Rathbone Hospital, Mill Lane, Liverpool
Correspondence: Dr L. Williams, Hesketh Centre, 51-55 Albert Road, Southport PR9 0LT, UK
Clozapine is widely regarded as the gold standard treatment for treatment-resistant schizophrenia, after failure of two anti-psychotics at adequate doses for an adequate duration of time. However, even after 1 year, a number of patients fail to respond to clozapine alone. We question the term treatment-resistant, which implies that little further can be done and generates therapeutic nihilism, and instead suggest the term neuroleptic-resistant schizophrenia as a more positive alternative. In this editorial we suggest a number of treatment options for patients resistant to clozapine monotherapy, and hope to generate a fresh and positive approach.
Confirming neuroleptic-resistant schizophrenia
Before discussing possible treatment options, the importance of a thorough
assessment and review of the diagnosis must be emphasised. In addition, the
identification of perpetuating factors such as comorbid drug use or
non-compliance should be addressed. Clozapine plasma concentration monitoring
should be performed to investigate the latter, and should be used frequently
as a guide to assessing outcome of interventions where a sub-therapeutic
clozapine concentration is recognised.
TREATMENT STRATEGIES: MEDICATION
Antipsychotics
When antipsychotic monotherapy with clozapine fails, combination strategies
to enhance the antipsychotic effect of clozapine can be considered. Shiloh
et al (1997) have
conducted the only randomised controlled trial to date. They showed that,
compared with placebo, sulpiride augmentation of clozapine produced a
reduction in psychotic symptoms at 10 weeks. Other smaller, open studies have
shown clinical improvement using pimozide
(Friedman et al,
1997) or loxapine (Mowerman
& Siris, 1996) in conjunction with clozapine.
Atypical antipsychotic drugs also have been used for augmentation, although all the reports to date are case reports or small, open studies. Gupta et al (1998) reported two cases of patients who made good progress after olanzapine was added. Further studies have reported good responses when risperidone was added to clozapine (Morera et al, 1999; Raskin et al, 2000). Although some authors have attempted to use other atypical antipsychotics after clozapine has failed, because of either non-response or intolerance (Weiss et al, 1999; Dossenbach et al, 2000; Wahlbeck et al, 2000), it appears that such approaches may be unjustified (Chakos et al, 2001; Tuunainen et al, 2001).
Antidepressants
There have been several reports describing the augmentation of clozapine
with a selective serotonin reuptake inhibitor (SSRI). Evidence is unconvincing
except as a result of the increased clozapine serum level using the
SSRIclozapine interaction. Buchanan et al
(1996) found no effect on
positive or negative symptoms with the addition of fluoxetine to clozapine.
Therapeutic use of this interaction should be considered only when compliance
is assured, maximal dosing has been achieved and the serum level is below 350
ng/ml. It should be attempted cautiously and with regular monitoring of plasma
levels. When adding an SSRI, the dose of clozapine should be reduced in
anticipation of the likely rise in plasma concentrations. Five- to tenfold for
fluvoxamine (Koponen et al,
1996) and approximately twofold for fluoxetine and paroxetine
(Centorrino et al,
1994). This interaction may be useful clinically, but use of it to
reduce drug costs is not advisable
(Markowitz et al,
1996).
Mood stabilisers
Valproate is suggested as the anticonvulsant of choice for
clozapine-induced seizures (Novartis
Pharmaceuticals UK Ltd, 1998). Valproate may be effective in
managing refractory psychotic or manic symptoms in addition to seizure
prophylaxis, although combination with clozapine is not specifically mentioned
(Kando et al,
1994).
Both carbamazepine and lamotrigine have been used in combination with clozapine but are not recommended because both drugs have the potential to depress bone marrow function. However, despite these risks, Dursan et al (1999) describe some benefits following the addition of lamotrigine to clozapine.
Electroconvulsive therapy
Electroconvulsive therapy (ECT) has been used in combination with clozapine
and has been found to be safe and clinically beneficial
(Bonator et al, 1996;
Bhatia et al, 1998).
Combining ECT and clozapine also has been described for achieving rapid
control of disturbed behaviour, when time would not allow for dose titration
with clozapine as monotherapy (James &
Gray, 1999). However, the improvement with this combination may
not be sustained after ECT is discontinued
(Kales et al,
1999).
