Treating and Preventing Adolescent Mental Health Disorders: Treating and Preventing Adolescent Mental Health Disorders

Book Title: Treating and Preventing Adolescent Mental Health Disorders > pp. [125]-[129]

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Treating and Preventing Adolescent Mental Health Disorders

Print ISBN 9780195173642, 2005
pp. [125]-[129]

there are no specific guidelines or sufficient evidence to determine which second-generation antipsychotic to use. Side effects are the primary distinguishing features among the various drugs.

Young patients without prior exposure to antipsychotic drugs may be more sensitive to the antipsychotic side effects than patients in other stages of the illness. In a sample of 70 treatment-naive patients who received fluphenazine at 20 to 40 mg/day for the first 10 weeks of treatment, 34% developed parkinsonism, 18% developed akathisia, and 36% developed dystonia (Chakos, Mayerhoff, Loebel, Alvir, & Lieberman, 1992). Lower doses of antipsychotics may be adequate to achieve positive symptom remission, but less likely to cause side effects (Cullberg, 1999; Zhang-Wong, Zipursky, Beiser, & Bean, 1999). For example, in a post hoc analysis, low-dose risperidone (maximum of ≤6 mg/day) was more effective and better tolerated than high-dose risperidone (maximum of ≥6 mg/day; Emsley, 1999). Another recent study of 49 acutely psychotic, neuroleptic-naive patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with either 2 mg or 4 mg daily of risperidone showed the two doses to be comparable in efficacy with an advantage for the lower dose in fine motor functioning (Merlo et al., 2002). The greater sensitivity to side effects of first-episode patients than that of chronic patients was dramatically demonstrated by McEvoy, Hogarty, and Steingard (1991) in comparing their neuroleptic thresholds for extrapyramidal symptoms. In the context of a gradual dose titration paradigm, first-episode patients exhibited lower thresholds to develop signs of extrapyramidal symptoms than previously treated more chronic patients. Younger patients are also more susceptible to other side effects, such as weight gain (Kumra et al., 1998; Lieberman, Gu, et al., 2003). Consistent with these studies, the Schizophrenia Patient Outcomes Research Team recommended that patients in a first psychotic episode be treated with relatively lower doses (300 to 500 mg chlorpromazine equivalents per day) of antipsychotics than for patients with schizophrenia in general (300 to 1,000 mg chlorpromazine equivalents per day; Lehman & Steinwachs, 1998). Clinical experience and available research findings suggest that lower doses of antipsychotics are as effective as higher doses in patients experiencing a first episode of schizophrenia, with superior tolerability.

Since the first episode is a time when patients form their attitudes about treatment, efforts to minimize unpleasant side effects may influence patients' willingness to take medications over the long term. In a study of first-episode patients, the only variable that predicted whether patients would attend a follow-up assessment was antipsychotic dosage, with those on higher doses less likely to comply (Jackson et al., 2001).

Treatment of Positive Symptoms

Available data indicate that in prodromal and first-episode patients, positive symptoms, including hallucinations and delusions, will usually remit with antipsychotic treatment. Thus, clinicians should expect remission of positive symptoms in prodromal and first-episode patients. A series of adequate trials of available agents should be employed with this goal in mind. If residual symptoms persist, a trial of clozapine or the addition of adjunctive treatments should be considered.

Treatment of Negative and Cognitive Symptoms

While positive symptoms in first-episode patients tend to respond well to antipsychotic drug treatment, negative and cognitive symptoms of schizophrenia generally take longer to respond or are less responsive to antipsychotic medications (Kopala et al., 1996; Sanger et al., 1999; Scottish Schizophrenia Research Group, 1987). This indicates that negative and cognitive symptoms may have a different time course for response than positive symptoms or that the relative refractoriness of negative and cognitive symptoms may contribute to the less than optimal functional recovery that is often observed in first-episode patients. Improving treatments for negative and cognitive symptoms in the first episode of schizophrenia is an area of major importance in future research and drug development efforts, especially since these symptoms likely affect these patients' functional abilities.

