CME. Pharmacotherapy of Depression in Older Adults. Introduction. Major Depression

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1 CME Pharmacotherapy of Depression in Older Adults This CME learning activity is available at Participating physicians are entitled to one () MAINPRO-M credit by completing this online course, offered under the auspices of the CE department of the Faculty of Medicine, University of Toronto. Do you have a question about this CME activity? Post your question in our online forum, found at to discuss this topic with the author. Depression in the older population is a condition commonly encountered by the primary care physician. However, it is frequently underdiagnosed and undertreated. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are the first-line choice of antidepressants for the treatment of depression. and bupropion are second-line agents with tricylics and monoamine oxidase inhibitors (MAOIs) being considered for refractory patients. Although equally effective, these agents exhibit varying levels of tolerability and different adverse events profiles. After remission, patients need maintenance treatment, the duration varying with the number of episodes experienced. Treatment nonresponse is often associated with the presence of concurrent medical illnesses, poor compliance, and the presence of ongoing psychosocial stressors. Partial or nonresponse to optimum doses of antidepressants will necessitate either switch augmentation or combination strategies, but caution should be exercised to prevent drug interactions. Depression in the older adult is treatable, with key goals being recognition, diagnosis, aggressive acute treatment, and planned maintenance. Key words: depressive disorders, older adult, antidepressants, nonresponse, augmentation Lakshmi Ravindran, MD, Department of Psychiatry, University of Toronto and St. Michael s Hospital, Toronto, ON. David Conn, MB, FRCPC, Department of Psychiatry, University of Toronto and Baycrest Centre for Geriatric Care, Toronto, ON. Arun Ravindran, MB, PhD, FRCPC, FRCPsych, Department of Psychiatry, University of Toronto and the Centre for Addiction and Mental Health, Toronto, ON. Introduction Depression in the older adult is a common and frequently undiagnosed condition, which is more often than not treated in the primary care setting. Depressive symptoms with functional impairment may affect 5 5% of the older adults in the community and may constitute a third of patients presenting to the primary care physician. In spite of its high morbidity, depression in the older adult remains undertreated. It is estimated that less than half the patients presenting with depression are treated with antidepressants in the primary care setting. Possible reasons for undertreatment are shown in the textbox. 3 In the majority of older patients, depression is a treatable condition with good outcomes. Its effective management involves a biopsychosocial approach in both evaluation and treatment. Effective treatment results in alleviation of symptoms, improved function, and improved quality of life, as Possible Reasons for Undertreatment of Depression in the Clinical Setting Depression is often mistakenly perceived as a normal part of aging. Older patients with depression often present with somatic complaints rather than depressed mood. 4 Depressive symptoms are often attributed to medical conditions. There is a lack of confidence among physicians when diagnosing depression. The depressogenic effects of drugs and medical illnesses are overlooked. well as reduction in relapse and recurrence. Pharmacotherapy and psychosocial interventions are equally relevant, but this article will focus only on pharmacological management. Specifically, it will attempt to review the literature and outline basic therapeutic strategies. Major Depression Although combining antidepressants and psychotherapy is the treatment of choice for an acute episode of depression, in practice medication alone is often the first line of strategy. 5 Useful reminders in the treatment of the older population are presented in the textbox. 8 GERIATRICS & AGING September 005 Volume 8, Number 8

2 Optimizing Therapy in the Older Population Always consider a trial of antidepressants in the presence of significant depressive symptoms. Always ask about suicidal ideation or plans given the high suicide rate among older patients. Antidepressants may benefit depression associated with medical issues. Electroconvulsive therapy (ECT) should be considered for psychotic and severe nonpsychotic depression, especially when accompanied by acute suicide risk. Psychotherapy alone is not sufficient to treat severe major depression. Choice of Antidepressants Selective serotonin reuptake inhibitors (SSRIs) and the serotonergic/noradrenergic reuptake inhibitor (SNRI) venlafaxine are considered the antidepressants of choice for the treatment of depression in the older patient. 