in phenomenology, pathoetiology, comorbidity, and treatment. These disorders are highly prevalent and often misdiagnosed and underrecognized. For bipolar patients who are correctly identified, the time from onset of symptoms to correct identification is often 10 to 15 years. It is disquieting that mortality studies indicate that bipolar disorder is associated with approximately 15 to 25 years of life lost largely because of associated cardiometabolic disorders.

Despite the development and widespread use of several novel pharmacological, psychosocial, and neuromodulatory approaches for bipolar disorder during the past decade, outcomes remain rather disappointing. For example, results from efficacy as well as effectiveness studies indicate that the majority of individuals with bipolar disorder who receive guideline-concordant measurement-based care fail to achieve symptomatic, syndromal, or functional recovery. Moreover, phenomenological studies indicate that the longitudinal course in bipolar disorder largely consists of depressive symptoms and episodes.

Research into bipolar depression symptoms is particularly important because bipolar depression symptoms carry a much higher illness burden-these symptoms are by far more prevalent than manic symptoms.

 This latter observation provides the impetus for developing genuinely novel disease-modifying treatment strategies.

Except for lithium, most treatments for bipolar disorder symptoms were not primarily developed as “antibipolar therapies” (eg, anticonvulsants, conventional unimodal antidepressants). Most were initially used off-label and only later were evaluated in bipolar disorder (eg, atypical antipsychotics). Still others continue to be frequently prescribed off-label (eg, antidepressants). A major limitation to genuinely novel drug discovery in bipolar disorder is the absence of a consensually agreed-on neuropathology as well the unavailability of a sufficient animal model with appropriate face, construct, and pathological and pharmacological validity.

Although the field continues to be preoccupied with the monoamine hypothesis, it is abundantly clear that monoamine dysregulation has never been established as a central disturbance in bipolar disorder and that targeting monoamines is not sine qua non for symptom relief. Other models that have been proposed to exist alongside the monoamine hypothesis include the excitotoxicity, neurotrophic/neuroplasticity, neuroinflammatory, metabolic, and cellular redox (ie, oxidative stress to the cell) models. Novel treatments for bipolar disorder that are a focus of clinical research attempt to target one or more of the effector systems within these pathophysiological models.

Currently, only quetiapine, quetiapine XR, and an olanzapine/fluoxetine combination are FDA-approved for the acute treatment of bipolar depression. Although these agents are highly beneficial for some individuals, most fail to sufficiently benefit and/or are intolerant of these agents, which underscores the need for novel alternatives. This article aims to provide a succinct summary of novel pharmacological treatment avenues that are under investigation as treatment for bipolar depression. We present some of these novel treatments according to the overarching disease model that they derive from.

Several lines of evidence suggest that glutamatergic system dysfunction (eg, N-methyl d-aspartate [NMDA] receptor complex) may play a critical role in the pathophysiology of bipolar disorder. In keeping with this view, the use of glutamatergic modulators may be predicted to alleviate symptoms and modify the disease process. Postmortem studies indicate that altered NMDA receptor complexes are observed in the brain tissue of patients with bipolar disorder. Moreover, genetic polymorphisms for genes implicated in the glutamate receptor complex have been associated with this disorder.

Riluzole, an inhibitor of glutamate release, is approved by the FDA for the treatment of amyotrophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS).

Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.

 Results from a double-blind, randomized, placebo-controlled, crossover study indicate that a single intravenous infusion of ketamine combined with lithium or valproate was capable of alleviating depressive symptoms within 40 minutes of administration when compared with placebo.

 The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was not associated with significant increases in hypomania or mania but was associated with dissociative symptoms.

Abnormal activation in function of the inflammatory network has been implicated as causative and consequential in bipolar depression symptomatology. For example, elevated concentrations of proinflammatory cytokines (interleukin-6 and tumor necrosis factor [TNF]-a) have been implicated in bipolar depression and mania.

 Conventional pharmacotherapy for bipolar disorder (eg, lithium) exerts a modulatory effect on the proinflammatory–anti-inflammatory network.

 Proinflammatory cytokines are known to induce behavioral symptoms (eg, anorexia, psychomotor retardation) in humans that are thought to mimic sickness behavior described in animals.

Cyclooxygenase-2 (COX-2) inhibitors have been shown to protect against glutamate-induced neurotoxicity; to prevent normal aging-related increases of cytokines, prostaglandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis.10 The COX-2 inhibitor celecoxib was evaluated as a potential antidepressant in adults with bipolar I/II depression (N = 28).

 This drug was administered at a dosage of 400 mg daily in combination with a mood stabilizer or antipsychotic medication as part of a 6-week, randomized, double-blind, placebo-controlled study. Depressive symptoms in both the treatment group and the placebo group improved, with a statistically significant (P = .01) advantage at week 1 in patients treated with celecoxib compared with patients who received placebo. Although there was an advantage in favor of the treatment group at week 1, both the active-treatment and placebo groups had similar reductions for each of the remaining observation points.

Taken together, the results suggest that an anti-inflammatory approach may offer a rapid onset of antidepression action in bipolar disorder. More work is needed to replicate/extend or refute these findings, however.

Neuronal insulin mediates multiple biological actions characterized as metabolic (eg, increases in glucose uptake), neuromodulatory (eg, inhibition of neuronal reuptake of noradrenaline), growth regulatory (eg, promotion of neurite outgrowth and synaptogenesis), and neuroendocrine. For example, insulin modulates the CNS concentration of neuropeptides, monoamines, and other neurotransmitters (eg, acetylcholine) implicated in the pathophysiology of mood disorders, schizophrenia, and Alzheimer disease. Insulin inhibits the firing of neurons in the hippocampus and hypothalamus, inhibits the reuptake of noradrenaline in rat brains, modulates catecholamine turnover in the hypothalamus, stimulates phosphoinositide turnover in the hippocampus, and regulates the noradrenaline and dopamine transporter messenger RNA concentration in neurons.

Insulin is transported into the CNS across the blood-brain barrier by a saturable insulin receptor–mediated transport process.

 Long-term potentiation, the neurobiological model of learning, is partially modulated by insulin. Insulin deficiency in diabetic rats triggers a retraction of dendrites and reduces NMDA transmission of hippocampal neurons, with associated decrements in memory performance. Taken together, cellular, molecular, and physiological data indicate that insulin is important for normal (and pathological) memory processes.

The evidence-based approach to bipolar depression symptoms includes treatment with lithium, conventional unimodal antidepressants, lamotrigine, or divalproex.

Roger S. Mcintyre, MD, FRCPC

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Psychiatric Issues for Patients With Renal Disease

Novel Treatment Avenues for Bipolar Depression

Which of the Following is the Most Common Neuropsychiatric Disorder in Bipolar Disorder?

Substance Use With Comorbid Obesity in Patients With Bipolar Disorder

Bipolar Disorder: Defining Remission and Selecting Treatment