Refractory Psychosis: Treatment Options and Strategies

Jan 20, 2014

Psychosis is one of the key dimensions of schizophrenia, bipolar disorder, and psychotic depression. Clinicians are familiar with patients whose psychosis improves dramatically with antipsychotic treatment; however, these patients may be left with cognitive impairment, negative mood symptoms, or suicidal symptoms, as well as impaired work and social functioning.

Premiere Date: January 20, 2014Expiration Date: January 20, 2015 [Expired]

This activity offers CE credits for:
1. Physicians (CME)
2. Other

Activity Goal

This article provides strategies for assessing and treating refractory psychosis in patients with schizophrenia.

Learning Objectives

At the end of this CE activity, participants should be able to:

1. Assess refractory psychosis.

2. Recognize the causes of refractory psychosis.

3. Describe how to treat refractory psychosis in patients with schizophrenia.

Target Audience

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

Credit Information

CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™.

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It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Herbert Y. Meltzer, MD, reports that he is a shareholder of ACADIA(pimavanserin) and AstraZeneca. He receives, or has received, grant support from, or is a consultant to, ACADIA, Alkermes, Astellas, Bristol-Myers Squibb, Eli Lilly, EnVivo, Janssen, Novartis, Otsuka, and Teva.

Cameron Carter, MD (peer/content reviewer), has no disclosuresto report.

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Psychosis is one of the key dimensions of schizophrenia, bipolar disorder, and psychotic depression. Delusions of various types and auditory or visual hallucinations are core psychotic symptoms. Unlike cognitive impairment in schizophrenia, an enduring feature, psychotic symptoms are intermittent in both schizophrenia and mood disorders with psychotic features. Treatment of psychotic symptoms with antipsychotic drugs is often effective. Moreover, remission of psychotic symptoms can occur as a result of diminished stress, cessation or treatment of substance abuse, and supportive treatments.

Psychosis, sometimes refractory to standard antipsychotic treatment, is also a feature of a large body of neurological disorders, such as Huntington chorea, Parkinson disease, Alzheimer disease, and other dementias. Thought disorder (disorganized thinking) is sometimes included in the list of psychotic symptoms, but it is more closely associated with cognitive impairment than with delusions and hallucinations in course and severity. Improvement in delusions or hallucinations with antipsychotic treatment does not necessarily predict improvement in disorganized thinking. This article focuses on refractory psychosis characterized by delusions and hallucinations.

Psychosis has been established as an independent dimension of psychopathology in patients with schizophrenia, most likely with a pathobiology different from other key dimensions, such as negative symptoms, cognitive impairment, mood symptoms, suicidal behaviors, obsessive-compulsive symptoms, and anxiety. This independence is consistent with the virtual absence of any correlations between severity of psychosis and the other dimensions mentioned above, whether assessed at first clinical encounter, entry into controlled clinical trials, or as a small amount of shared variance in clinical change in these dimensions during longitudinal assessments.

Clinicians are familiar with patients whose psychosis improves dramatically with antipsychotic treatment; however, these patients may be left with cognitive impairment, negative mood symptoms, or suicidal symptoms, as well as impaired work and social functioning. In the InterSept study, in which clozapine was found to be superior to olanzapine in preventing suicidal behaviors in patients with refractory and non-refractory schizophrenia or schizoaffective disorder, there was no relationship between treatment resistance, the severity of psychotic symptoms at baseline, the change in psychosis during treatment, and the anti-suicidal effect of clozapine or olanzapine.1

Assessing refractory psychosis

When faced with the challenge of devising a treatment plan for a patient who presents with persistent delusions and hallucinations, which may or may not be refractory, the following approach is recommended:

• Obtain a thorough history of the illness to establish the psychiatric diagnosis and the onset and response to treatment of delusions or hallucinations

• Exclude medical illnesses that might be responsible for the psychosis, through physical examination and appropriate laboratory testing

• Determine whether refractory psychotic symptoms were present during the first psychotic episode or, more likely, whether there had been a period of treatment responsiveness followed by intermittent or persistent refractory symptoms

• Compare current psychotic symptoms with those at earlier stages of the illness

• Ascertain which treatments have been tried and which were effective or ineffective

Reliable information may be extremely difficult to obtain without medical records and knowledgeable informants. When obtaining the history, it is important to be mindful that low (or excessive) dosages of antipsychotics, short duration of trials, medication nonadherence, and concomitant medications may have minimized the chances of a good response.