6 These agents have a superior side effect and safety profile, particularly in the presence of comorbid medical conditions. and bupropion are considered second-line alternatives, although in certain cases, as will be elaborated on in the next section, they may be used initially. Tricylic antidepressants (TCAs) are usually employed as third-line agents, with nortriptyline and desipramine being the preferred agents as they have lower anticholinergic and sedating effects compared to imipramine and amitriptyline. Monoamine oxidase inhibitors (MAOIs) are reserved for the most severe and refractory patients. 5 The initial dose and dose ranges of common antidepressant agents is provided in Table. The following are useful pointers in selecting first-line agents. All SSRIs and venlafaxine appear to be equally effective in the treatment of depression in old age. However, overall, citalopram and escitalopram appear to be the best tolerated, followed by sertraline, paroxetine, fluoxamine, venlafaxine, and fluoxetine. While fluoxamine and venlafaxine are most likely to be associated with GI adverse effects, discontinuation effects may be more prominent with paroxetine and venlafaxine due to severe side effects, requiring slow tapering when stopping the medication. Sexual dysfunction is a frequent adverse effect with all SSRIs (to a lesser extent with fluoxamine and fluoxetine compared to others), but this is less of a problem with mirtazapine and bupropion. Cytochrome P450 enzyme related drug interactions appear to be less significant with citalopram, escitalopram, venlafaxine, mirtazapine, and bupropion, and thus these drugs are safer in patients taking multiple medications for medical illnesses. Due to the long half-life (T / hours) of fluoxetine and its active metabolite, it should be avoided in individuals with renal dysfunction, but it has the advantage of being free of sudden discontinuation effects as the long elimination half-life of the drug assures that, even when dosing is suddenly stopped, active metabolite will persist in the body for a long period. Fluoxetine and, to a lesser extent, other SSRIs and venlafaxine may cause jitteriness, and thus worsen the agitated depressed patient. The textbox below lists a number of points that physicians should consider when initiating treatment for depression in acute cases. 7 Reminders for Initiation and Acute Treatment Start low (e.g., half the recommended starting dose for adults) and titrate slowly to reduce adverse effects, specifically the transitory GI events. Monitor the antidepressant response frequently and regularly (ideally, every two weeks). Be more vigilant about adverse effects, and titrate even more cautiously at the higher end of the dose range. Be aware that the onset of therapeutic response may vary and may take up to six weeks and that fewer than half of patients have full response to the first antidepressant. Patients who have not responded after six weeks of treatment are unlikely to achieve remission by weeks. Duration of Treatment The risk of recurrence increases with the number of episodes previously experienced by the patient. Evidence supports maintenance treatment for at least a year after remission for the first episode, for two years after the second episode, and for three years after the third episode. 8 Many patients may need lifetime antidepressants after multiple episodes. The effective dose should remain the maintenance dose. Those who have had several recurrences, a refractory illness that was difficult to stabilize, and those with ongoing psychosocial stressors and medical illnesses may need long-term maintenance. 9 Challenges in Treatment Less than 50% of patients with major depression respond to the first prescribed antidepressant. If the patient is compliant and tolerating the medication but exhibits only partial response, gradual increase to the maximum recommended dose is recommended. For patients with partial or no response after treatment with optimum dose for an adequate time (at least six weeks), or for those who are intolerant, switch, combination, or augmentation strategies should be used. The assessment of risk factors for depression, such as medical illness, disability, use of concurrent medications, and 0 GERIATRICS & AGING September 005 Volume 8, Number 8

