Rayan k. Al Jurdi, MD

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Clinicians need to consider and manage multiple medical and cognitive comorbidities when working with the elderly population. This slideshow provides an overview of key points relevant to geriatric bipolar disorder as it relates to comorbidity.

5 Key Issues About Comorbidity in Geriatric Bipolar Disorder

The world’s elderly population is growing at an unprecedented pace, and it is expected that within the next 50 years the number of individuals aged 60 or older 

 The health care community has to prepare for sharply ramped-up service needs for older adults, including those with chronic mental conditions, such as bipolar disorder (BD). Elderly patients may represent up to 25% of the population with BD.

 This article provides an overview of key issues relevant to geriatric BD, including epidemiology, assessment, medical and psychiatric comorbidity, and treatment.

Epidemiologic studies suggest that 0.5% to 1% of elderly people have type I or II BD.

 summarizes the key epidemiologic points on BD in elderly patients. Similar to what is seen in late-life schizophrenia, BD in the geriatric population is only one-third as common as in younger populations.

 In both younger and geriatric persons, BD may be misdiagnosed or underdetected.

Older patients with BD are a group with variable evolutionary pathways. The great majority of elderly persons with BD have illness onset in early adulthood and have aged with BD. A smaller subgroup, 5% to 10%, are aged 50 or older at the time of a first definitive manic or hypomanic episode.

 While there is no “official” cutoff, it is agreed that age 50 is a reasonable defining threshold for lateonset BD.

 Since there are higher rates of familial transmission in early-onset cases and late-onset cases are usually more associated with neurological comorbidity, it is possible that early-onset BD and the lateonset variant are different illnesses. Clinical presentation and course of illness in later life also vary. Older patients may have more severe depressive episodes and less severe manic episodes than younger patients.

The epidemiology and clinical presentation of geriatric BD must be interpreted cautiously, since most study samples are cross-sectional and are probably survivor cohorts. The individuals in these samples may be healthier or more resilient than the general population of people with BD. Longitudinal analyses that include mortality data are needed to arrive at a more definitive understanding of course and presentation of BD across the life span.

Recognition and accurate diagnosis of late-life BD can be challenging. Assessment of mood symptoms in elderly patients should start with a careful history taken from the patient and collaborative sources. Evaluation should focus on mood, anxiety, and cognitive and neuropsychiatric symptoms as well as on assessment for comorbidities, use of new medications or herbal/alternative supplements, and adherence to prescribed medications.

Pop Quiz: Disturbances, Disorientation, and Delirium

The differential diagnosis of acute mania is often complicated by comorbidities, such as medical illness. It is therefore important to differentiate between idiopathic late-onset BD and secondary mania due to medical causes. Several medical conditions have been associated with mania, including CNS disorders (vascular dementia, encephalitis, neurosyphilis, HIV encephalopathy, strokes, Huntington disease, multiple sclerosis, traumatic brain injury), tumors (right temporal lobe, orbitofrontal, hypothalamic), and systemic diseases (systemic lupus erythematosus, hyperthyroidism, vitamin B12 deficiency). Substances that can induce mania include stimulants, cocaine, sympathomimetics, corticosteroids, TCAs, thyroid replacement therapies, hydralazine, and levodopa.

Mania in the elderly should also be differentiated from delirium or dementia. Sudden cognitive disturbances, disorientation, and cloudiness of consciousness are more suggestive of delirium than mania. Impulsivity, disinhibition, and irritability are more common in moderate and severe dementia but could also be related to underlying mood symptoms. Familiarity with the typical symptom patterns of individual patients, the chronology of presenting symptoms supported by physical and neurological examination, and laboratory and imaging investigations can help clarify the presenting picture and guide treatment.

Laboratory tests and imaging studies can help rule out mania due to medical causes. A recommended basic workup typically includes a complete blood cell count; electrolytes profile; liver, kidney, and thyroid function tests; vitamin B12 and folate levels; urinalysis; urine drug screen; and ECG. The clinical picture and relevant differential diagnosis should dictate the need for other assessments. Imaging studies (head CT or MRI) are indicated in all cases of new-onset mania to rule out vascular and other intracranial pathology. If the clinical presentation is suggestive of brain neoplasm, encephalitis, multiple sclerosis, or vasculitis, a brain MRI scan is preferred.