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Adjunctive Treatments of Residual Symptoms and Comorbid Syndromes

Often antipsychotic medications are insufficient by themselves to achieve full symptom remission and functional recovery in early-stage schizophrenia patients. For these reasons, a variety of adjunctive treatments both pharmacologic and nonpharmacologic can be used to enhance and optimize treatment response. Adjunctive treatments have different roles in the management of first-episode schizophrenia, targeting residual symptoms and treating comorbid syndromes. A clinical approach to treatment-refractory, first-episode schizophrenia, as described in a recent manual on first-episode schizophrenia, should include the strategies that promote medication adherence, attention to substance abuse, sequential trials of antipsychotic agents, or dose adjustment if clinical improvement is not seen by 6 to 12 weeks of treatment, and consideration of clozapine even early in the course of treatment (Edwards & McGorry, 2002).

While not yet systematically studied in prodromal or first-episode patients, data from studies in chronic patients suggest that cognitive therapy also may benefit residual symptoms (Cormac et al., 2002). Even given the lack of specific trials in first-episode patients, it is likely that CBT may have a role in the treatment of prodromal and first-episode schizophrenia, especially in helping patients to comply with treatment and the transition to outpatient care.

Adjunctive treatments that have been studied in the treatment of schizophrenia include benzodiazepines, anticonvulsants, and antidepressants. Benzodiazepines are often used as adjuncts to antipsychotics in acute schizophrenia. There have been no controlled studies of benzodiazepines in groups of first-episode patients with schizophrenia. Literature on mixed populations of patients with schizophrenia suggest overall that benzodiazepines have a role in treating agitation, anxiety, and aggression in patients with acute psychosis (Barbee, Mancuso, Freed, & Todorov, 1992; Battaglia et al., 1997; Kellner, Wilson, Muldawer, & Pathak, 1975; Salzman et al., 1991) and in preventing an impending psy chotic relapse (Carpenter, Buchanan, Kirkpatrick, & Breier, 1999).

Mood stabilizers, including anticonvulsants and lithium, are widely used in patients with schizophrenia (Citrome, Levine, & Allingham, 2000), and there is some evidence that they may also have a role in reducing aggression and agitation (Christison, Kirch, & Wyatt, 1991; Ko, Korpi, Freed, Zalcman, & Bigelow, 1985; Leucht, McGrath, White, & Kissling, 2002; Linnoila & Viukari, 1979; Wassef et al., 2000). Although there is no evidence as to their efficacy in early stage patients, mood stabilizers should be considered for patients who have mood symptoms of excitement and mood lability during residual to the prodromal and first episodes of schizophrenia.

Depressive syndromes are common in prodromal and first-episode patients. Patients who ultimately manifest symptoms of schizophrenia often report a previous depressive episode (Hafner, Loffler, Maurer, Hambrecht, & an der Heiden, 1999) or suicide attempt in their prodromal period (Cohen, Lavelle, Rich, & Bromet, 1994). On presentation with an acute psychotic episode, first-episode patients often have mood symptoms (Addington, Addington, & Patten, 1998). Depressive symptoms will often resolve as psychotic symptoms remit (Koreen et al., 1993), however, in some cases they may persist or occur in the episode's aftermath (“postpsychotic depression”). Antidepressants should be used cautiously in prodromal and first-episode schizophrenia as they could possibly provoke or exacerbate psychotic symptoms. In addition, residual negative symptoms that persist after the stabilization of the acute episode may respond to antidepressant treatment (Berk, Ichim, & Brook, 2001; Hogarty et al., 1995; Silver, Barash, Aharon, Kaplan, & Poyurovsky, 2000; Silver & Nassar, 1992).

Suicidal behavior can occur in prodromal and first-episode schizophrenia patients (Steinert, Wiebe, & Gebhardt, 1999). While depression in the presenting psychotic episode or in the postpsychotic period is an important risk factor for suicide (Axelsson & Lagerkvist-Briggs, 1992), prodromal and first-episode patients with schizophrenia may attempt suicide in the ab

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sence of prominent depressive symptoms as a result of hallucinations, paranoia, disorganization, or other symptoms considered more primary to psychosis or other factors. Mounting literature supports the use of clozapine (Meltzer et al., 2003; Meltzer & Okayli, 1995; Reid, Mason, & Hogan, 1998; Sernyak, Desai, Stolar, & Rosenheck, 2001) in patients with psychotic disorder and suicidal behaviors. Although use of clozapine in first-episode schizophrenia has been studied recently (Lieberman, Gu, et al., 2003), it is not considered at this time a first-line drug for first-episode schizophrenia. It should be considered early in the course of treatment only in patients who are unresponsive to other second-generation antipsychotic drugs.

