What special issues do psychiatrists face when treating women, children and adolescents, and elderly people with schizophrenia? Are there recommendations for care and monitoring strategies to maintain patients on effective, long-term treatment regimens?
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Dr. Pies is clinical professor of psychiatry at Tufts University. His most recent books include Creeping Thyme, a collection of poetry (Brandylane Publishing); Zimmerman's Tefillin, a short story collection (PublishAmerica); and Handbook of Essential Psychopharmacology, 2nd edition, forthcoming from American Psychiatric Publishing. He has indicated that he has nothing to disclose regarding the nature of this article.
(This is the first part of a two-part series on long-term treatment issues in special populations. Part II will focus on bipolar disorder and dementia--Ed.)
The long-term treatment of patients with neuropsychiatric disorders can be quite challenging and sometimes frustrating for clinician and patient alike. Consider the following vignette:
"Mr. C" is a 38-year-old former engineer with a diagnosis of chronic paranoid schizophrenia and "episodic mood lability." He had been tried on numerous conventional antipsychotics since the mid-1980s, with only partial improvement of his delusions and auditory hallucinations. Mr. C had developed severe extrapyramidal side effects, including akathisia, on most of the first-generation antipsychotics and was eventually treated with clozapine (Clozaril). Although his psychosis improved considerably, Mr. C believed that the frequent blood drawings would "rob me of my vital spirits" and ultimately refused to take clozapine. Olanzapine (Zyprexa) treatment was helpful but led to significant weight gain, and again, the patient refused to continue treatment. Trials of risperidone (Risperdal), quetiapine (Seroquel) and aripiprazole (Abilify) were partially successful but also produced a variety of side effects the patient found unacceptable. Attempts to engage Mr. C in supportive psychotherapy were also only transiently successful, and he eventually required prolonged inpatient hospitalization. He was eventually discharged on two atypical antipsychotics in combination with divalproex (Depakote).
Mr. C's case is fairly typical of many chronic patients seen today by psychiatrists: a long history of partial responses to medication complicated by poor treatment adherence and troublesome side effects (Dewan and Pies, 2001). For certain special populations, these problems may be particularly debilitating and are often exacerbated by biological, psychosocial and demographic variables common to certain subgroups. We will see these themes played out in patients with schizophrenia, bipolar disorder (BD) and various types of dementia. Unless psychiatrists recognize that special populations have special needs, management of these conditions may suffer.
Issues in Schizophrenia
In general, patients with schizophrenia present a plethora of long-term treatment challenges. Flowers and Simpson (1997) reported that some 30% to 50% of patients with symptoms of schizophrenia do not respond well to conventional antipsychotics. Standard first-generation antipsychotics have minimal long-term effects on negative symptoms, neurocognitive symptoms and mood symptoms of schizophrenia (Flowers and Simpson, 1997). Although, in several respects, newer atypical antipsychotics represent an important advance, even these agents are far from ideal. Clozapine--arguably the gold standard of treatment--is effective in only about 40% to 78% of conventional antipsychotic-refractory patients (Buckman and Malan, 1999). Moreover, a recent meta-analysis concluded that none of the newer atypicals can match, much less surpass, clozapine for efficacy, even though they do have more benign side-effect profiles (Figure 1) (Davis et al., 2003). (Due to copyright concerns, this Figure cannot be reproduced online. Please see p67 of the print edition--Ed.) Nevertheless, side effects with newer atypical antipsychotics are often associated with poor medication adherence or compliance. Rates of nonadherence to antipsychotic medications range between 19% to 26% according to a recent Expert Consensus report. Rates of partial compliance range between 38% and 46% (Kane et al., 2003). The tablet-for-tablet costs of the newer atypical antipsychotics are also considerable, although these agents may bring down the long-term costs associated with hospitalization (Davis et al., 2003). A variety of augmentation strategies have been devised to cope with treatment-refractory schizophrenia, but there is a glaring deficiency of controlled data (Dewan and Pies, 2001; Oepen, 2002). In many cases, this leads to "irrational polypharmacy," which further complicates treatment and compliance. Given all these concerns, how are various subgroups of patients with schizophrenia affected?
Women With Schizophrenia
As Burt and Hendrick (1997) have observed, significant gender differences exist in the course and manifestation of schizophrenia (Table 1). In general, the onset of schizophrenia tends to occur later in women and is associated with fewer premorbid abnormalities. Moreover, women with schizophrenia tend to have more affective and positive symptoms than men and fewer negative symptoms, such as social withdrawal. There may even be differences in structural brain abnormalities between men and women with schizophrenia; e.g., increased ventricular size may be more common in men with schizophrenia (Burt and Hendrick, 1997). Hormonal factors in women may also affect the expression of schizophrenia. For example, symptomatic exacerbation of schizophrenia has been noted during the low-estrogen phase of the menstrual cycle and in the perimenopausal years (Burt and Hendrick, 1997). Females with schizophrenia may be more sensitive to antipsychotic effects than men, perhaps reflecting estrogenic modulation of dopaminergic effects (Szymanski et al., 1995).