A previous trial of a long-acting injectable typical or atypical antipsychotic for 3 to 6 months may provide information that at least one adequate trial of an antipsychotic has, or has not, failed. If such a trial has never been attempted, a trial with an atypical long-acting injectable antipsychotic may be indicated before clozapine, the preferred treatment for refractory psychosis, is considered.2,3 The patient’s insight and his or her attitude toward the psychotic symptoms should be assessed to determine how motivated he or she is for treatment. It may be desirable to attempt to optimize the current treatment regimen before initiating a novel approach in patients who are treatment-refractory. This may mean optimizing the dosage and eliminating polypharmacy. A family history of psychiatric illness and information on which treatments were effective may provide a clue to treatment.

How common is refractory psychosis?

Fortunately, most psychosis in schizophrenia, bipolar disorder, and psychotic depression responds to antipsychotic treatment. The same is true for neurological disorders such as Huntington chorea. It is generally accepted that 70% of patients with schizophrenia and schizoaffective disorder have few or no psychotic symptoms following initiation of antipsychotic treatment at adequate dosages.2,3 However, about 30% of patients with schizophrenia, and many fewer with bipolar disorder, continue to have auditory or, sometimes, visual hallucinations and delusions of various kinds-most often paranoid or grandiose-despite at least two trials of antipsychotic drugs of adequate duration and dosage.

Emergence of refractory psychosis

Refractory psychosis can be present from the first episode, or it can develop after years of prolonged response to antipsychotic treatment with periods of remission. The cause of psychosis in those whose psychotic symptoms respond to typical antipsychotics may involve enhanced release of dopamine. The efficacy of haloperidol-like antipsychotics (typical antipsychotics) is likely the result of the blockade of limbic dopamine D2 receptors. However, the fact that weeks of treatment may be necessary even in some patients who respond, and in the 30% of those who do not, suggests that other mechanisms contribute to psychosis, including diminished stimulation of NMDA glutamate receptors, as well as mechanisms that may or may not involve excessive dopamine D2 receptor stimulation.4

Serotonin 2A receptor blockade has been shown to be a component of the action of atypical antipsychotics such as clozapine, the only drug approved for the treatment of refractory schizophrenia.2,5,6 Atypical antipsychotics are as effective as typical antipsychotics for the treatment of psychosis in most schizophrenic patients or of psychotic symptoms in patients with bipolar disorder.6-8 Other than clozapine, atypical antipsychotics do not treat positive symptoms any better or more rapidly than typical antipsychotics in non‒treatment-resistant patients with schizophrenia.7,9,10 Nevertheless, they carry less risk of tardive dyskinesia-an adverse effect that impairs cognition and increases morbidity and mortality. The only other class of atypical antipsychotics is the substituted benzamides.11 Although not used in the US, sulpiride and amisulpride are substituted benzamides currently used in many other parts of the world. However, there is no evidence for their efficacy in refractory schizophrenia.