TREATMENT STRATEGIES: PSYCHOSOCIAL APPROACHES
There is a growing body of evidence for the effectiveness of psychosocial treatment approaches in psychosis. The majority of studies are not specific to clozapine resistance but may be useful in guiding strategies for such patients. However, Pinto et al (1999) have conducted a small randomised controlled trial demonstrating that clozapine plus cognitivebehavioural therapy was superior to clozapine plus supportive psychotherapy.
Working with systems
Knowing that some patients continue to suffer enduring symptoms, in spite
of treatments such as clozapine, challenges mental health service providers.
Effective treatment relies on a diversity of approaches, delivered by a
multi-disciplinary team as a clearly defined care package. The increased
awareness of the importance of psychosocial approaches in psychosis has been
accompanied by the development of staff training courses. The Thorn Nursing
Initiative (Gamble, 1995) was
the first systematic training course for mental health professionals working
in the community. Good outcomes included reductions in positive symptoms and
an improvement in social functioning
(Lancashire et al,
1997). There is still a lack of such training in institutional
settings, and recent concerns have been expressed in The National
Visit regarding the deficiencies of care within in-patient settings
(Sainsbury Centre for Mental Health &
Mental Health Act Commission, 1997).
As a result of high expressed emotion attitudes found in nurses working with patients with chronic psychosis (Herzog, 1998), training within in-patient settings has been undertaken. Finnema et al (1996) found that their programme led to general changes in the ward atmosphere, such as a decrease in ward rules. We have used a combined psychoeducational and therapeutic training approach, which produced positive results on levels of knowledge and stress among staff (further details available from the author upon request).
Working with individuals
General principles
In the past it was thought that psychological therapies were
contraindicated in psychosis, but studies such as the LondonEast Anglia
study (Garety et al,
1997; Kuipers et al,
1997,
1998) have shown that this is
not the case, with good outcomes following 9 months of therapy and at 18-month
follow-up. In addition, for both positive and negative symptoms of
schizophrenia there is good evidence to support psychological approaches, such
as manualised cognitivebehavioural therapy
(Sensky et al, 2000).
Usually, a lengthy assessment period is required before a detailed formulation
can be developed. This should lead to specific interventions related directly
to the formulation. However, those patients who are resistant to clozapine are
among the most severely disabled, both socially and emotionally, and any
psychosocial strategy undertaken will require a flexible approach.
Engagement
Kingdon & Turkington
(1998) describe two components
to engagement: coming to an understanding of why the person has developed
unusual beliefs; and providing credible alternative explanations. Specific
techniques used to promote engagement include using the patient's own words,
agreeing to disagree, avoidance of jargon and accepting the unlikely as
possible but unlikely, all of which supplement the general techniques of
warmth, empathy and unconditional positive regard. Tailoring the therapy to
the patient's particular needs may include short, frequent sessions. The use
of a normalising rationale, which reframes a person's psychotic experiences
into understandable and explainable terms, reduces the anxiety and distress
associated with psychotic symptoms.
Positive symptoms
Treatment for positive symptoms is well researched and has been described
elsewhere in detail (Chadwick et
al, 1996; Dickerson,
2000) and therefore will not be covered in depth here. However,
because negative symptoms and thought disorder are often more problematic in
this patient group, their treatment has been described.
Therapy for thought disorder
Working with patients with thought disorder is challenging, but there are
techniques that may be helpful, such as keeping sessions short. Just spending
time with the person is important, as he or she may have had many years of not
being understood and being avoided by others. Themes emerge in apparently
unintelligible speech during regular sessions, and tape-recording can help.
Once themes have been identified, the patient is helped to focus on them in a
structured way before moving on to problem-solving, reframing or
reality-testing where appropriate. If able, the person may get some control
over his or her speech by writing the thoughts down.