Medical, cognitive, and psychiatric comorbidity

 summarizes key points about comorbidity in geriatric BD. Physical illnesses are common in the elderly, with an average of 3 or 4 medical conditions. This population is particularly vulnerable to metabolic syndrome (up to 50%), hypertension (45% to 69%), diabetes mellitus (18% to 31%), and cardiovascular disease (9% to 49%).

 Cardiovascular comorbidity partially explains the increased rates of cerebrovascular disease in late-life BD, and vascular events may be etiologically involved in late-onset BD. Cardiovascular and other medical conditions probably arise from a combination of factors, including biological stressors inherent to BD (eg, inflammation, oxidative stress), lifestyle (eg, dietary habits, physical activity, substance use), and psychotropic medication exposure (eg, antipsychotics, mood stabilizers).

Although patients with BD die on average 10 years earlier than persons in the general population because of medical comorbidities, rates of medical comorbidity may not be higher in late-life BD patients than in geriatric controls.

 As noted earlier, geriatric BD studies should be interpreted cautiously because they may represent a comparatively healthy survivor cohort. Given the high prevalence of medical comorbidity in late-life BD, it is important to regularly monitor for medical adverse effects and levels of psychotropic drugs such as lithium, valproate, and carbamazepine. Medications can reach toxic levels because of declining renal and hepatic functioning with aging and medical comorbidity and because of drug interactions (eg, use of diuretics and lithium).

Cognitive dysfunction affects many older BD patients, and it is often associated with functional disability. Although impairment exists in multiple domains, including attention, executive function, processing speed, working memory, and verbal memory, it is unclear whether dysfunction is comparatively more severe in older BD patients. As with medical comorbidity, cognitive dysfunction has a number of causes in BD, including inflammatory and oxidative processes. Medications with higher anticholinergic burden may be a contributing factor (eg, certain antipsychotics), as may be substance use and cardiovascular disease.

Effective therapies, including cholinesterase inhibitors, have not yet been found for cognitive dysfunction in BD. Epidemiological evidence suggests that lithium users experience lower rates of dementia than do other BD patients.

 Whether lithium can treat or prevent BDrelated cognitive decline remains unclear, and further research is needed.

Psychiatric comorbidities are less common in geriatric BD patients than in younger adults with BD. The most prevalent comorbidities are substance use (up to 9% to 29%, mostly alcohol use) and anxiety disorders (up to 22%).

Age-specific treatment guidelines are lacking. Other than an ongoing large-scale randomized controlled trial (RCT) that has not yet been published, no large-scale prospective study has been conducted in geriatric BD patients. The current literature consists largely of uncontrolled, retrospective, open-label, or secondary analysis of large mixed-age population studies with a wide range of reported outcomes.

Clinicians could start by using treatments with both RCT evidence in adults and some data in older adults, followed by medication with evidence of fewer risks. Conclusions and treatment recommendations based on the extant literature must be tempered with the consideration that all are based on suboptimal data sources.

Treatment of late-life bipolar depression

. Lithium, lamotrigine, quetiapine, lurasidone, and some mood stabilizer/antidepressant combinations may be helpful in bipolar depression, but geriatric-specific data on their use are limited. A few small studies reported efficacy of lithium and valproate in later-life bipolar depression-lamotrigine and adjunctive aripiprazole may also be helpful.

Electroconvulsive therapy (ECT) is well tolerated and effective in the elderly, and findings indicate that it is an effective treatment for bipolar depression.

 Other neurostimulation techniques, such as transcranial magnetic stimulation, may potentially be useful, but more research in geriatric patients is needed.

A treatment algorithm for geriatric bipolar depression might be to start with lithium or lamotrigine, then move to agents such as quetiapine, lurasidone, valproate, and adjunctive aripiprazole. If response to these agents is poor, ECT could be tried, with cautious surveillance for cognitive dysfunction.