Another important comorbid syndrome in the treatment of first-episode schizophrenia is substance abuse with its possible role in lowering initial vulnerability to the onset or recurrence of psychosis (Chouljian et al., 1995; DeQuardo, Carpenter, & Tandon, 1994; Gupta, Hendricks, Kenkel, Bhatia, & Haffke, 1996; Hambrecht & Hafner, 2000; Linszen, Dingemans, & Lenior, 1994; Rabinowitz et al., 1998). Thorough evaluations of substance abuse habits of prodromal and first-episode schizophrenia patients are critical to directing appropriate clinical attention to this issue throughout care of the patient.

Treatment After Remission of Symptoms in Prodromal and First-Episode Schizophrenia

Continuation and Maintenance Treatment

As the symptomatic response to treatment of young early stage patients is generally very good, clinicians should expect and aim for achieving maximal remission of symptoms, recognizing that psychosis may resolve first and then negative and cognitive symptoms. Residual symptoms should be targeted with adjunctive therapies as needed. After achieving optimal treatment response, the next goal of treatment is to maximize the functional recovery of patients. To an extent, this is dependent on the resolution of symptoms but may not necessarily occur fully concurrently with symptom remission. Maximization of functional recovery involves the use of adjunctive pharmacologic treatments for any residual symptoms but then various nonpharmacologic treatments to enhance functional recovery. These may include psychoeducation about the nature of the illness, supportive psychotherapy, supported employment, social and vocational rehabilitation, and case management. We think of many of these psychosocial interventions as being associated with the care of chronic patients; however, they can and should also be adapted to young early-stage patients. It is also important to keep in mind that it is necessary to be patient and not rush patients prematurely into the activities with which they may have been previously engaged.

The need for interventions aimed at achieving functional recovery is reflected by the results of outcome studies in first-episode patients. Although patients typically recover from a first episode of schizophrenia, the long-term course for most patients is still characterized by chronic illness, disability, and relapse. Studies report that a minority of patients, about 15% to 20%, will maintain good symptomatic and functional recovery from a first episode. For example, in a study of 349 patients followed up to 15 years after their first onset of schizophrenia, 17% had no disability at follow-up, whereas 24% still suffered from severe disability, and the remaining 69% had varying degrees of disability (Wiersma et al., 2000; Wiersma, Nienhuis, Sloof, & Giel, 1998). The long-term prognosis of patients in the pre-antipsychotic era is similar, with about 20% of patients having good symptomatic and functional recovery (Bleuler, 1978). In a study of first-episode patients with operationally defined criteria for recovery (a period of 2 years of remission of positive and negative symptoms, fulfillment of age-appropriate role expectations, performance of daily living tasks without supervision, and engagement in social interactions), 16.8% of the 118 patients achieved full functional recovery (Robinson et al., 1999b). However, a recent study of 1,633 patients with psychotic disorders from diverse cultures found more optimistic rates of favorable outcome, with nearly half of the patients with schizophrenia considered to be recovered (Harrison et al., 2001).

The next question in the clinical management

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of prodromal and first-episode patients is, after achieving maximal therapeutic response, how long should treatment (particularly pharmacologic treatment) be continued? There are not sufficient data to answer that question in prodromal patients. Thus, treatment of prodromal symptoms should be considered time limited and aimed at alleviating current symptoms and stabilizing the patient. There is a growing body of evidence on first-episode patients, however, that suggests the value of continuing medication for a sustained and possibly indefinite period. Ideally, this decision would be informed by data from prospective, controlled studies answering the following questions: (1) How likely is relapse with and without antipsychotic medication? (2) Is it possible to predict who will relapse after remission of a first episode? (3) Will antipsychotic therapy improve the course and long-term outcome of the illness or merely suppress symptoms in the short to medium term? Table 6.3 summarizes the six controlled studies of maintenance antipsychotic treatment of remitted first-episode schizophrenia (Crow, MacMillan, Johnson, & Johnstone, 1986; Gitlin et al., 2001; Kane, Rifkin, Quitkin, Nayak, & Ramos-Lorenzi, 1982; McCreadie et al., 1989; Nuechterlein et al., 1994).