Negative symptoms
Careful assessment of negative symptoms is required, because they are
likely to co-exist with other problems, such as side-effects of medication,
depression or institutionalisation. The pace of the interview needs to be
slow, to give the patient time to respond. Clear, simple, open questions will
promote the development of the therapeutic relationship, and writing down key
points can help the patient to recall the sessions. Modification of the
environment has been shown to be very effective for patients with negative
symptoms (Wing & Brown,
1970). Other simple techniques include activity-scheduling, rating
mastery and pleasure, and social skills training
(Hogg, 1996).
Early warning signs
Many individuals can identify their own idiosyncratic, prodromal signs of
relapse. It is useful to map the exacerbation of symptoms and correlate these
with potential personal and environmental stressors that may precipitate
deterioration. Birchwood et al
(1989) used early warning sign
questionnaires with patients and staff. Patients can often link feeling worse,
or being more concerned about their psychotic symptoms, with environmental
factors.
Dealing with hopelessness
Clozapine-resistant patients generally have long psychiatric histories.
They have received many psychotropic drugs and often have lost faith in
medication. Clozapine may be described as the last chance of obtaining relief
from psychotic symptoms, and the patient may have high expectations. If
clozapine fails to live up to expectations, a sense of
hopelessness may be generated. Therefore, it is particularly important to deal
with such feelings in patients, families and carers, as well as with the
negative impact on the person's self-esteem.
Compliance therapy
Kemp et al (1998)
conducted one of the few randomised controlled trials of compliance therapy
for patients with mental health problems. Although the intervention was
complex, it led to improvements in insight, attitude to medication and
compliance. However, there was little effect on functioning. Important
components include: conceptualising the problem, focusing on symptoms and
side-effects, exploring benefits and drawbacks of treatment, exploring
ambivalence, highlighting discrepancies between actions and beliefs, focusing
on adaptive behaviours, encouraging self-efficacy, and emphasising the value
of staying well and the importance of treatment.
Working with families
Family interventions are effective in reducing the likelihood of relapse in
psychosis. Early work examined the association between high expressed emotion
among caregivers and poor clinical outcome following discharge
(Vaughn & Leff, 1976).
Manualised approaches to family work are now available
(Barrowclough & Tarrier,
1992). Key features of such interventions include education,
enhancing problem-solving and coping strategies and an emphasis on
communication styles between family members.
Families are likely to have had lengthy contact with services that may not all have been positive. They may have received unclear or conflicting information in the past and may require a period to offload their concerns. Regular family sessions to improve communication between professionals and families may, in itself, prove an effective way of reducing the stress and burden felt by families.
DISCUSSION
One of the biggest problems in managing treatment-resistant patients is therapeutic nihilism, and this is likely to increase after an unsuccessful trial of clozapine monotherapy. Although, by definition, patients must be treatment-resistant to be eligible for clozapine, treatment encompasses many therapeutic strategies that can be successful within this group, and therefore we suggest the term neuroleptic-resistant. Clozapine should not be viewed as a last ditch attempt; it is a stepping stone to further treatments.
The treatments proposed require a staff group with skills, time and appropriate organisational structures to support such complicated care packages. The choice of treatment should be applied on an individual basis. It should be implemented following an in-depth assessment, as part of a multi-disciplinary care plan, and the effects of the interventions should be monitored objectively. Although various treatment strategies exist and may be used in this group, few firm conclusions can be drawn from the current literature. Many of the strategies suggested in the literature take the form of case reports and open studies. Few randomised controlled trials exist, and in the climate of evidence-based practice there is still much research to be done. However, there are encouraging results from the use of psychological therapies with patients with a diagnosis of schizophrenia and there is considerable scope for adapting these therapies in patients who are resistant to clozapine monotherapy, justifying a more positive approach.
REFERENCES
Barrowclough, C. & Tarrier, N. (1992) Families of Schizophrenic Patients: Cognitive Behavioural Interventions. London: Chapman & Hall.