. Lithium has long been used in acute mania. Delirium, cognitive impairment, ataxia, tremors, renal dysfunction, hypothyroidism, rash, weight gain, and peripheral edema have been reported with use of lithium in geriatric patients.

 Concerns about tolerability and drug-drug interactions (eg, with diuretics, angiotensin-converting enzyme inhibitors, NSAIDs) and the availability of other treatment options have contributed to fewer lithium prescriptions for the elderly.

However, up to 40% of patients have been found to primarily respond to lithium.

 Moreover, lithium discontinuation was responsible for symptomatic mood relapse in 50% of geriatric responders.

 With regular laboratory monitoring (serum levels less than 0.8 mmol/L, and lower if possible) and clinical neurotoxicity assessment, lithium can often be safely used in older adults.

Divalproex has also been used for acute mania in older adults.

 GI problems, sedation, weight gain, and metabolic syndrome are the most common adverse effects.

 Rare adverse effects include thrombocytopenia, pancreatitis, fatal hepatotoxicity, and encephalopathy.

 Aspirin, digoxin, warfarin, phenytoin, and lamotrigine affect divalproex clearance.

Although many atypical antipsychotics have RCT evidence for mania, the data for geriatric use are limited. Quetiapine data pooled from RCTs in adults showed efficacy.

 A small uncontrolled trial of asenapine also showed efficacy in the older adult population.

 The benefits of antipsychotics need to be carefully weighed with the potential risks, including weight gain, metabolic syndrome, QTc prolongation, somnolence, and extrapyramidal symptoms.

Lithium, valproate, and quetiapine could be considered as initial choices in late-life mania. Given that depression may be especially burdensome in late-life BD, agents that are potentially helpful for both mania and depression may also be preferred, such as lurasidone and aripiprazole.

. There are few geriatric-specific data for preventing mood relapse in geriatric BD. Lamotrigine and lithium may be best at preventing depression and mania, respectively, while secondary analysis of a large NIH study showed that 80% of elderly patients recovered with a stepped-care pharmacotherapy approach.

 While patients on average took 2.05 psychoactive medications, 42% of those who achieved symptomatic remission were receiving lithium monotherapy.

Lithium monotherapy can be recommended for late-life BD maintenance for individuals who are able to tolerate lithium. For those who are unable to tolerate or who do not respond to lithium, lamotrigine, valproate, and quetiapine can be considered. Lurasidone and aripiprazole may also be helpful in preventing mania and/or depression, although more data on geriatric maintenance are needed. The use of adjunctive antidepressants is controversial, although older adults with depression may be less prone to manic switching.

Although cognitive-behavioral therapy, interpersonal therapy, social rhythm therapy, and psychoeducation can be useful adjuncts in BD, there is almost no literature regarding psychosocial interventions in late-life BD. While some older patients with BD could improve with behavioral interventions promoting treatment adherence, more research is necessary.

Despite the rapidly growing elderly population, there is limited evidence to guide treatment of geriatric patients with BD. Existing data suggest that standard medications may be useful; lower doses are preferred, and clinicians need to consider and manage multiple medical and cognitive comorbidities.

Dr Rej is Geriatric Psychiatry Fellow at the University of Toronto, and Lead of the JGH Geri-PARTy Research Group at the Jewish General Hospital in Montreal. Dr Al Jurdi is Deputy Executive at the Mental Health Care Line at the Michael E. DeBakey Veterans Affairs Medical Center and Associate Professor in the Menninger Department of Psychiatry and Behavioral Sciences at the Baylor College of Medicine in Houston. Dr Sajatovic is Professor of Psychiatry and of Neurology at the Case Western Reserve University School of Medicine, University Hospitals Case Medical Center in Cleveland. Drs Rej and Al Jurdi report no conflicts of interest concerning the subject matter of this article. Dr Sajatovic reports that she has received research grants from the CDC, Janssen, Merck, Ortho-McNeil-Janssen, the NIH, Pfizer, Reinberger Foundation, Reuter Foundation, and Woodruff Foundation; she is a consultant for Amgen, Bracket, Otsuka, Pfizer, ProPhase; she receives royalties from Johns Hopkins University Press, Oxford Press, Springer Press, UpToDate, Lexicomp; and she has consulted on CME activities for the American Physician Institute and MCM Education.