The risk of eventual relapse after recovery from a first psychotic episode is very high and is greatly diminished by maintenance antipsychotic treatment. However, even with strong evidence of the risk of relapse without antipsychotic medication, there is still no clear consensus on the recommended duration of treatment for patients who have recovered from a first episode of schizophrenia. Clinicians may have a difficult time convincing patients who have recovered from one episode of schizophrenia that indefinite and possibly lifelong antipsychotic treatment is indicated because of the diagnostic uncertainty and instability associated with a first psychotic episode (Amin et al., 1999), limited patient understanding and awareness of the illness (Thompson, McGorry, & Harrigan, 2001), and risks of long-term antipsychotic therapy. Most practice guidelines for the treatment of patients with schizophrenia recommend that patients who have had only one episode of positive symptoms and have been symptom-free during the subsequent year of maintenance therapy can be considered for a trial period without medication, provided that dose reductions are made gradually over several months with frequent visits (Rose, 1997). Similarly, the Schizophrenia Patient Outcomes Research Team (Lehman & Steinwachs, 1998) recommended in their report that patients continue treatment for at least 1 year after remission of acute symptoms, with continual reassessment of the maintenance dose for possible reduction. The draft consensus statement of 26 international consultants (Addington, 2002) recommends taking into consideration the severity of the first episode when deciding how long to continue maintenance treatment. They suggest that patients who achieve full remission be offered gradual withdrawal of medication after 12 months of maintenance treatment, but that patients experiencing more severe episodes and are slow to respond be maintained for 24 months. This panel further suggests that patients who respond incompletely to medication, but clearly benefit from treatment, be maintained for 2 to 5 years on medication.

Conclusion

Patients in the prodromal phase or first episode of schizophrenia respond very favorably to antipsychotic treatment in terms of their positive symptoms. However, cognitive and negative symptoms are often slower to respond or are refractory to treatment, leaving many of these individuals with significant social disability. Sequential trials of adequate dose and duration of antipsychotics and adjunctive treatments should be employed to help patients achieve their optimal response. Psychosocial therapies such as CBT and education groups may be helpful in addressing residual symptoms and helping patients to adhere to their medication regimens.

In addition to lessening the morbidity of the presenting episode, early intervention in prodromal and first-episode schizophrenia may improve the long-term course of the disorder, as evidenced by studies showing an inverse correlation between the duration of untreated psychosis and outcome. The outcome of schizo

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Table 6.3 Studies of Maintenance Treatment in First-Episode Schizophrenia