3 the presence of stressful life events is imperative prior to initiating treatment (Table ). Lack of response to optimum antidepressant therapy should be a reminder to re-evaluate such factors; firstly, older patients are more likely to take multiple medications that can cause or exacerbate depressive symptoms, including beta-blockers, steroids, antihypertensives, and anti-parkinson s agents. Secondly, many diagnosed and undiagnosed medical conditions may contribute to the suboptimal response to antidepressants. Thirdly, the similarity of symptom manifestations of depression and dementia disorders may lead to misdiagnosis. Finally, cognitive factors associated with the aging process, lack of psychosocial support, as well as the depressive illness may contribute to poor compliance with the pharmacotherapy. Switching Antidepressants A switch is considered for a patient when there is partial or nonresponse to an adequate dose of the first-line agent; it is usually from an SSRI to venlafaxine or vice versa. For those who are able to tolerate high doses, it has been recommended that a switch be made after three to six weeks if there is little or no response, and four to seven weeks if there is partial response. 7 This waiting time should be reduced if there is a problem with tolerability. Literature suggests that switching from one SSRI to another is less likely to be helpful in cases of no response but might be helpful in cases of poor tolerability. 0 Alternatively, the switch could be from an SSRI or SNRI to mirtazapine or bupropion., which has both noradrenergic and serotonergic activity, is considered a good choice in older patients with weight loss and sleep difficulties. It is effective in a spectrum of both mood and anxiety disorders, 0 and has the advantage of not influencing cytochrome P450 isoenzymes. Bupropion, with its relative absence of anticholinergic, antihistaminic, and cardiovascular side effects, may be useful in many patients but requires monitoring for its agitating effect and its potential to decrease seizure threshold. Combination and Augmentation Therapy Combination therapy is the addition of another antidepressant to an existing regimen. Common strategies for combination include the addition of mirtazapine in small doses to existing SSRI/SNRI monotherapy, the addition of bupropion to nonstimulating SSRIs (e.g., citalopram), and the addition of a TCAsuch as nortriptyline or desipramine to an SSRI. Augmentation is the addition of another pharmacological agent, which in itself has insufficient antidepressant effect as a monotherapy (e.g., lithium or tryptophan). It is likely to be most helpful in patients with partial response, in particular those who are unable to tolerate high doses of the first antidepressant. The most evidence is for the use of lithium (usual dose range mg/day) and it is recommended that the serum lithium levels be kept at mq/l. It should also be noted that there is high likelihood Table : Antidepressants Prescribing Information for Older Adults SSRIs Initial Dose Usual Dose Ranges Special Considerations (mg/day) (mg/day) Citalopram Few drug interactions Fluoxetine Long half-life, may cause agitation and insomnia Fluvoxamine GI side effects common, weight gain Paroxetine Discontinuation effects, sexual side effects, increased anticholinergic effects Sertraline Few drug interactions, may be agitating Escitalopram Newer agent, similar to citalopram Other Agents Venlafaxine Effects on blood pressure, discontinuation effects, wide effective dose range Bupropion SR b.i.d. Agitation, insomnia, lowered seizure threshold, less sexual dysfunction Weight gain, sedation Desipramine Anticholinergic and cardiovascular side effects; needs therapeutic drug monitoring Nortriptyline Anticholinergic and cardiovascular side effects; needs therapeutic drug monitoring * modified from (website of American Geriatric Society)

4 Figure : Serotonergic Noradrenergic Inhibitor Neurotransmitters are released from the synaptic vesicles into the cleft when a nerve impulse arrives at a serotonin or noradrenalin nerve terminal. The neurotransmitters bind to their specific s on the postsynaptic membrane, allowing the nerve impulse to be transmitted. The neurotransmitters are then released from their s and are transported into the nerve terminal via their reuptake transporters. Serotonin and noradrenaline are degraded by monoamine oxidase (MAO) in the mitochondria of the nerve terminal. SNRIs restore the levels of serotonin and noradrenaline in the synaptic cleft by binding to their respective reuptake transporters, preventing the reuptake and subsequent degradation of serotonin and noradrenaline. This reuptake blockade leads to the accumulation of monoamines in the synaptic cleft, thus raising their concentrations Serotonin (5-HT) presynaptic nerve terminal Noradrenaline (NA) presynaptic nerve terminal Degraded 5-HT Degraded NA MAO in mitochondria transporter transporter Normal process of serotonin transmission 5-HT 5-HT NA NA Normal process of noradrenaline transmission Synaptic vesicle Synaptic vesicle SNRI SNRI Mechanism of action of SNRIs amount of 5-HT is blocked is blocked amount of NA Mechanism of action of SNRIs GERIATRICS & AGING September 005 Volume 8, Number 8

