Psychiatric Times.
No. 13
Depression in Patients With Alzheimer Dementia
By Nicholas A. Kozauer, MD, Paul B. Rosenberg, MD, and Constantine G. Lyketsos, MD, MHS |
November 1, 2006
The role of medications
When depression is severe or a CSDD score is above 12,19 when the patient is suicidal or violent, or when the patient is not eating or drinking, antidepressant therapy is likely required.15 Currently, there is no FDA-approved treatment for dAD; however, Table 3 summarizes the results of existing controlled trials of antidepressant medications in AD. It should be noted that most of these studies used DSM-IV diagnostic criteria, because the NIMH criteria for dAD were not in existence at the time.
As discussed, routine diagnostic criteria do not likely capture an accurate picture of the condition and could overlook aspects of treatment response. Other challenges in the interpretation of this literature are inconsistencies in efficacy findings, limited replication studies, and several negative studies that indicated no superiority of the drug over placebo. As a function of these limitations, these data cumulatively serve as a general guide to the treatment of dAD, but do not yet offer any definitive man agement recommendations.
At this point, the initial approach is to begin with an SSRI. The evidence seems to indicate a similar efficacy be tween tricyclic antidepressants (TCAs) and SSRIs, with the latter being better tolerated with fewer cognitive side ef fects. Common side effects of SSRIs are largely related to their serotonergic activity and include GI distress, tremor, headache, restlessness, and insomnia. No controlled studies exist that examine the effects of newer antidepressant categories (serotonin-norepinephrine reuptake inhibitors, bupropion, or mirtazapine(Drug information on mirtazapine)) in dAD. The best safety and efficacy data exist for sertraline and citalopram (with the latter arguably extrapolated to escitalopram(Drug information on escitalopram) based on their pharmacologic similarity), which make them a reasonable starting point in treatment.
These clinical trials seem to indicate that antidepressant dosing in dementia should be similar to that in younger patients. This is a key distinction from the standard lower dosing of other neuroleptic agents in this population. Titration to the maximal target dose over 4 weeks is ideal; however, slower schedules are appropriate as clinically indicated. If no response is seen after that time, a change is likely warranted or consideration may be given to augmentation with an antipsychotic or anticonvulsant. If partial benefit is seen after 4 weeks, full benefit may require up to 12 weeks of treatment. Scales such as the CSDD can be useful in monitoring this response.
If there is still inadequate response at 12 weeks, consider a medication change following a 2-week taper. Reasonable second-line agents include nor adrenergic drugs such as venlafaxine, mirtazapine, secondary amine TCAs, or a monoamine oxidase inhibitor. This choice theoretically relates to the previously described finding of the loss of noradrenergic neurons in the locus cae ruleus. If mood is im proved but agitation remains, a subsequent step can include adding an anticonvulsant such as divalproex. In our experience, initial dosages of 250 mg bid or 500 mg qhs are often required, with a titration to a serum level of 50 to 100 µg/mL; how ever, clinical re sponse is often seen at lower levels. This initial dosing may be somewhat higher then standard geriatric dosing.
For treatment-refractory patients, consideration should be given to electroconvulsive therapy, especially when patient safety is at risk because of suicidality, violence, or poor self-care. The concern for increased postictal delirium can be minimized by careful patient selection and in many cases, treatment has also been demonstrated to result in improved cognitive functioning in dementia.20
Conclusion
Depression is a very frequent neuropsychiatric symptom in AD and is responsible for significant morbidity and caregiver burden. The symptom constellation of dAD differs from that of major depressive episodes, frequently including irritability, agitation, delusions, anxiety, and anhedonia. This syndrome has only recently been identified and provisional diagnostic criteria for dAD should help in understanding causes and treatments. Successful management requires the thoughtful integration of pharmacologic and non pharmacologic treatment strategies. The desire to maximize the quality of life for those dealing with this devastating disease fuels this effort.
Dr Kozauer is a neuropsychiatry postdoctoral fellow in the division of geriatric and neuropsychiatry, Dr Rosenberg is assistant professor of psychiatry and behavioral sciences in the division of geriatric and neuropsychiatry, and Dr Lyketsos is professor and chair of the department of psychiatry at The Johns Hopkins Hospital in Baltimore, Md. Dr Kozauer and Dr Rosenberg report that they have no conflicts of interest concerning the subject matter of this article. Dr Lyketsos receives grant support from NIMH, NIA, Associated Jewish Federation of Baltimore, Forest Labora tor ies, GlaxoSmithKline, Eisai, Pfizer, Astra-Zeneca, Eli Lilly, Ortho-McNeil, Bristol-Myers Squibb, and Novartis. He is a consultant/advisor for Astra-Zeneca, GlaxoSmithKline, Eisai, Novartis, Forest Laboratories, and Supernus Pharmaceuticals. He has received speaking honoraria from Pfizer, Forest Laboratories, and GlaxoSmithKline.
Drugs Mentioned in This Article
Amitriptyline (Limbitrol)
Benztropine (Cogentin)
Bupropion (Wellbutrin)
Carbamazepine (Tegretol, others)
Chlorpromazine (Thorazine)
Citalopram (Celexa)
Clomipramine (Anafanil)
Digoxin (Lanoxin)
Divalproex (Depakote)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Sarafem)
Imipramine (Tofranil)
Lithium (Eskalith, Lithobid)
Mirtazapine (Remeron)
Moclobemide (Manerix)
Paroxetine (Paxil)
Phenytoin (Dilantin, Phenytek)
Sertraline (Zoloft)
Thioridazine (Mellaril)
Venlafaxine (Effexor)
Evidence-based References
Geldmacher DS, Whitehouse PJ Jr. Differential diagnosis of Alzheimer's disease. Neurology. 1997;48(suppl 6):S2-S9.
Ross GW, Bowen JD. The diagnosis and differential diagnosis of dementia. Med Clin North Am. 2002;86:455-476.
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