Answer. I am not aware of any controlled, persuasive evidence that Thorazine (chlorpromazine) or any standard antipsychotic – in low doses or high – is particularly effective as an antidepressant. The exception to this claim may be in so-called delusional depression, in which psychotic features are present; antipsychotics such as Thorazine may be somewhat effective for the agitation and delusional thinking in this condition, but probably not for the core depressive features, such as lack of pleasure, lack of energy, and slowing of mental functions. On the other hand, depression is often encountered as a side effect of standard antipsychotics (neuroleptics).

Having said all this, I would hasten to add that new, atypical antipsychotics, such as risperidone and clozapine, do, indeed, seem to have antidepressant properties. However, the standard treatment of depression remains the antidepressants.

Most initial published data on atypical antipsychotic drugs in the elderly are clinical trials in nondemented patients with schizophrenia or Parkinson’s disease. In the last two to three years, controlled trials evaluating risperidone (Risperdal) and olanzapine (Zyprexa) in patients with dementia have been published. There is now evidence that these two atypical antipsychotic drugs offer efficacy in this patient population with fewer adverse effect concerns than the typical antipsychotic drugs.

Risperidone (Risperdal). In 1999, Katz et al. published the first large multicenter, double-blind, placebo-controlled study of risperidone in treating psychosis and behavioral disturbances in an elderly demented population. Among the 625 patients, 73% had a diagnosis of Alzheimer’s disease; average age was 83 years; and their mean baseline Mini-Mental State Examination (MMSE) score was 6.6+6.3, indicative of the most severe stages of dementia. In this 12-week trial, patients received either placebo or risperidone 0.5 mg, 1 mg or 2 mg daily. At endpoint, significantly greater reductions in Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, as well as the psychosis and aggressiveness subscale scores were seen in patients receiving daily doses of 1 mg (p=0.005) and 2 mg (p=0.001) of risperidone compared to those receiving placebo. The 0.5 mg daily dose of risperidone was superior to placebo at week 12 in reducing BEHAVE-AD aggression scores (p=0.02). Improvement based upon total BEHAVE-AD scores for risperidone 1 mg or 2 mg was 56% in patients under 85 years old and 72% in older patients, while placebo response rate was 51% and 54%, respectively. While risperidone was clearly efficacious, the high placebo response rate indicates what Schneider (1999) described as “the waxing and waning and evanescence of disruptive behavior” in this patient population. The most common adverse effects from risperidone were motor symptoms, dose-related sedation and mild peripheral edema. Extrapyramidal symptoms did not differ significantly between placebo and risperidone 0.5 mg or 1 mg. Risperidone 2 mg daily produced significantly more parkinsonism and hypokinesia than placebo.

A 13-week study compared risperidone and haloperidol (flexible doses of 0.5 mg to 4 mg; 1 mg mean daily doses for both drugs) to placebo in 344 patients with dementia. At week 12, a reduction of 30% in the BEHAVE-AD total score was observed in 72%, 69% and 61% of patients receiving risperidone, haloperidol and placebo, respectively, and in 54%, 63% and 47% of patients by intention-to-treat analysis (no statistically significant difference). At endpoint, risperidone-treated patients did have significantly greater reductions in the aggressiveness scores compared to placebo. The most common adverse effects for both haloperidol and risperidone were sedation and falls, with haloperidol causing significantly more extrapyramidal effects.

Olanzapine (Zyprexa). In 2000, Street et al. published a large double-blind, randomized, placebo-controlled trial evaluating olanzapine in patients with Alzheimer’s disease. In this six-week trial, 206 patients were given placebo or a fixed olanzapine daily dose of either 5 mg, 10 mg or 15 mg. Mean baseline MMSE scores were 6.7+6.4, indicating severe dementia. Significantly greater improvements in agitation/aggression and delusions/hallucinations were observed in patients treated with olanza-pine 5 mg or 10 mg compared to placebo and olanzapine 15 mg. The most improvement was seen in patients treated with 5 mg. The total MMSE score did not change significantly over the course of the clinical trial, although there was a modest improvement in the 5 mg dose group and a modest decline in the 10 mg and 15 mg dose groups. Somnolence was the most common dose-related adverse effect, occurring in 25% to 36% of olanzapine-treated patients compared to 6% with placebo. Gait disturbance occurred in patients receiving 5 mg or 15 mg (20% and 17%, respectively), compared to 2% with placebo. There was no significant cognitive impairment, increase in extrapyramidal effects or central anticholinergic effects at any olanzapine dose compared to placebo. Vital signs and laboratory and electrocardiogram measures were unchanged in each dose group compared to placebo.

Discussion

The modest efficacy of conventional antipsychotic drugs in patients with dementia, coupled with their high potential for extrapyramidal effects, tardive dyskinesia, anticholinergic effects and worsening cognition has meant that many patients’ behavioral symptoms and psychosis have been inadequately treated. The atypical antipsychotic drugs, notably risperidone and olanzapine, now have evidence supporting their efficacy and lower potential for adverse effects. Daily doses of no more than 1 mg to 2 mg of risperidone or 5 mg to 10 mg olanzapine can provide significant therapeutic benefit without the risk of significant adverse effects compared to conventional antipsychotic drugs.

Effective pharmacologic and nonpharmacologic treatment of these symptoms is desirable and, in addition, might delay nursing home placement. Pharmacologic and nonpharmacologic interventions are indicated based upon consideration of the safety of both the patient and those around them. Conventional antipsychotic drugs have limited value for psychotic and behavioral symptoms, but recently the results of several large controlled trials of atypical antipsychotic drugs have become available.

Conventional Antipsychotics

The use of conventional antipsychotic drugs in patients with dementia has a long history of concerns regarding limited efficacy as well as adverse effects that often exceed any therapeutic benefits. In the 1980s, these concerns led to the nursing home provisions of the 1987 Omnibus Budget Reconciliation Act (OBRA 1987) mandating reductions of antipsychotic drugs in an effort to limit their use. OBRA 1987 identified specific indications for antipsychotic drugs that included psychotic symptoms and specific aggressive behaviors, and it also identified symptoms of impaired memory, uncooperative attitude, poor self-care and wandering as inappropriate indications for antipsychotic drug therapy. It was recognized that while low doses of conventional antipsychotic drugs (e.g., haloperidol [Haldol] 1 mg/day to 3 mg/day) could be effective for severe aggressive behaviors and psychotic symptoms, higher doses could in fact worsen cognition. Furthermore, extrapyramidal effects could limit improvements in quality of life achieved through improvement in behavioral symptoms.

In 1990, Schneider et al. published a meta-analysis of controlled clinical trials of conventional antipsychotic drugs published from 1954 to 1989. While the authors concluded that these drugs were effective, only 18% of patients received beneficial effects beyond those from placebo. A later meta-analysis evaluated published studies from 1962 to 1995 comparing conventional antipsychotic drugs to placebo in treating behavioral disorders of dementia. Their conclusion was similar in that no significant difference was found in efficacy between individual antipsychotic drugs, with a modest therapeutic benefit of 26% for antipsychotic drugs beyond that from placebo.

Thioridazine (Mellaril) and haloperidol have been the most commonly used drugs in this patient population. Thioridazine poses particular concerns regarding orthostasis, anticholinergic effects and sedation, while haloperidol carries a high risk of movement disorders and the need to use an anticholinergic drug to treat them. Daily doses of haloperidol above 2 mg or of thioridazine above 75 mg tend to be less effective and are associated with greater adverse effects.