Antidepressants have now become the first line of clinical treatment for depression and anxiety disorders, however, elderly patients have special physiological and psychological characteristics, and the use of antidepressants in elderly patients is still an extremely complex issue. What are the principles of antidepressant use in elderly patients? How to choose antidepressants? What are the issues that need to be paid attention to in the process of drug treatment? Understanding these issues can be very helpful in the use of antidepressants in elderly patients. Although the treatment of elderly patients with depression or anxiety disorders sometimes also uses emotion stabilizers such as lithium carbonate (e.g., for bipolar depression) or certain atypical antipsychotics (e.g., for delusional depression), this article focuses on antidepressants, with the application of new antidepressants in elderly patients as a reference for clinicians.
1. Physiological and psychological characteristics of elderly patients
1.1 Multiple somatic diseases
Physiological and psychological changes in the elderly involve many aspects, and multiple somatic diseases may affect the use of antidepressants in elderly patients. Elderly patients often suffer from a variety of physical diseases, especially cardiovascular diseases, such as hypertension, coronary heart disease, atherosclerosis, and some patients have diabetes and chronic bronchitis, emphysema and renal impairment. Elderly patients are prone to mood disorders and poor sleep due to dysfunction of the neuroendocrine regulatory system, which affects sleep rhythm and weakens the role of neurotransmitters, or hypothalamic-pituitary-adrenocortical axis (HPA) overactivity during stress and depression, or affects the function of hypothalamic-pituitary-thyroid axis (HPT), with a high incidence of hypothyroidism in the elderly, and are more likely to develop depression. Severe cases may increase the occurrence of dementia.
The association between impaired growth hormone synthesis and cognitive decline in older patients is also observed. 30%-70% of elderly patients with dementia also suffer from depression, so it has been suggested that new-onset depression in the elderly may be a symptom of Alzheimer’s disease (AD). A long-term follow-up study showed that 57% of elderly patients with depression were diagnosed with AD after 3 years. due to the multimorbidity of elderly patients, psychological disorders are easily masked by symptoms of physical diseases and symptoms are atypical, which can often cause diagnostic difficulties. Moreover, the coexistence of psychosomatic co-morbidities and multiple somatic disorders increases the complexity of treatment, increases adverse drug reactions, and the co-administration of multiple drugs can lead to adverse drug interactions.
1.2 “Somatization” phenomenon
Another physiological and psychological change associated with antidepressant use in older patients is the phenomenon of “somatization”. Older patients with depression more often complain of fatigue, pain, gastrointestinal discomfort and constipation, and depressed patients with anxiety may also experience functional cardiovascular symptoms such as palpitations, chest tightness and vertigo. Elderly patients may also have significant anxiety, agitation, suspicion or fear due to certain somatic discomfort (e.g. constipation). Due to the clinical focus on physical examination in general hospitals, the lack of awareness of the “somatization” of psychological disorders often results in repetitive and excessive examination, which enhances the patient’s attention to physical discomfort and leads to “medically induced psychological disorders” and may even give harmful “treatment”.
1.3 Sleep disorders
Sleep disturbances are also a physiological and psychological change associated with antidepressant use in elderly patients. Changes in sleep patterns occur in older adults with increasing age, with a decrease in stage 4 sleep and an increase in stage 1 light sleep, resulting in delayed sleep onset, lighter sleep and increased awakenings. Up to 98% of depressed patients have sleep disorders, and elderly patients with anxiety disorders tend to have difficulty falling asleep or waking up more often at night. Sleep disorders can cause severe distress or mood disorders in older patients, affecting their daily lives or leading to the indiscriminate use of sedative-hypnotics.
Because of the vicious circle between sleep disorders and mood disorders, poor sleep often leads to poor mood, so special attention should be paid to improving sleep in elderly patients. As the brain ages, neurotransmitters such as 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) decrease, and the decrease in DA leads to decreased motor ability, slower movement and reduced cognitive function in elderly patients. In clinical practice, there are often elderly patients who use hypnotic drugs excessively due to poor sleep, resulting in dependence on hypnotic drugs, and discontinuation may cause more serious insomnia, and this kind of “rebound insomnia” caused by drug discontinuation should be a clinical concern.