It is well known that serotonin 2A receptor agonists, such as LSD (lysergic acid diethylamide), and other indole hallucinogens, such as psilocy-bin, can produce psychosis. It has recently been shown that the selective serotonin 2A inverse agonist, pimavanserin, is effective for L-dopa (L-3,4-dihydroxyphenylalanine) psychosis in patients with Parkinson disease and can augment and accelerate the antipsychotic effect of a sub-effective dose of the atypical antipsychotic risperidone in acutely psychotic patients with schizophrenia.12,13

NMDA receptor noncompetitive antagonists, such as phencyclidine (PCP) and ketamine, can induce, and may exacerbate, psychotic symptoms in patients with schizophrenia.4 Selective serotonin 2A inverse agonists such as pimavanserin and M100907 are more effective than haloperidol in blocking the psychotomimetic effects of PCP in laboratory animals.14 Patients whose psychotic symptoms have never responded to typical or atypical antipsychotics or later become refractory may represent unique subgroups within the psychotic spectrum disorders. Various genetic markers have been reported for these patients, but they remain to be verified and made available as laboratory tests.15


In the US Clozaril trial, clozapine was shown to be the first effective drug for refractory schizophrenia.2 This is now considered an established treatment paradigm.6 I have reviewed its optimal use in refractory schizophrenia and delineate the main points here. It is essential to discuss the special nature of clozapine and how it differs from other antipsychotic drugs. Key issues to be discussed before and during treatment include the need to:

• Increase the dosage to the average therapeutic range of 300 to 500 mg/d over 3 to 4 weeks; sometimes dosages up to 900 mg/d are necessary

• Anticipate adverse effects, such as tachycardia, hypersalivation, weight gain, drowsiness, myoclonic jerks, and seizures

• Have a plan to minimize or, if necessary, treat any emergent adverse effects

• Discontinue other antipsychotics before or during titration, recognizing that a slow taper may be needed in some patients

• Expect a trial of at least 6 months before determining the benefits of the drug

Furthermore, explain the benefits of clozapine-eg, an expected reduction in motor adverse effects and reduced risk of tardive dyskinesia-and discuss the necessity for adherence and the risk of relapse if clozapine is stopped abruptly. Maintaining adequate plasma levels of clozapine, which may require dosages of up to 900 mg/d, will more likely achieve symptom improvement.6 Not all patients will achieve symptom remission after a trial of clozapine monotherapy.6,16 A course of ECT, including maintenance ECT, is often the most effective means of augmenting clozapine.3,16 The addition of a second antipsychotic drug is rarely beneficial.

Clozapine is also effective for refractory bipolar disorder, but it is not effective for psychotic depression or other neurological disorders. More studies of this issue are needed. At this time, any use of clozapine for refractory psychosis associated with diagnoses other than schizophrenia or schizoaffective disorder should be considered off-label. This off-label experimental treatment is based on the judgment of the prescriber, and informed consent is needed from patients and their significant others or guardians; court-sanctioned approval may be necessary. Trials of up to 6 months are needed to identify all refractory patients who will respond to clozapine.17 Trials that last less than 6 months may miss 30% to 60% of potential responders.17

It is regrettable that many patients with refractory schizophrenia-let alone patients with other types of refractory psychoses-have never had a trial of clozapine. Many of these patients would likely be partial responders. Clinical predictors of who will respond are not robust enough to warrant bypassing a clozapine trial for a refractory schizophrenia patient. For those who respond partially to clozapine, many drugs have been tried as augmenting agents, but the results are generally disappointing.16 Pharmacological augmentation of clozapine with a second antipsychotic is controversial; in particular, little or no benefit has been found with the addition of risperidone. Psychosocial treatment augmentation improves negative symptoms and cognitive impairment that may emerge in the months after clozapine therapy is started; this may maximize the benefits of clozapine. Family and group therapy, cognitive-behavioral therapy, supportive employment, and activity therapy have all been used with considerable success.3,6

Alternatives to clozapine

There is some evidence that olanzapine at dosages 2- to 3-fold higher (ie, 25 to 45 mg/d) than those needed for patients who are not treatment-resistant (10 mg/d) may be as effective as clozapine.17,18 Both clozapine and high-dose olanzapine required trials as long as 6 months before response was observed or maximal.6,17 There is no evidence that high doses of typical antipsychot-ics are effective in refractory schizophrenia.3,8 Higher doses of typical antipsychotics will most certainly increase the risk of tardive dyskinesia and, thus, increase cognitive impairment and mortality.19,20