Bhatia, S. C., Bhatia, S. K. & Gupta, S. (1998) Concurrent administration of clozapine and ECT: a successful therapeutic strategy for a patient with treatment-resistant schizophrenia. Journal of Electroconvulsive Therapy, 14, 280-283.[Medline]
Birchwood, M., Smith, J., MacMillan, F., et al (1989) Predicting relapse in schizophrenia: the development and implementation of an early signs monitoring system using patients and families as observers. Psychological Medicine, 19, 649-656.[Medline]
Bonator, R., Sirota, P. & Megged, S. (1996) Neuroleptic-resistance schizophrenia treated with clozapine and ECT. Convulsive Therapy, 12, 117-121.[Medline]
Buchanan, R. W., Kirkpatrick, B., Bryant, N., et al (1996) Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. American Journal of Psychiatry, 153, 1625-1627.[Abstract]
Centorrino, F., Baldessarini, R. J., Kando, J., et al (1994) Serum concentrations of clozapine and norclozapine in patients treated with selective serotonin reuptake inhibitors. American Journal of Psychiatry, 151, 123-125.[Abstract]
Chadwick, P., Birchwood, M. & Trower, P. (1996) Cognitive Therapy for Delusions, Voices and Paranoia. Chichester: John Wiley & Sons.
Chakos, M., Liberman, J., Hoffman, E., et al
(2001) Effectiveness of second-generation antipsychotics in
patients with treatment-resistant schizophrenia: a review and meta-analysis of
randomised trials. American Journal of Psychiatry,
158,
518-526.
Dickerson, F. B. (2000) Cognitive behavioural psychotherapy for schizophrenia: a review of recent empirical studies. Schizophrenia Research, 43, 71-90.[CrossRef][Medline]
Dossenbach, M. R. K., Beuzen, J. N., Avnon, M., et al (2000) The effectiveness of olanzapine in treatment-refractory schizophrenia when patients are non-responsive to or unable to tolerate clozapine. Clinical Therapeutics, 22, 1021-1034.[CrossRef][Medline]
Dursan, S. M., McIntosh, D. & Milliken, H.
(1999) Clozapine plus lamotrigine in treatment resistant
schizophrenia (letter). Archives of General
Psychiatry, 56,
950.
Finnema, E. J., Willem, J., Sloof, C. J., et al (1996) Expressed emotion on long stay wards. Journal of Advanced Nursing, 24, 473-478.[Medline]
Friedman, J., Ault, K. & Powchik, P. (1997) Pimozide augmentation for the treatment of schizophrenic patients who are partial responders to clozapine. Biological Psychiatry, 42, 522-523.[CrossRef][Medline]
Gamble, C. (1995) The Thorn Nursing Initiative. Nursing Standard, 9, 31-34.
Garety, P., Fowler, D., Kuipers, E., et al (1997) LondonEast Anglia randomised controlled trial of cognitivebehavioural therapy for psychosis. II: Predictors of outcome. British Journal of Psychiatry, 171, 420-426.[Abstract]
Gupta, S., Sonnenberg, S. J. & Frank, B. (1998) Olanzapine augmentation of clozapine. Annals of Clinical Psychiatry, 10, 113-115.[CrossRef][Medline]
Herzog, T. (1998) Nurses, patients and relatives: a study of family patterns on psychiatric wards. In Family Intervention in Schizophrenia: Experiences and Orientation in Europe (eds C. L. Cazzullo & G. Invernizzi). Milan: ARS.
Hogg, L. (1996) Psychological treatments for negative symptoms. In Cognitive Behavioural Interventions with Psychotic Disorders (eds G. Haddock & P. D. Slade), pp. 151-167. London: Routledge.
James, D. V. & Gray, N. S. (1999) Elective combined electroconvulsive and clozapine therapy. International Clinical Psychopharmacology, 14, 69-72.[Medline]
Kales, H. C., Dequardo, J. R. & Tandon, R. (1999) Combined electroconvulsive therapy and clozapine in treatment resistant schizophrenia. Progress in Neuropsychopharmacology and Biological Psychiatry, 23, 547-556.[CrossRef][Medline]
Kando, J. C., Tohen, M., Castillo, J., et al (1994) Concurrent use of clozapine and valproate in affective and psychotic disorders. Journal of Clinical Psychiatry, 55, 255-257.
Kemp, R., Kirov, G., Everitt, B., et al (1998) Randomised controlled trial of compliance therapy. 18-month follow-up. British Journal of Psychiatry, 172, 413-419.[Abstract]
Kingdom, D. & Turkington, D. (1998) Cognitive behaviour therapy of schizophrenia. In Outcome and Innovation in Psychological Treatment of Schizophrenia (eds T. Wykes, N. Tarrier & S. Lewis), pp. 59-79. New York: John Wiley & Sons.