The issues of pregnancy, parturition and breast-feeding may also arise for many women with schizophrenia of child-bearing age. First-generation antipsychotics, as well as risperidone, may substantially elevate prolactin levels, which inhibit estrogen release. This in turn may lead to amenorrhea and lack of ovulation. On the other hand, women with schizophrenia are at high risk for unplanned pregnancy, owing to ineffective birth control and/or high incidence of sexual assault (Burt and Hendrick, 1997). Education and counseling regarding these issues are important components of treatment in this subgroup. Although antipsychotics are not believed to have high teratogenic potential, the use of these agents during and after pregnancy requires careful discussion and planning (Newport et al., 2004).
Unfortunately, women with schizophrenia may also be more susceptible to extrapyramidal side effects, tardive dyskinesia (TD) in postmenopausal women and perhaps antipsychotic-induced agranulocytosis in elderly women (Szymanski et al., 1995). These factors clearly affect the risk-benefit calculation in long-term treatment of women with schizophrenia. Nevertheless, the risk of relapse with antipsychotic discontinuation is very high in all subgroups of patients with schizophrenia. Thus, women with this disorder--like their male counterparts--generally require lifelong antipsychotic treatment. Appropriate psychosocial treatment should also be a part of long-term care. In some cases, this may involve individual and family-educational approaches or assertive community outreach (Dewan and Pies, 2001).
The take-home message regarding women and schizophrenia. Clinicians treating women with schizophrenia should be particularly observant for the presence of affective symptoms and for exacerbation of psychotic symptoms in relation to the menstrual cycle. The medication regimen may need augmentation or dosage increase in relation to these factors. In theory, as younger female patients transition to the perimenopausal years, increased antipsychotic medication may be necessary, as psychosis may worsen. However, because females with schizophrenia may be more sensitive to antipsychotic effects than their male counterparts, dosing should be conservative in this population. The role of supplementary estrogen in women with schizophrenia has not been well-researched. The issues of pregnancy, parturition and breast-feeding must be carefully considered when treating women with schizophrenia of child-bearing age (see Table 2 for treatment recommendations).
Children and Adolescents
Although schizophrenia in children under the age of 13 is rare, the prevalence rises in adolescence. Clinical features of schizophrenia are generally similar in youths and adults. However, one study of patients with schizophrenia with onset of illness between the ages of 11 and 21 found an interesting interaction between age and gender (Galdos and van Os, 1995). The frequency of typical first-rank schizophrenic symptoms (e.g., auditory hallucinations, thought insertion) increased linearly with age in male patients, but did not vary with age in their female counterparts. The authors speculated that these differences might be explained by the "later manifestation of puberty and associated maturational processes in boys."
As Wagner (2004) cautioned, most information about both older and atypical antipsychotics in younger cohorts comes from short-term open-label studies, case reports and retrospective chart reviews. Antipsychotic doses recommended for pediatric patients are generally much lower than those used in adults; for adolescents, doses are only somewhat lower than the usual adult doses (Kane et al., 2003).
It is not yet clear which class of antipsychotic is safest and most efficacious in children and adolescents, although atypical agents are preferred. Some recent controlled and open data suggest that risperidone, olanzapine and quetiapine may be effective in children and/or adolescents at dosage ranges comparable to those used in adults; however, EPS, weight gain, agitation, drowsiness and other side effects may be associated with these agents (see Wagner et al.  for a review). An open-label study of risperidone in adolescents with schizophrenia found it effective at doses of about 3 mg/day, but not for negative symptoms of schizophrenia (Zalsman et al., 2003). Findling et al. (2003b) completed an eight-week, open-label, outpatient study of adolescents (n=16, ages 12 to 17) with a diagnosis of schizophrenia, schizoaffective or schizophreniform disorder, treated with olanzapine up to 20 mg/day. Psychotic symptoms significantly improved during study, and overall, olanzapine was well tolerated. However, increased appetite and sedation were reported, and two participants required treatment for EPS.
Controlled, long-term studies of children with schizophrenia are sorely lacking. Indeed, it is sobering that Wagner (2004) concluded that there are no data to guide the clinician in maintenance treatment. Long-term treatment with atypical agents could pose risks in younger populations, such as the development of TD, weight gain or impaired glucose tolerance (Keck et al., 2003). Antipsychotic-induced prolactin elevations are also of concern, although a recent study of long-term risperidone use in children and adolescents was somewhat reassuring. Findling et al. (2003a) found that with long-term risperidone treatment, serum prolactin levels tended to rise and peak within the first one to two months, but then declined to near-normal values within three to five months (Figure 2) (due to copyright concerns, this Figure cannot be reproduced online. Please see p68 of the print edition--Ed.). Nonetheless, adolescent issues regarding body image, weight gain and the stigma surrounding the use of psychiatric medication may all interfere with long-term adherence to treatment. Some data in adolescents suggest that females have a greater fear of weight gain than their male counterparts (Diehl, 1999); this could reduce compliance with long-term antipsychotic treatment among adolescent females, depending on the medication used. Unfortunately, there is a high risk of relapse with medication discontinuation, especially in younger populations (Wagner, 2004).