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Articles

Key issues about geriatric bipolar disorder-epidemiology, assessment, medical and psychiatric comorbidity, and treatment-are the focus. 

Managing Late-Life Bipolar Disorder: Current Issues and Clinical Tips

The World Health Organization projects that by 2020, MDD will be the second leading cause of disability worldwide, trailing only cardiovascular diseases.

 Despite decades of research, the response to conventional antidepressant treatments is suboptimal. Based on Sequenced Treatment Alternatives to Relieve Depression (STAR*D) data, one-third of patients achieved remission after 12 weeks of treatment with a first-line antidepressant; one-third never achieved remission, even after 4 consecutive levels of treatments.

There is growing evidence for the role of ketamine, an 

-methyl-D-aspartate (NMDA) receptor antagonist used for many years as an anesthetic, in rapidly alleviating depressive symptoms in patients who have treatment-resistant depression (TRD). The mechanism of action through which ketamine exerts its antidepressant effects is not fully understood. However, the direct modulation of glutamatergic pathways is unique compared with currently approved antidepressant medications that mostly target mono-aminergic systems. As such, the discovery that a single intravenous infusion of low-dose (subanesthetic) ketamine exerts rapid antidepressant effects constitutes an expansion in the understanding of the neurobiology of depression and provides new avenues for drug development.

Ketamine has a very complex pharmacological profile with a variable affinity for numerous receptors. Besides being an open-channel nonselective NMDA receptor antagonist, ketamine interacts with several receptors, including the intracellular Ï receptors, the opioid Î¼ receptors, serotonin-3 receptors, and muscarinic receptors, as well as the serotonin, norepinephrine, and dopamine transporters.

 Research on the molecular signaling pathways associated with the antidepressant effects of ketamine has only recently begun in preclinical models.

In rodent models of depression, a single dose of ketamine was found to increase the number and function of new spine synapses in the prefrontal cortex and reverse the loss of spine density in animals exposed to chronic unpredictable stress.

 The antidepressant effects of ketamine were replicated using a selective antagonist of the NMDA receptor (NR2B subunit).

 These effects were blocked by adding a mammalian target of rapamycin (mTOR) inhibitor and were not observed in brain-derived neurotrophic factor (BDNF)-mutant mice.

 The findings suggest a role for specific neurotrophic signaling cascades in the therapeutic mechanism of ketamine.

Our study team published a preliminary finding that BDNF levels were significantly increased (

 < .05) at 240 minutes postinfusion in patients who responded to ketamine, and BDNF levels were highly correlated with Montgomery-Ãsberg Depression Rating Scale (MADRS) scores at 240 min (

 = −0.700; P = .007).12 Similar results were seen by kavalali and Monteggia

 These results form the basis of our understanding of ketamine’s possible antidepressant mechanism of action.

Several studies suggest that by blocking the excitatory NMDA receptors on Î³-aminobutyric acid inhibitory interneurons, ketamine leads to activation of downstream glutamatergic neurons. This results in an increase in extracellular glutamate levels and activation of the Î±-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. AMPA receptors regulate synaptic function through the activation of voltage-dependent calcium channels and the release of BDNF, which stimulates mTOR and spine formation.

These studies have identified new targets for understanding the neural basis of the antidepressant properties of ketamine that extend beyond the NMDA receptor channel and glutamate. But most important, these data are consistent with hypotheses that link the antidepressant effects of NMDA receptor antagonists to enhancement of neurotrophic and neuroplasticity-related factors and fit more broadly within neurotrophic theories of depression.

 provides a detailed illustration of the link in the induction of mTOR signaling and BDNF release through ketamine and novel glutamatergic modulators.

There is rapidly growing literature on the quick antidepressant effect of ketamine since the first published report by Berman and colleagues

 in 2000. In this early study, 4 of 8 patients demonstrated a 50% or greater reduction in Hamilton Depression Rating Scale (HDRS) scores at 72 hours postinfusion. A subsequent larger study by Zarate and colleagues

 using a cross-over design found that of the 17 participants who received ketamine, 12 (71%), 8 (47%), 6 (35%), and 2 (12%) met response criteria at 24 hours, 72 hours, 1 week, and 2 weeks postinfusion, respectively. Despite the encouraging results of these two studies, they included a fairly small number of patients and used a cross-over design with an inert placebo-control condition.

