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Leaving aside the controversy over the efficacy (or lack thereof) of homeopathic treatment, data for their prescription rates would be far harder to get ahold of, as they are not prescribed under the same systems as conventional medicines.
As this guide is intended to serve an educational role for both the psychiatrist-in-training and the nonpsychiatric physician less familiar with the interactions of psychoactive drugs, the bulk of the background discussion on drug metabolism and mechanisms of drug interactions remains unchanged. New knowledge related to the benefits of psychiatric drug treatment results in earlier initiation of drug therapy for some psychiatric disorders, and maintenance therapy is more and more commonplace during asymptomatic periods. As the population ages, more drugs are prescribed on a chronic basis for maintenance of health without treatment of overt symptoms. Some drug interactions at sites of action are specifically exploited for their therapeutic benefits. Based on an abundance of theoretical and experimental data, drug interactions as a result of competitive inhibition for the same metabolizing enzyme can be predicted.
In the current approach to new drug development, candidate compounds are screened for their affinity for various P450 enzymes. The genes for the expression of the CYP 2A subfamily are localized on the long arm of chromosome 19. Several antidepressants with affinity for CYP 2C (sertraline, fluoxetine, fluvoxamine) appear to have a moderate although measurable affinity for the CYP 2C isoenzymes. Poor metabolizers lack sufficient functional enzyme to metabolize the CYP 2D6 substrates listed in Table 3. In this section, specific drug interactions are discussed for some of the major psychoactive agents in widespread clinical use. Paroxetine is also a potent in vivo and in vitro inhibitor of CYP 2D6, and lower doses of drugs that are substrates for the isoenzyme should be used if paroxetine is combined in treatment.
Gabapentin has been reported to have mood stabilizing effects and to be effective for social phobia. Modafinil is a recently introduced psychostimulant labeled for the treatment of narcolepsy. ABSTRACT: Depression in the elderly significantly affects patients, families, and communities. Depression is the most common mental health problem in the elderly[1] and is associated with a significant burden of illness that affects patients, their families, and communities and takes an economic toll as well.
Because of our aging population, it is expected that the num­ber of seniors suffering from depression will increase.
There is also often a tendency for people to see their symptoms as part of the normal aging process, which they are not. The Geriatric Depression Scale (GDS) is a well-validated screening tool for depression in the elderly that comes in two common formats: the 30-item (long form) and 15-item (short-form) self-rating scale.
The CCSD relies on an interview with a family member or caregiver as well as with the patient, and is validated for use with nondemented and demented depressed elderly.
TreatmentThe current Canadian practice guidelines for the treatment of depression in the elderly were developed by the Canadian Coalition for Seniors’ Mental Health (CCSMH) in 2006.[1] They were created by experts in the field, are evidence-based, and include both pharmacological and nonpharmacological strategies. Note that most depression studies have been conducted on younger populations, and when mixed-aged groups have been studied older adults have been underrepresented. Choice of antidepressantFortunately there are several antidepressants that have been shown to be efficacious in elderly patients being treated for a major depressive episode without psychotic features.
Of the SSRIs, fluoxetine is generally not recommended for use in the elderly because of its long half-life and prolonged side effects. Given the side effect profile and high rates of drug-drug interactions, monoamine oxidase inhibitors (MAOIs) are not considered first- or even second-line agents for depression in the elderly.
DosingOnce an antidepressant is selected for an older patient, the starting dose should be half that prescribed for a younger adult[1] in order to minimize side effects. It is also important at each visit to monitor for any worsening of depression, emergence of agitation or anxiety, as well as for suicide risk, especially in the early stages of treatment. Treatment to remissionAccording to the current CCSMH guidelines, if there is no improvement in depressive symptoms after 4 weeks or insufficient improvement in symptoms after 8 weeks on the maximum recommended or tolerated dose of an antidepressant, then the antidepressant should be changed. Atypical antipsychotics used as add-on therapy in the treatment of depression shows some promise.
The latest 2009 CANMAT national practice guidelines for the treatment of major depressive disorder in adults[28] recommend the use of atypical antipsychotic agents such as rispiridone, olan­zapine, and aripiprazole as first-line add-on agents in the treatment of depression, while quetiapine is recommended as a second-line add-on agent owing to fewer studies. Nonetheless, atypical antipsychotics may prove to be an effective treatment for severe or refractory depression in the elderly who fail to respond fully to other medications.
AcknowledgmentsI would like to thank Dr Martha Donnelly for her encouragement and support in the preparation of this manuscript. His primary care physician diagnosed major depressive disorder last December and began the first of a series of antidepressant medications that eventually included fluoxetine, mirtazapine, and bupropion.