5 Figure a: Selective Serotonin Inhibitors Figure b: Degraded 5-HT Normal process of serotonin transmission α-auto stimulates post synaptic α--adrenos on serotonergic neuronal cell bodies. transporter NA α-adreno 5-HT amount of 5-HT Synaptic vesicle 5-HT SSRI is blocked Selective serotonin reuptake inhibitors restore the lowered levels of 5-HT by binding to the 5-HT reuptake transporter. This blockade leads to the accumulation of 5-HT in the synaptic cleft. 5-HT 3 NA 5-HT A 5-HT α-hetero 5-HT 3 α-auto α-adreno blocks presynaptic α-- adrenergic s in serotonergic neurons. It enhances serotonin release and neurotransmission. also blocks serotonin subtypes; 5-HT A, 5-HT c, and 5-HT 3. blocks presynaptic α-- adrenergic s on noradrenergic neurons increasing the release of noradrenaline, which stimulates postsynaptic α--adrenoceptors on the serotonergic neuronal cell bodies and enhances the release of serotonin. of relapse if lithium is discontinued during the maintenance phase in patients who respond to the augmentation. Thyroid hormone augmentation should be avoided because of lack of evidence and the effect it may have on the cardiovascular system. Evidence for benefit of augmentation with atypical antipsychotics and mood stabilizers, such as lamotrigine, are preliminary but may have some potential. The benefits of combination and augmentation strategies are often seen earlier than with monotherapy. Initial improvement in symptoms is often observed in the first two weeks following initiation of augmentation or combination. While combination treatment has the advantage of broader spectrum effect and scope on the neurotransmitter system, there is increased likelihood of toxicity, in particular serotonergic side effects, including agitation, restlessness, sleep difficulties, and gastrointestinal adverse effects. Therefore, caution should be exercised, using lower doses and monitoring carefully for such interactions. Treatment Resistance Once a patient has failed two or more antidepressant trials, or is unable to tolerate adequate doses, it will be time to initiate a specialist referral. For truly refractory patients, several pharmacological and other interventions may be useful. These include the following: Tricyclic antidepressants: Nortriptyline and desipramine are preferred choices because of their superior adverse event profiles. An ECG prior to initiating treatment is mandatory and, if results are marginal, weekly monitoring of ECGs for sinus tachycardia and heart block may be necessary for up to four weeks. 3 Therapeutic drug monitoring is advised as plasma levels reflect severity of adverse effects, drug interactions, and clinical benefit. Frequent follow-up is also recommended to monitor for anticholinergic effects and delirium risk. Monoamine oxidase inhibitors: MAOIs have a special role in treating severe treatment resistant depression and bipolar depressions. 4 They may also be useful in maintenance of sta- 3

6 bilized treatment refractory patients. The biggest disadvantage with nonselective MAOIs is the potential to lead to hypertensive crisis when combined with sympathomimitic drugs and tyramine-enriched foods such as mature cheeses. It also cannot be combined with SSRIs, tricyclics, or tryptophan. The recent development of a simplified MAOI diet has facilitated the use of these agents. Moclobemide, with its significantly lower adverse-event profile, may be useful in some patients with depression nonresponsive to other agents, or for those who are intolerant of them. Moclobemide does not demand dietary restrictions. 5 ECT: Electroconvulsive therapy (ECT) should be considered for patients with depression and psychotic symptoms, and for patients with severe nonpsychotic depression that has proven nonresponsive to adequate trials of antidepressants. Medical contraindications should be ruled out before ECT. ECT is an effective short-term treatment but relapse rates are higher in 6 months after the treatment. Table : Factors that Influence Choice of Antidepressant Therapy Frequency and severity of past episodes Target symptoms of depression History of response to an antidepressant Concomitant illnesses Cognitive function Tolerability of the agent Safety in case of overdose Renal and hepatic impairment Simplicity of administration Drug/drug interactions Drug/disease interactions Drug/food interactions Cost Patient preference Subtypes of Depression Major Depression with Psychotic Features The recommended treatment for this condition is a combination of antidepressants and either antipsychotic medication or ECT. As for treatment of nonpsychotic depressed patients, SSRIs and venlafaxine are the first-line agents, and tricyclics are a high second-line alternative. The preferred antipsychotics are the atypical agents: risperidone, olanzapine, and quetiapine. Like antidepressants, the antipsychotics should be used conservatively, starting with low doses and titrating the doses very slowly upwards. There is little information on maintenance treatment of this combination, and the impression (from the adult population s perspective) is that the antipsychotics should be tapered off first (after a year of remission) and slowly. 