The take-home message regarding children with schizophrenia. Long-term treatment planning in younger populations with schizophrenia requires conservative dosing and the use of atypical antipsychotics as agents of first choice. As yet, there is no antipsychotic of first choice in this population. Careful monitoring for EPS, weight gain, agitation, drowsiness and other side effects is critical. Because adolescent issues regarding body image and the social stigma of taking medication may undermine treatment adherence, the clinician needs to explore these issues carefully. Owing to the high risk of relapse with medication discontinuation in younger populations with schizophrenia, most such patients will require long-term maintenance treatment with antipsychotics.
As Jeste (2003) observed:
The numbers of older persons with schizophrenia and other psychotic disorders are expected to rise rapidly in coming decades; yet most studies of the safety and efficacy of treatments ... have focused on younger adults.
This subgroup may pose special challenges, given that cognitive deficits may sometimes interfere with informed consent (see Dementia section). Complex polypharmacy regimens are also a major problem in elderly and medically ill populations with schizophrenia (Cremens, 2002).
Kasckow (2003) noted that the use of atypical antipsychotics is preferred in the elderly, given the increased risk of EPS and TD. Clinicians should start with a low dose and titrate until the lowest effective dose is reached. Agents with strong anticholinergic effects should be avoided whenever possible. Sometimes agents with few anticholinergic effects but relatively high risk of EPS may lead to long-term use of anticholinergic "rescue" medications, such as benztropine (Benztrop, Cogentin). Unfortunately, this may negate the pharmacodynamic advantages of the drug and lead to peripheral and central anticholinergic side effects, including constipation, urinary retention and confusion (Jacobson et al., 2002). Most of the atypical antipsychotics can also produce postural hypotension, and this is of particular concern in elderly patients, who are in danger of falls and strokes. Atypicals with a relatively low degree of a-1 adrenergic blockade, such as olanzapine, aripiprazole and ziprasidone (Geodon), may be preferable from this standpoint (Pies, in press).
Jacobson et al. (2002) noted that for maintenance treatment of elderly patients with schizophrenia, reassessment should occur at least every three to six months. This should involve evaluation of drug efficacy and side effects and, if clinically feasible, dosage reduction in selected cases. Finally, as Kasckow (2003) noted, antipsychotic medications "do not cure the underlying illness." Thus, appropriate psychosocial treatment should be part of the overall long-term care plan with elderly patients with schizophrenia.
The take-home message regarding the elderly and schizophrenia. The elderly patient with schizophrenia is at increased risk for a variety of medication-related side effects, such as postural hypotension and anticholinergic side effects. Atypical antipsychotics are preferred in the elderly, given the increased risk of EPS and TD in this age group. "Start low, go slow" is the guiding principle in this population. Agents with strong anticholinergic effects should be avoided, and complex polypharmacy regimens should be scrutinized critically for potential drug-drug interactions.
Buckman RW, Malan RD (1999), Clozapine for refractory schizophrenia: the Illinois experience. J Clin Psychiatry 60(suppl 1):18-22, 28-30.
Burt VK, Hendrick VC, eds. (1997), Concise Guide to Women's Mental Health. Washington, D.C.: American Psychiatric Press.
Cremens C (2002), Polypharmacy in the elderly. In: Polypharmacy in Psychiatry, Ghaemi SN, ed. New York: Marcel Dekker, pp213-229.
Davis JM, Chen N, Glick ID (2003), A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 60(6):553-564.
Dewan MJ, Pies R, eds. (2001), The Difficult-to-Treat Psychiatric Patient. Washington, D.C.: American Psychiatric Press.
Diehl JM (1999), [Attitude to eating and body weight by 11- to 16-year-old adolescents.] Schweiz Med Wochenschr 129(5):162-75.
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Kane JM, Leucht S, Carpenter D, Docherty JP, eds. (2003), Expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. J Clin Psychiatry 64(suppl 12):2-97, quiz 98-100.
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Oepen G (2002), Polypharmacy in schizophrenia. In: Polypharmacy in Psychiatry, Ghaemi SN, ed. New York: Marcel Dekker, pp101-132.
Pies R (in press), Handbook of Essential Psychopharmacology, 2nd ed. Washington, D.C.: American Psychiatric Press.
Szymanski S, Lieberman JA, Alvir JM et al. (1995), Gender differences in onset of illness, treatment response, course, and biologic indexes in first-episode schizophrenic patients. Am J Psychiatry 152(5):698-703.
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