He recounts that for a few weeks in 1998, his mood became quite elevated; the euphoria was accompanied by increased energy and a loss of any need to sleep. A careful patient history is critical; on closer questioning, Mr Smith revealed what appears to have been a previous manic episode, as well as several potential signs of bipolar depression. It is far from uncommon for patients such as Mr Smith to receive multiple courses of standard antidepressant medications.2 Unfortunately, there are real risks associated with using these medications for bipolar depression.
Some studies suggest that there may be other, less concrete effects of prolonged depression in bipolar patients as well. Only 1 medication and 1 medication combination are approved by the FDA to treat depression in patients with bipolar disorder. For example, by searching “drug treatments for depression” and pressing “Show drugs” and then selecting “Generic drugs” from the available options, we can see that though Lexapro, Zoloft, and Celexa are the top three most prescribed brand-name selective serotonin reuptake inhibitor (SSRI) drugs, switching to the generic drug view indicates that escitalopram, sertaline, and fluoxetine are the top-ranked generic drugs. For Mathematica Online, just use a web browser—zero configuration, instant collaboration.
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For the repeat reader, we have summarized in Table 1 important new findings on drug interactions appearing since the last update. In fact, maintenance therapy for affective anxiety and psychotic disorders, often continuing for years or decades, is now the accepted standard of care, especially for patients with a history of recurrent episodes of illness. The degree of documentation varies for many interactions, from theoretical conjecture, to clinical experience with patients, to well-established research outcomes. The pharmacodynamic interactions of competitive antagonists at receptor sites are the basis for development of several therapeutically useful drugs.
Once a solid form (tablets, capsules) of a drug dosage is dissolved into solution in the GI tract, it transverses the gut lumen and wall in transit to the liver. This process presents an opportunity for drug-drug interactions to occur by one highly bound drug displacing another from its protein-binding sites.
For example, sertraline produced a small increase in the free fraction of warfarin and a modest increase in prothrombin time in a study involving healthy male volunteers, but neither effect was considered to be clinically significant. Prediction rests upon knowledge of substrate specificity for particular enzymes, the degree of affinity of a competing drug for the same enzyme, and the concentrations of the substrate and inhibitor.

A high affinity for one or more enzymes suggests a likelihood of interactions with other drugs metabolized by the same enzyme. Psychoactive drugs that inhibit or induce the enzymes listed in Table 2 would be expected to interact with the substrates of those particular enzymes. Clearly, their presence in the GI tract (especially CYP 3A4) and in the liver is important for the elimination of administered drugs. CYP 2B6 plays a role in the metabolism of the anticancer drug cyclophosphamide and is the major enzyme responsible for converting bupropion to its primary active metabolite, hydroxybupropion. The nature of the dose response curves for the NSAIDs may minimize or preclude important interactions unless substantial rises in plasma drug concentration occur. For example, adding fluoxetine or paroxetine to a drug regimen including desipramine will increase the plasma TCA concentration by interference with the hydroxylation pathway. For each drug class, tables are presented that list the medications with which the drugs in the class may interact, how the drugs may interact, and the type of data that support the relevance of the interaction. Their generic status, allowing for relatively low cost, is a major factor in their continued prescription.
Five drugs are available for prescribing that vary considerably in their specificity and potency to inhibit various P450 enzymes. The usual precautions involving combinations of drugs resulting in excessive serotonergic activity are warranted for nefazodone. While mirtazapine is highly metabolized, it apparently possesses insufficient affinity for any of the specific CYP enzymes to be a meaningful metabolic inhibitor. This possibility requires the counseling of patients receiving these drugs regarding the potential for diet constituents and OTC medications to interact with MAOIs. Case series and formal pharmacokinetic evaluations document the interaction, but the precise mechanism is uncertain.
These characteristics account for the autoinduction and decrease in its plasma concentration observed several weeks following initiation of dosing.
A pharmacokinetic interaction study observing methylphenidate concentration with and without quinidine found no evidence for the involvement of CYP 2D6 in its metabolism.
Awareness of predisposing and precipitating factors can help identify patients in need of screening with tools such as the Geriatric Depression Scale. However, it is necessary first to identify and diagnose depression, which can be challenging in this population owing to communication difficulties caused by hearing or cognitive impairment, other comorbidities with physical symptoms similar to those of depression, and the stigma associated with mental illness that can limit the self-reporting of depressive symptoms. Depression in the elderly still goes undertreated and untreated, owing in part to some of these issues. Thus, it is important to schedule regular follow-up visits to monitor treatment response while assessing for side effects and titrating accordingly.
For example, if fluoxetine is being discontinued, then a wash-out period of several weeks is recommended because of the drug’s long half-life. If a second antidepressant is added, monitor for the emergence of serotonin syndrome, which can arise if both medications are serotonergic. However, the CANMAT recommendations are based on studies of younger adults and are not intended for the elderly.