Our group recently published a parallel-arm, randomized controlled trial (RCT) of ketamine in 72 patients with TRD in whom 3 or more trials of an antidepressant have failed. Patients were randomized to ketamine (0.5 mg/kg over 40 minutes) or midazolam under triple-masked conditions (patient, rater, anesthesiologist).

 Patients in the ketamine group had significantly greater improvement in the MADRS score at 24 hours compared with the midazolam group (t [68] = 3.34; 

 < .001]. After adjusting for baseline scores and site, the MADRS score was 7.95 points lower in the ketamine group than in the midazolam group (95% confidence interval [CI], 3.20 to 12.71), corresponding to a large effect size (Cohen’s 

 = 0.81). ketamine also increased the likelihood of response at 24 hours compared with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14; 

 < .006). Our results provided further evidence that supports the use of ketamine as a novel option for patients with TRD.

A main advantage of ketamine over currently FDA-approved antidepressants is the robustness and rapidity of its effect. Based on the STAR*D study, fewer than half of depressed patients will respond to first-line treatment, about two-thirds of whom achieve response criteria after 6 weeks of treatment. A meta-analysis of ketamine double-blind RCTs showed a statistically significant difference on HDRS as early as 80 minutes after the start of treatment.

 Of note, the clinical effects of ketamine were not mediated by nonspecific mood-elevating effects, but rather by targeting core depressive symptoms, such as sad mood, helplessness, and worthlessness, as well as suicidality.

Ketamine’s effects on suicidal ideation seems independent of its antidepressant effect.

 A post hoc analysis of 2 trials in TRD found that open-label intravenous ketamine was associated with rapid reductions in explicit and implicit suicidal cognition within the first 24 hours. This effect persisted for patients who received up to 5 additional infusions over 2 weeks.

The rapid antisuicidal effects of a single administration of ketamine were recently replicated in an RCT.

 saw decreases in the Scale for Suicidal Ideation scores within 40 minutes of ketamine infusion (0.5 mg/kg over 40 minutes). These results further support the possibility of ketamine’s rapid antisuicidal effects.

 reported complete resolution of suicidal ideation in 14 actively suicidal patients following an intravenous bolus of ketamine (0.2 mg/kg) over 1 to 2 minutes in the emergency department (ED). MADRS item 10 (suicidality) score decreased significantly, from 3.9 at baseline to 0.6 within 40 minutes of treatment; this improvement was maintained for 10 days postinfusion.

Feasibility of using ketamine in clinical practice

There has been some skepticism regarding the practicality of administering intravenous ketamine infusions in clinical practice.

 However, one of the most important features of the Larkin and Beautrais study is that it took place in the ED, which suggests the feasibility of using ketamine in a busy ED setting. ketamine is available in oral, subcutaneous, intranasal, intramuscular, and intravenous formulations. This is a significant advantage over current antidepressants.

Intramuscular formulation could be considered for acutely suicidal patients when access to intravenous lines are limited.

 An intranasal formulation with a controlled delivery system may address concerns of ketamine abuse if prescribed in outpatient settings. Indeed, a recent report found that a single administration of intranasal ketamine was effective for patients with depression.

 Studies of intranasal esketamine (the S-isomer of racemic ketamine) for acute suicidal depression have been initiated (ClinicalTrials.gov Identifier NCT02133001).

Another advantage of ketamine is the potential use of BDNF, a peripheral biomarker, to predict antidepressant response to ketamine.

 Thus, within 24 hours of the first ketamine dose, clinicians are able to make informed decisions on whether to continue ketamine or use a different therapeutic modality.

ketamine is classified as a schedule class III agent by the FDA, with potential for abuse liability. However, ketamine’s safety and utility in specific clinical populations is well characterized based on years of use in anesthesiology and emergency medicine. Perry and colleagues

 reviewed the safety of ketamine in a psychiatric research setting and concluded that ketamine was safe in healthy volunteers. The emerging evidence of patients with TRD who receive subanesthetic doses of ketamine further cements its safety and tolerability.