Reference	Population	Inclusion/Exclusion	Design/Protocol	Relapse Criteria	Relapse Rates
Kane et al. 1982	28 patients referred for aftercare with a diagnosis of a single episode of schizophrenia; 19 of 28 patients met RDC criteria for schizophrenia	1.At least 4 weeks of remission 2.1 year or less since hospitalization 3.No treatment prior to 3 months before hospitalization 4.No evidence of drug abuse, alcoholism, or important medical illness	Double-blind, 1-year duration Random assignment to fluphenazine hydrochloride (5–20 mg/day), fluphenazine decanoate (12.5–50 mg/2 weeks) or placebo. Only patients thought to have possible compliance problems were randomized to decanoate. Procyclidine hydrocholoride for all patients, with substitution of placebo in second month for placebo patients	Substantial clinical deterioration with a potential for marked social impairment Patients were considered dropouts only if they showed no clinical deterioration at the time they left the study	For all patients: 0% (0 out of 11) on fluphenazine and 41% (7 out of 17) on placebo relapsed Of those with RDC schizophrenia: 0% (0 out of 6) on fluphenazine and 46% (6 out of 13) on placebo relapsed Follow-up with 26 patients (mean interval of 3.5 years): 69% had a second relapse; 54% had a third relapse
Crow et al., 1986	120 patients diagnosed with first-episode schizophrenia, recruited from both psychiatric and district general practices in Harrow, England	1.Age 15–70 years 2.Suffering from a first psychotic episode that was “not unequivocally affective” 3.Admission to an inpatient psychiatric unit for at least 1 week 4.Clinical diagnosis of schizophrenia 5.Absence of organic disease of probable etiological significance	Drugs [fluphenthixol (40 mg/month IM), chlorpromazine (200 mg/day orally), haloperidol (3 mg/day orally), pimozide (4 mg/day), or trifluoperazine (5 mg/day)] chosen by clinicians, then patients randomized to either drug or placebo 1 month after remission of initial episode Adjunctive medications allowed	Psychiatric readmission for any reason; readmission deemed necessary by treating clinician, but not possible; or active antipsychotic medication considered to be essential because of features of imminent relapse Relapse determinations made by treating clinicians	Actuarial relapse rates: 6 months: placebo 43%, drug 21%; 12 months: placebo 63%, drug 38%; 18 months: placebo 67%, drug 46%; 24 months: placebo 70%, drug 58%
Scottish Schizophrenia Research Group, 1987	15 patients who had suffered a first episode of schizophrenia	Patients had to respond to acute treatment and then be relapse-free for an additional year of treatment on either once-weekly pimozide or IM fluphenthixol decanoate	Double-blind trial of active medication (either once-weekly pimozide or IM fluphenthixol decanoate) or placebo for 1 year	Deterioration in schizophrenia symptoms or behavior sufficient to warrant patient's withdrawal from study	0% (0 out of 8) of the patients who received active drug, but 57% (4 out of 7) who received placebo were readmitted in second year of study treatment
Nuechterlein et al., 1994	106 patients from four public hospitals and an outpatient clinic of an academic medical center 66% had never taken antipsychotic medication and the remainder had a mean duration of treatment of 2.7 months (SD = 3.1)	Inclusion: recent-onset psychotic symptoms lasting at least 2 weeks and not more than 2 years, age 18–45 years, and RDC diagnosis of schizophrenia or schizoaffective disorder (mainly schizophrenia) Exclusions: known neurological disorder, recent significant substance abuse, or African-American descent^a	Phase I: stabilized patients were treated with 12.5 mg fluphenazine decanoate every 2 weeks for 12 months Phase II: those who remitted in Phase I were recruited into Phase II. They were treated for 12 weeks with either placebo or fluphenazine, followed by crossover to the opposite treatment	Operationally defined as a 2-point worsening on any three BPRS psychotic items, excluding changes where the scores remained at nonpsychotic levels; a score of 6 or 7 was obtained on any three items; or clinical deterioration warranting a change in treatment as judged by treating psychiatrist	Phase I: 11 patients needed to have dose lowered because of side effects and 6 were prescribed antidepressants Phase II: 6% (3 of 53 subjects) had a relapse while on active medication and 13% (7 out of 53) relapsed on placebo
Robinson et al., 1999b	104 patients who responded to treatment of their index episode of schizophrenia and were at risk for relapse	1.RDC-defined diagnosis of schizophrenia or schizoaffective disorder 2.Total lifetime exposure to antipsychotic medications of ≤12 weeks 3.Rating of ≥4 (moderate) on at least one psychotic symptom item on SADS−C+PD 4.No medical contraindications to treatment with antipsychotic medications 5.No neurologic or endocrine disorder or neuromedical illness that could affect diagnosis or biological variables in study	Patients were treated openly according to a standard algorithm, progressing from one phase of the algorithm to the next until they met response criteria. The sequence was initial treatment with fluphenazine, then haloperidol, then lithium augmentation, then molindone hydrochloride or loxapine, then clozapine	At least “moderately ill” on the CGI Severity of Illness Scale, “much worse” or “very much worse” on the CGI Improvement Scale, and at least “moderate” on one or more of the SADS-C+PD psychosis items listed above; these criteria had to be sustained for a minimum of 1 week	5-year overall relapse rate: 81.9%; the second relapse rate. By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2%. Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times
Gitlin et al., 2001	53 patients with RDC schizophrenia or schizoaffective disorder who had been stabilized for 1 year on fluphenzine decanoate	Patient who completed Phase II of the Nuechterlein et al. study (above) and did not relapse	Open-label discontinuation of drugs	Two-point worsening on any three BPRS psychotic items, excluding changes where the scores remained at nonpsychotic levels, a score of 6 or 7 was obtained on any three items, or the treating psychiatrist deemed that there was clinical deterioration warranting change in treatment	78% relapsed by 1 year and 96% by 2 years with low threshold for relapse. Only 13% required hospitalization

^a Excluded because of differences in electrodermal conductivity from other groups because this was a biological variable being studied.

BRPS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; IM, intramuscular; RCT, randomized control trial; RDC, Research Diagnostic Criteria; SADS-C+PDI, Schedule for Affective Disorders and Schizophrenia Change Version with Psychosis and Disorganization Items rating scale; SD, standard deviation.

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doi:10.1093/9780195173642.003.0007