Atypical antipsychotics at the lowest doses for symptom control are also recommended for the treatment of psychotic symptoms associated with depression. Besides medications, other therapies for depression that might be considered include various forms of psychotherapy and neurostimulation, with electroconvulsive therapy still being the gold standard for severe or psychotic depression.
National guidelines for seniors’ mental health: The assessment and treatment of depression.
While none of the episodes were as debilitating as his current state, many persisted for more than 2 weeks and interfered with his ability to work as well as with family life. He reports numerous episodes of depression that began when he was young and a possible family history of bipolar disorder. Standard antidepressants may precipitate manic episodes in a minority of bipolar patients and may be ineffective.7 A delayed diagnosis may prolong depression and further affect the patient’s ability to function effectively at home and at work. Treatment choices in psychiatry are rarely straightforward, and bipolar depression is no exception to this general rule.
His Web site, PsychEducation.org, gathers no information on visitors and produces no income for him or others. For example, “hypertension drug treatment”, initially shows us that, of all the patients diagnosed with hypertension, 25% were prescribed angiotensin converting enzyme inhibitors, 22% HMG-CoA reductase inhibitors, 21% cardioselective beta blockers, 19% antihypertensive combinations, and 16% calcium channel blocking agents. This is interesting because if we switch back to the brand-name list, escitalopram (generic for Lexapro) and sertraline (generic for Zoloft) remain at the top two positions, but citalopram (generic for Celexa) drops off the top three and is replaced by fluoxetine (generic for Prozac). These drugs can be taken for primary prevention, regardless of whether or not the patient has previously experienced a vascular event such as myocardial infarction or stroke. The recent introduction of ziprasidone reflects the high level of activity in drug development for treatment of psychotic conditions. Some portion of the absorbed dose undergoes glomerular filtration and passes out through the urine in an unchanged form.
For cyclosporine, this interaction with grapefruit juice can increase drug bioavailability and result in decreased dosage requirements for immunosuppression and economic cost savings for patients. This occurs when two drugs have such a strong affinity for the same enzyme that one is preferentially metabolized at the expense of the other.
This approach provides a rough screen to predict the potential for pharmacokinetic interactions. Because the elevation of serum theophylline could double or more, it is recommended that when this antidepressant is prescribed for a patient receiving this bronchodilator, the patient’s theophylline dose be reduced by one third of the prior dosage.
A variant allele for CYP 2A6 has been associated with individuals who are deficient in their ability to metabolize warfarin. The accumulating evidence of significant drug interactions with SJW (Table 13) should serve as an example for clinicians to be aware of the potential for herbal products to participate in important herb-drug interactions. Bupropion’s proconvulsant effects in a small number of patients suggest that it should be combined cautiously with other drugs that may increase the seizure threshold, though the sustained-release form of the drug has reduced this risk.
The drug is a very potent CYP 3A4 inhibitor and will theoretically inhibit the metabolism of the relevant substrates listed in Table 3. The specific oxidizing enzymes for the metabolism of haloperidol and the atypical drugs have been reported, but fewer data are available for the older conventional drugs from which to predict drug-drug interactions. Formal pharmacokinetic studies have revealed mutual metabolic interactions with the TCAs, but dosage adjustments as a result are rarely considered in clinical practice. For a list of commonly used antidepressants and associated doses for older adults, see the accompanying Table. By the middle of March, his physician had grown concerned at his lack of progress and suggested that Mr Smith see a psychiatrist as soon as possible for further evaluation; it is now mid-April, and there has been no remission of symptoms. Bipolar symptoms in even a second-degree relative increase a person’s risk for the disorder. For example, the angiotensin converting enzyme inhibitor Lisinopril is more commonly prescribed to male hypertension patients than females, but looking further down the list, we can see that female patients are more commonly prescribed Enalapril than are males.
No claims or endorsements are made for any drug or compound currently under clinical investigation.

However, as a result of more free (unbound) drug being in the systemic circulation not bound to plasma protein, more drug becomes available for hepatic metabolism. Eventually, the increased enzyme activity results in an enhanced clearance of drugs that are substrates for the induced enzyme. Foremost among the drugs that inhibit lithium clearance and increase its plasma concentration are most non-steroidal anti-inflammatory drugs (NSAIDs) and the thiazide diuretics. Some enzymes exist in a polymorphic form, meaning that a small percentage of the population possesses mutant genes that alter the activity of the enzyme, usually by diminishing or abolishing activity.
The most prominent enzymes are discussed below, due to their importance for drug metabolism and participation in drug interactions.