Because of its sympathomimetic effects, ketamine may produce increases in blood pressure, heart rate, and cardiac output, and it can provoke ischemia in patients with underlying coronary artery disease.

 Although frequently mild and self-limited, ketamine-induced perceptual disturbances have been reported in up to 30% of study samples.

 Psychotomimetic disturbances may manifest as vivid dreams, visualization of psychedelic color, suspension in space, kaleidoscopic floating, and out-of-body experiences. Some patients describe these psychic experiences as bizarre or frightening, while other patients find them pleasurable, joyful, and fascinating.

 Finally, repetitive high anesthetic doses of ketamine have been linked to apoptosis and increased brain cell death in rodents and nonhuman primates.

 The available data support a favorable risk to benefit profile of subanesthetic low-dose ketamine; however, the long-term effects in humans have not been explored.

The clinical use of ketamine in the treatment of TRD is still unsettled. The optimal dose of ketamine has not been established, which is the focus of a new NIMH-sponsored trial (ClinicalTrials.gov Identifier NCT01920555). Most of the studies thus far have used a slow infusion over 40 minutes of 0.5 mg/kg, but the study by Larkin and Beautrais

 showed antisuicidal effectiveness at a lower dose given as a bolus. Moreover, higher anesthetic doses of ketamine (2 to 3 mg/kg) seem to lack effect on mTOR signaling.

While the ketamine antidepressant effect is fast, it is short-lived. Most patients relapse within 2 weeks of a single infusion.

 Repeated ketamine infusions have not led to substantial prolongation of the antidepressant effects. Two studies piloted a 2-week course of ketamine (0.5 mg/kg) administered 3 times weekly on a Monday-Wednesday-Friday schedule in patients with TRD.

 The response rate after the sixth infusion was 71% in the report by Murrough and colleagues.

 However, the median to relapse was 18 days. The augmentation of a single ketamine infusion with the glutamate modulator riluzole showed no difference from placebo in preventing relapse post-ketamine.

 Using ketamine in combination with electroconvulsive therapy (ECT) did not improve outcomes whether at anesthetic or subanesthetic dose. While earlier response was noted in the groups receiving ketamine, no difference was noted between the study groups at the end of the ECT course.spe

It is important to recognize that RCTs for ketamine as treatment for MDD are still in their early stages, and the evidence is limited. Several treatment modalities have been recommended for patients who have inadequate responses to repeated antidepressant trials, including augmentation with lithium, triiodothyronine, or second-generation anti- psychotics, and neuromodulatory techniques, such as repetitive transcranial magnetic stimulation. Although, its use is curtailed by cognitive adverse effects and the public’s opinion about “shock therapy,” ECT remains the most effective therapy for patients with TRD.

While there is understandable enthusiasm regarding ketamine’s potential, there are insufficient data to support its integration in clinical care at this time. The broader effectiveness of ketamine in varied clinical settings has not been systematically examined. More studies are needed on critical issues, such as dose optimization, alternative drug delivery routes, methods to prevent relapse following resolution of depressive symptoms, and understanding neurobiological mechanisms underlying the putative antidepressant actions of ketamine.

-This article is the result of work supported with resources from and the use of facilities at the Michael E. DeBakey Veterans Affairs Medical Center in Houston.

Drs Al Jurdi and Mathew are Associate Professors at the Mental Care Line at the Michael E. DeBakey Veterans Affairs Medical Center and the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston. Dr Al Jurdi reports no conflicts of interest concerning the subject matter of this article. Dr Mathew reports that he has received research support from Janssen Research and Development, AstraZeneca, and the NIMH; he is a consultant to Bristol-Myers Squibb, Genentech, and Naurex.

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The discovery that a single IV infusion of low-dose (subanesthetic) ketamine exerts rapid antidepressant effects constitutes an expansion in our understanding of the neurobiology of depression and provides new avenues for drug development. 

Author | Rayan k. Al Jurdi, MD

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