1.4 Atypical somatic symptoms
Elderly patients often have “painless myocardial infarction” and “asymptomatic pneumonia” due to dull sensation and hyperalgesia, etc. Due to the low organ reserve function of the elderly, the disease often progresses rapidly after the onset, and organ failure and electrolyte disorders easily occur. The elderly are often prone to organ failure and electrolyte disturbance after the onset of acute physical diseases, such as infections and strokes. It should also be noted that elderly patients have reduced acetylcholine and are more prone to dry mouth and constipation with anticholinergic antidepressants, antipsychotics, or certain benzodiazepines (BZD), which can lead to impaired consciousness or cognitive impairment.
Elderly patients with insidious renal decompensation and reduced ability to handle potassium are prone to hypokalemia in cases of decreased appetite, diarrhea, vomiting, and possibly hyperkalemia in cases of co-infection, so laboratory tests should be paid attention to, especially in elderly patients who have been using lithium for a long time. Elderly patients often have osteoporosis and are prone to fractures. BZD drugs may have adverse effects such as ataxia, muscle relaxation and cognitive impairment, which may cause fractures in elderly patients who fall and aggravate poor memory, so the pros and cons should be weighed and BZD drugs should be used with caution or avoided.
1.5 Pharmacokinetic and pharmacodynamic changes
Clinical understanding of the pharmacokinetic and pharmacodynamic changes associated with aging is essential. Alterations in pharmacokinetic parameters in the elderly mainly include effects on drug absorption or delayed absorption, increased volume of distribution of fat-soluble drugs (most psychotropic drugs are fat-soluble) leading to prolonged unexpected drug action, increased free drug concentration due to decreased plasma protein, decreased hepatic drug metabolism (biotransformation) capacity and impaired renal clearance, resulting in increased drug accumulation and prolonged drug clearance (increased drug half-life). The concentration of antidepressants and their active metabolites increases significantly, which prolongs their effects and enhances the toxicity of antidepressants and their metabolites, so the dosage of antidepressants should be reduced in elderly patients.
Pharmacodynamic changes are mainly due to changes in the sensitivity of central nervous system (CNS) receptors in elderly patients, resulting in decreased neurotransmitter function, significantly delayed drug onset, and significantly increased adverse effects. For example, decreased CNS dopamine neurotransmission in the elderly, clinically manifested by delayed psychomotor activity and increased risk of extrapyramidal reactions when using antipsychotics or certain antidepressants; decreased CNS cholinergic transmission in the elderly, easily leading to greater sensitivity to certain antidepressants with anticholinergic effects such as tricyclics as well as paroxetine and antipsychotics, resulting in a greater risk of consciousness in elderly patients blurring, disorientation and memory loss.
2. Principles of antidepressant use in elderly patients
2.1 Comprehensive examination and assessment
It is very important to make a comprehensive assessment before treatment because elderly patients are very sensitive to diseases and antidepressants due to multiple diseases, use of multiple drugs, aging of organs and changes in receptor sensitivity, and increased adverse drug reactions. Thus, a comprehensive assessment is necessary to ensure safe and effective medication use. Examination and assessment should include:
(i) liver and kidney function tests (regular rechecking should also be noted during treatment);
②Thyroid function test;
③Electrocardiogram;
④List all medications being used, including over-the-counter medications and other substances such as tobacco and alcohol use;
⑤ Monitor blood levels if possible; ⑥ Carefully identify psychological disorders and physical disorders such as heart disease, chronic obstructive pulmonary disease, stroke, diabetes mellitus, gastrointestinal disorders and cognitive impairment (AD) in the elderly.
2.2 Definitive diagnosis
Geriatric depression contains many symptoms involving sleep disorders and depression after which evidence-based medical evidence should be sought to select appropriate antidepressants according to the clinical characteristics and adverse drug reactions and possible drug interactions of elderly patients.