Koponen, H. J., Leinonen, E. & Lepola, U. (1996) Fluvoxamine increases the clozapine serum levels significantly. European Neuropsychopharmacology, 6, 69-71.[CrossRef][Medline]
Kuipers, E., Garety, P., Fowler, D., et al (1997) LondonEast Anglia randomised controlled trial of cognitivebehavioural therapy for psychosis. I: Effects of the treatment phase. British Journal of Psychiatry, 171, 319-327.[Abstract]
Kuipers, E., Fowler, D., Garety, P., et al (1998) LondonEast Anglia randomised controlled trial of cognitivebehavioural therapy for psychosis. III: Follow-up of economic evaluation at 18 months. British Journal of Psychiatry, 173, 61-68.[Abstract]
Lancashire, S., Haddock, G., Tarnier, V., et al (1997) Effects of training in psychosocial interventions for community psychiatric nurses. Psychiatric Services, 48, 39-41.[Medline]
Markowitz, J. S., Gill, H. S., Lavia, M., et al (1996) Fluvoxamineclozapine dose-dependent interaction. Canadian Journal of Psychiatry, 160 (suppl. 17), 22-29.
Morera, A. L., Barreiro, P. & Cano-Munoz, J. L. (1999) Risperidone and clozapine combination for the treatment of refractory schizophrenia. Acta Psychiatrica Scandinavica, 99, 305-307.[Medline]
Mowerman, S. & Siris, S. G. (1996) Adjunctive loxapine in a clozapine-resistant cohort of schizophrenic patients. Annals of Clinical Psychiatry, 8, 193-197.[Medline]
Novartis Pharmaceuticals UK Ltd (1998) Clozaril® (clozapine) Summary of Product Characteristics. Camberley: Novartis Pharmaceuticals UK.
Pinto, A., La Pia, S., Mennella, R., et al
(1999) Cognitivebehavioural therapy and clozapine for
clients with treatment-refractory schizophrenia. Psychiatric
Services, 50,
901-904.
Raskin, S., Katz, G., Zislin, Z., et al (2000) Clozapine and risperidone combination/augmentation treatment of refractory schizophrenia: a preliminary observation. Acta Psychiatrica Scandinavica, 101, 334-336.[CrossRef][Medline]
Sainsbury Centre for Mental Health & Mental Health Act Commission (1997) The National Visit. London: Sainsbury Centre.
Sensky, T., Turkington, D., Kingdon, D., et al
(2000) A randomised controlled trial of
cognitivebehavioural therapy for persistent symptoms in schizophrenia
resistant to medication. Archives of General
Psychiatry, 57,
165-172.
Shiloh, R., Zemishlany, Z., Aizenberg, D., et al (1997) Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. British Journal of Psychiatry, 171, 569-573.[Abstract]
Tuunainen, A., Wahlbeck, K. & Gilbody, S. M. (2001) Newer atypical antipsychotic medication versus clozapine for schizophrenia. Cochrane Library, issue 3. Oxford: Update Software.
Vaughn, C. E. & Leff, J. P. (1976) The influence of family and social factors on the course of psychiatric illness. A comparison of schizophrenic and depressed neurotic patients. British Journal of Psychiatry, 129, 125-137.[Abstract]
Wahlbeck, K., Cheine, M., Tuisku, K., et al (2000) Risperidone versus clozapine in treatment-resistant schizophrenia: a randomised pilot study. Progress in Neuropsychopharmacology and Biological Psychiatry, 24, 911-922.[CrossRef][Medline]
Weiss, E. L., Longhurst, J. G., Bowers, M. B., Jr., et al (1999) Olanzapine for treatment-refractory psychosis in patients responsive to, but intolerant of, clozapine. Journal of Clinical Psychopharmacology, 19, 378-380.[CrossRef][Medline]
Wing, J. K. & Brown, G. W. (1970) Institutionalism and Schizophrenia. Cambridge: Cambridge University Press.
Received for publication July 23, 2001. Revision received February 25, 2002. Accepted for publication February 25, 2002.
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