The publication of several case reports of a similar nature frequently stimulates further investigation in the form of formal pharmacokinetic studies. Fluvoxamine also inhibits CYP 2C19 and CYP 3A4 to a significant extent, and dosage modifications are recommended for some substrates, such as alprazolam. The extensive list of medications that these drugs have been reported to interact with has limited their popularity, despite their efficacy for major depression, atypical depression, panic disorder, and other anxiety syndromes. Subsequent studies with poor and extensive CYP 2D6 metabolizers have failed to confirm evidence for CYP 2D6 involvement.
The number of FDA-approved medications for bipolar mania has literally tripled over the past decade while the pharmacopeia available for bipolar depression remains quite limited (Table 2). Harris Professor and chairman of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine in Atlanta, Ga. The major psychoactive drugs, classified according to their primary therapeutic indication, are listed in Table 2. However, these types of interactions are rarely of concern, because the vast majority of psychoactive drugs are prescribed for oral administration. Drug metabolism can occur in several tissues in the body, but hepatic metabolism is generally recognized as the most important, because proportionally the liver contains the highest enzyme content compared with other organs and is therefore most responsible for drug biotransformation. The magnitude of inhibition depends upon several factors, including the affinity of the drugs for the enzyme, the drug concentration in the plasma, the degree of partitioning into hepatocytes, and others. Drug interactions involving changes in renal elimination are unlikely to occur with the antidepressants, antipsychotics, and anxiolytics because these are highly metabolized drugs with typically less than 5% of an administered dose excreted in the urine in an unchanged form. The significance of blocking or inducing a particular cytochrome enzyme for a drug interaction will depend upon the importance of the enzyme in the overall elimination of the drug. While not all TCAs have been carefully scrutinized, it can be expected that, for example, the metabolism of doxepin and trimipramine proceeds in a similar fashion. Although these psychoactive drugs are not substrates for CYP 2E1, they have the potential to modulate the toxicity of nondrug xenobiotics metabolized by this isoenzyme.
This would partly account for why older children and adolescents require larger doses of some drugs than adults.
Given the importance of case reports to the clinician, who must decide whether a particular case represents a sufficiently significant finding to merit a change in prescribing behavior, questions are posed in Table 5 as guidelines for interpretation of reports of suspected drug interactions. The estimated potencies are based on a consideration of in vitro evidence, case reports, and formal pharmacokinetic studies. The continued development of anticonvulsant mood stabilizers for treatment of bipolar disorder means that some patients will receive these drugs in combination with lithium. Should these appear, dosage should be decreased and plasma drug concentration should be assessed for subsequent monitoring. In cases of severe, psychotic, or refractory depression in the elderly, electroconvulsive therapy is recommended. Although other psychoactive drugs, including haloperidol, some tertiary amine tricyclic antidepressants, and olanzapine, are partially metabolized by CYP 1A2, their participation in competitive enzyme interactions appears to be a result of a stronger affinity for enzymes other than CYP 1A2. The most important of the enzymes for psychopharmacology are discussed below and listed with prominent substrates in Table 4. The pharmacokinetic consequences of coadministration of bupropion with other CYP 2D6 substrates have not been published, but caution is advised for this potential interaction. Remarkably, for many drugs in clinical use for years, the enzymes involved in their metabolism have not been identified. CYP 2E1 is an active area of investigation, with limited current relevance, however, for the practice of clinical psychopharmacology. Reduced haloperidol has recently been shown to be a potent CYP 2D6 inhibitor, which suggests a basis for interactions of haloperidol and CYP 2D6 substrates. He denies any history of psychiatric symptoms in his first-degree relatives but notes that his grandmother often had “spells” and was hospitalized for a nervous breakdown. Fluoxetine has no recognized inhibitory potential for CYP 1A2 substrates, but its effects on CYP 3A4 are complex.
Self-rated depression scales and screening for major depression in the older hospitalized patient with medical illness.
Of course, in vitro predictions must be confirmed with in vivo studies, but supporting clinical data may not be available for months or years. The association of depression and mortality in elderly persons: A case for multiple, independent pathways. National guidelines for seniors’ mental health: The assessment of suicide risk and prevention of suicide. Development and validation of a geriatric depression screening scale: a preliminary report. Pharmacological and psychological treatments for depressed older patients: A meta-analysis and overview of recent findings. Feasibility and effectiveness of treatments for depression in elderly medical inpatients: A systematic review. Antidepressant pharmacotherapy in the treatment of depression in the very old: A randomized, placebo-controlled trial. Time to response for duloxetine 60 mg once daily versus placebo in elderly patients with major depressive disorder. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults.
Efficacy and safety of adjunctive aripiprazole in major depressive disorder in older adult patients: A pooled subpopulation analysis. Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults.
Risk of death with atypical antipsychotic drug treatment for dementia: Meta-analysis of randomized placebo-controlled trials.

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