2.3 Individualization of drug dosage and use of the lowest effective dose
The goal of pharmacological treatment for elderly patients is to strive for complete or substantial symptom relief and maximum recovery, improve quality of life, and maintain their community life in order to delay or avoid nursing home admission. Dose individualization is the basic principle of psychotropic drug therapy for the elderly. Due to the physiological changes of increasing age and pharmacokinetic changes, adverse drug reactions increase in elderly patients, so the dosage of medication needs to be appropriately changed. The use of the lowest effective dose to achieve a more satisfactory therapeutic effect should be a rule for the use of antidepressants in elderly patients.
2.4 Careful drug selection and attention to adverse drug interactions
Careful selection of effective drugs with high safety, few adverse effects, and good tolerability, taking into account low cost, ease of administration, and evidence of good evidence-based studies, should be used for elderly patients. Selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) have become the first-line choice for elderly patients with psychological disorders. Since elderly patients often use multiple drugs simultaneously, special attention should be paid to drug interactions when using SSRIs. Fluoxetine and paroxetine inhibit CYP2D6, and sertraline is also a weaker CYP2D6 inhibitor.
CYP2D6 is important for the metabolism of tricyclic antidepressants, antipsychotics and type IA antiarrhythmics, beta-blockers, and verapamil. Blood concentrations of these drugs are elevated in SSRI-treated patients, so the doses of these drugs should be reduced during fluoxetine and paroxetine treatment, and blood concentrations of these drugs should be monitored when possible. An exception is fluvoxamine, which inhibits CYP3A4 and CYP1A2, but not CYP2D6.
While CYP3A4 is related to the metabolism of drugs such as alprazolam, triazolam, carbamazepine, quinidine, erythromycin, terfenadine and astemizole, inhibition of CYP3A4 leads to increased blood concentrations of these drugs, causing adverse drug reactions and even serious adverse events, so patients using fluvoxamine should avoid co-administration of these drugs. Similarly, patients using fluvoxamine should be careful when giving theophylline, because inhibition of CYP1D12 by fluvoxamine can reduce theophylline clearance.
3. Selection of antidepressants for elderly patients
The clinic should deeply understand the pharmacokinetic and pharmacodynamic characteristics of each antidepressant, and carefully select antidepressants based on comprehensive consideration of the clinical characteristics of elderly patients and evidence-based medical research. If the previous treatment of antidepressants is effective and there are few adverse effects, the drug can still be used to start treatment; if the medical history is unknown, further information on the medication history of the family members should be obtained, and if the first-degree relatives have good efficacy and few adverse effects to a certain antidepressant, the drug can also be used to start treatment.
If a thorough evaluation of the older patient indicates bipolar depression, attention should be paid to whether the patient has been on an emotion stabilizer, whether maintenance therapy is adequate, and whether there are any drug-induced somatic complications. Bupropion among antidepressants has good efficacy in bipolar depression, low rates of transient mania, safe use, and no cardiotoxicity, and can be listed as the drug of choice for the treatment of bipolar depressive episodes.
Since elderly patients are often treated with medications for their various physical illnesses, the addition of antidepressants will alter the metabolism and therapeutic concentration of these medications, so an in-depth understanding of the adverse effects of antidepressants is needed to weigh the pros and cons before selecting a medication to treat the patient’s symptoms.
If elderly depressed patients have poor sleep and low body weight, antidepressants with sedative-hypnotic effects and weight gain such as mirtazapine should be used; if depression is accompanied by chronic pain, duloxetine and venlafaxine extended-release agents (Enox) should be used, but patients with hypertension should not use venlafaxine and its extended-release agents; if elderly depressed patients with coronary artery disease have had myocardial infarction or conduction block, tricyclic antidepressants should be avoided SSRI antidepressants do not inhibit the cardiac conduction system, and their efficacy is similar to that of tricyclics, and their safety is better, so they are more preferable for elderly depressed patients with heart disease.