5 For severely depressed patients who have received and responded to ECT, the following are suggested as maintenance treatment: 6 For nonpsychotic depression, but no previous adequate antidepressant trial, use SSRIs or venlafaxine. For nonpsychotic depression with failed antidepressant trials, an antidepressant not previously used preferably broad spectrum (e.g., venlafaxine, mirtazapine, or a TCA) is recommended. Alternatively, a combination of mood stabilizers (e.g., lithium or lamotrigine) and broad-spectrum antidepressants is likely to be helpful in maintenance. For psychotic depression, use a combination of antidepressants and antipsychotics. TCAs are the preferred choice of antidepressants in psychotic depression. Dysthymia and Minor Depression Depending on the severity, duration, and presence of psychosocial stressors, either psychotherapy, medication, or a combination is used to treat these conditions. 7,8 Pharmacotherapy is likely to benefit patients with good premorbid personality and recent onset, when neurovegetative symptoms are present, and where there is a history of major depression with good recovery or a family history of major depression and response to antidepressants. As with major depression, SSRIs and venlafaxine are the first-line medications, with bupropion and mirtazapine as second-line agents. The dose range is the same as for major depression, but these patients often need lifelong maintenance treatment. With chronic psychosocial stressors and maladaptive personality traits, the focus should remain on psychosocial interventions. Anxious Depression Significant concurrent anxiety symptoms are seen in up to two-thirds of older adults with depression. 9 The presence of anxiety signifies a more severe depressive illness and is also associated with increased suicidality in this age group. It also has implications for treatment and outcome since concurrent anxiety often indicates intolerance to medications, poor response, and worse outcome. In older adults with anxious depression, some key strategies 9,0 include the following: Start at very low doses and titrate up slowly. 4 GERIATRICS & AGING September 005 Volume 8, Number 8

7 Emphasize psychoeducation, provide reassurance, and do frequent follow-up in the early stages of treatment. Use SSRIs and venlafaxine as the preferred first-line agents (avoid TCAs, bupropion, and fluoxetine). Consider small doses of benzodiazepines short-term to alleviate symptoms, using shorter acting agents such as lorazepam or oxazepam. Keep in mind that benzodiazepines can exacerbate confusion and contribute to risk of falls. Consider low doses of atypical antipsychotics as a temporary adjunct (e.g., quetiapine) to alleviate anxiety and agitation if the symptoms are severe. Depression with Medical Comorbidity and Medication-Induced Depression In patients where the onset of depression occurs in the context of a medical comorbidity, it is recommended that the comorbid condition be treated first, followed by antidepressants if symptoms persist. 5, SSRIs and venlafaxine are the first-line agents in depression with medical comorbidity. For individuals on several medications, consider SSRIs with the least effect on the cytochrome P450 system (e.g., citalopram or sertraline). For specific subgroups of patients, mirtazapine (e.g., for patients with severe weight loss associated with malignancy) or bupropion (e.g., for patients with extreme fatigue) may also be considered first-line agents. Nortriptyline may be useful in the presence of pain syndromes. For individuals with medication-induced depression, replace the offending agent if possible. If this is not possible, treat concurrently with antidepressant agents. Patients with comorbid depression and dementia should be treated with SSRIs and venlafaxine as first-line agents. TCAs should generally be avoided because of their anticholinergic effects. 3 Conclusions Depression in the older adult is a treatable condition. Key goals are recognition of the diagnosis, aggressive treatment, and prevention of recurrence. Although psychosocial interventions are a necessary component, pharmacotherapy remains a vital part of management. Dr. Lakshmi Ravindran has no competing financial interests to declare. Dr. David Conn has received honoraria for speaking at or attending advisory board meetings of Astra-Zeneca, Janssen, Lilly, Lundbeck, Organon, Novartis, Pfizer, and Wyeth. Dr. Arun Ravindran has received research funding from, participated in advisory boards, and participated in educational events supported by Astra-Zeneca, GlaxoSmithKline, Hoffman La Roche, Janssen, Lilly, Lundbeck, Novartis, Organon, Pfizer, Servier, and Wyeth. References. Koenig HG, Blazer DG. Epidemiology of geriatric affective disorders. Clin Geriatr Med 99;8: Luber MP, Hollenberg JP, Williams-Russo P, et al. Depression and service utilization in elderly primary care patients. Am J Geriatr Psychiatry 00;9: Alexopoulos, GS. Late-life mood disorders. In: Sadavoy J, Jarvik LF, Grossberg GT, et al., editors. 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