Polypharmacy is often attempted in patients with refractory schizophrenia before a trial of clozapine is started. This takes the form of multiple antipsychotics combined with mood stabilizers, antidepressants, and benzodiazepine anxiolytics. Evidence is lacking for beneficial effects, especially with regard to treatment with multiple antipsychotics.21,22

Long-chain omega-3 fatty acids have been suggested as augmentation of atypical antipsychotics for schizophrenia.23 Much more evidence is required before this treatment can be recommended over a trial of clozapine or augmentation with ECT. ECT should be considered for the treatment of refractory psychosis, regardless of the diagnosis. ECT is a safe procedure, even for patients with serious concomitant but stable medical problems.24 As with clozapine, discussion of concerns about memory loss and other risks and benefits is necessary to obtain patient acceptance and cooperation. ECT has been shown to be effective in patients with refractory psychotic symptoms associated with major depression, bipolar disorder, Huntington chorea, Parkinson disease, and vascular depression, among other disorders.25,26 Maintenance ECT may be needed to sustain remission.

Transcranial magnetic stimulation (TMS) for patients with refractory auditory hallucinations has been tried, with mixed results.27,28 Various protocols have been used, but none emerged as optimal. Findings indicate that adding TMS to clozapine for refractory schizophrenia may be effective.29 Additional research is needed to determine its utility for refractory psychotic symptoms in general.


About 10% of patients with first-episode schizophrenia will be refractory; another 20% become so shortly after an initial period of treatment response or possibly spontaneous remission. Some patients with any of the psychiatric disorders associated with psychotic symptoms-eg, bipolar disorder, Huntington chorea, and substance abuse-will be refractory to standard treatments for psychosis.

Before concluding that a patient is refractory, it is necessary to consider whether patients have been sufficiently adherent and that low dosage, short duration of treatment, or polypharmacy have not compromised earlier trials. A trial of an atypical long-acting injectable antipsychotic may be needed to determine that adherence is not an issue. Patients with refractory schizophrenia will respond to clozapine, with the onset of response often not beginning until after 3 to 6 months of treatment.

Clozapine may be useful for patients with refractory psychosis associated with diagnoses other than schizophrenia; however, clozapine is not FDA-approved for these other indications. Therefore, a full discussion of all available treatment options and the potential adverse effects of clozapine is particularly important. Discussion with the patient and his or her significant others about the special nature of a trial of clozapine is essential to minimize premature discontinuation. It is imperative that clinicians are prepared to prevent, minimize, and manage the adverse effects of clozapine, including the rarely occurring agranulocytosis.

Dosages of olanzapine that are much higher than those for non-refractory patients, eg, 25 to 45 mg/d, have been reported to be of benefit for some refractory symptoms in patients with schizophrenia. A course of ECT has proved useful for many refractory patients for whom no drug alone, including clozapine, has been effective enough to adequately control psychosis. Other dimensions of psychopathology, especially cognitive impairment and negative symptoms, need to be considered when devising a treatment plan for refractory patients. Psychosocial treatment, group therapy, cognitive-behavioral therapy, family therapy, and stress management may be useful adjuncts to pharmacotherapy for refractory patients. Refractory psychosis is a great challenge for clinicians, but one that can often be successfully treated.

[This CME is expired]


In the December issue of Psychiatric Times, there was an error in the CME posttest of the article by Tony Cohn, MD, Metabolic Monitoring for Patients on Antipsychotic Medication. The original question 9 has been replaced in the online test with the following:

9. Metabolic syndrome may be a particularly important marker of antipsychotic metabolic effects because antipsychotic treatment is associated with all of the following except:

A. Metabolic dyslipidemia (raised triglycerides and low HDL-cholesterol)

B. Increased blood pressure

C. Abdominal adiposity (increased waist circumference)

D. Dysglycaemia (increased glucose)

E. Hyperinsulinemia


Dr Meltzer is Professor of Psychiatry and Behavioral Sciences and Physiology at the Feinberg School of Medicine of Northwestern University in Evanston, Ill.


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