Among SSRIs, sertraline has the most evidence of safety studies, good efficacy in depression, improved cognitive function, and good tolerability, and can be used to treat elderly depressed patients with coronary artery disease and PD, as well as vascular depression or depression in early AD.
Escitalopram has good efficacy and safety, rapid onset of action, can quickly improve depressive symptoms, reduce the risk of suicide, and has good anxiolytic effect with few adverse effects, also suitable for elderly patients. Patients with severe gastrointestinal diseases often do not tolerate SSRI drugs well, bupropion is available and has no cardiotoxicity, but it is not suitable for epileptic patients.
4. Points to note when treating elderly patients with antidepressants
4.1 Start with low doses, monitor and manage adverse drug reactions
The dose of SSRI antidepressants should be gradually increased with the starting dose: fluoxetine 5-10 mg a day, paroxetine 5-10 mg a day, sertraline 25 mg a day, citalopram 10 mg a day. Higher. Fluvoxamine is also effective in geriatric depression, and its drug interactions with fluoxetine and paroxetine are more frequent and need to be noted when used.
The most common adverse effects of SSRIs are insomnia, fidgeting, nausea, anorexia, and sexual dysfunction. Selective 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRIs) with NEergic and specific 5-HTergic antidepressants (NaSSAs) should also be started at low doses. Adverse effects of antidepressants often appear early before the therapeutic effect is observed. Elderly patients are very sensitive to adverse effects and have increased complaints of somatic discomfort, which can easily lead to treatment interruption and should be monitored repeatedly during treatment and treated promptly (Table 1).
4.2 Efforts to gain the trust of patients and families and improve treatment compliance
Elderly patients have poor memory, are sensitive to somatic discomfort, and the delayed onset of antidepressants may lead to noncompliance. Therefore, clinicians should be good at discussing medication with patients and their families, patiently explaining the rationale for the chosen medication and the possible benefits of treatment, being good at explaining the possible adverse effects of medication without arousing patients’ suspicions, and asking patients and families to cooperate. In order to facilitate the elderly patients and their family members to remember the medical advice, we should simplify the variety and usage of medication, detail the dose and method of medication, or use sticky notes to fill in the number of drugs in a table according to morning, noon, night or bedtime, so that patients and family members can follow the implementation.
4.3 Strive for complete or partial remission of symptoms and maximum recovery, and adhere to the three phases of full treatment
The goal of treatment for geriatric depression or anxiety disorders should not stop at being effective, but should strive to achieve complete remission of symptoms, recovery or near recovery, improve quality of life, and maintain their community life. Because these disorders are chronic and prolonged or prone to relapse and recurrence, long-term treatment is required. In the case of pharmacological treatment of depression, three phases of treatment should be completed consistently.
The first phase lasts about 2-3 months and requires treatment to bring about a basic or major remission of symptoms; the second phase consolidates treatment for about 6 months so that the patient’s remission continues to be stable and relapse is prevented; and the third phase maintenance treatment, the length of which is determined by the clinical characteristics of the patient, ranges from 6 months to 2 years, sometimes longer, with the goal of preventing relapse. Close monitoring and timely management of adverse reactions and suicidal crises should still be carried out during the three full phases of treatment.
4.4 Combination of potentiators and antidepressants
Patients with psychological disorders are often treated with a booster (e.g., thyroxine, lithium, buspirone, or atypical antipsychotics) or a combination of two antidepressants when one antidepressant is only partially effective. The combination of antidepressants is usually more effective than one antidepressant alone, for example, fluoxetine treatment with trazodone, citalopram treatment with bupropion, SSRIs with low-dose mirtazapine, etc. are better choices.
Unfortunately, elderly patients often have difficulty accepting multidrug combinations and cannot tolerate adverse drug reactions, so the decision should be based on the clinical assessment of elderly patients. The basic principle should be to combine drugs with different mechanisms of action, because the combination of drugs with the same mechanism of action will increase adverse effects, such as the combination of two SSRIs or the combination of SSRI and SNRI has the risk of causing 5-hydroxytryptamine syndrome, which requires special attention.