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Evidence-Based Reviews

First psychotic episode—a window of opportunity: Seize the moment to build a therapeutic alliance

Intervening early and building a therapeutic alliance can improve medication adherence, reduce relapse risk, and favorably alter the course of schizophrenia

Vol. 2, No. 4 / April 2003

A first psychotic episode offers the opportunity to build a therapeutic alliance at a teachable moment—while patients and their families are dealing with a devastating diagnosis. With a proactive approach, you can influence how patients view themselves and their experience, including psychotic illness, your efforts to treat its symptoms, and the costs and benefits of interventions.

Unfortunately, the typical first psychotic episode goes undiagnosed and untreated for 1 to 2 years, which some studies suggest may allow schizophrenia to progress. Although controversial, evidence links a prolonged duration of untreated psychosis to poorer outcome.1 Interventions during a prodromal (ie, pre-psychotic but already symptomatic) phase of schizophrenia also is being investigated, with the goal of attenuating—or perhaps even preventing—progression to frank psychosis.2-6

The implication for clinicians: timely identification and treatment may improve response, reduce relapse rates, and ultimately improve schizophrenic patients’ quality of life.

High rates of response—and relapse

Patients with a first psychotic episode show a higher response rate to antipsychotics—up to 87% within 1 year7 —and are more sensitive to side effects than are multi-episode patients.8 Yet despite their high response rate, new-onset patients often suffer from residual symptoms, even when treated in controlled settings. They also have a high rate of relapse—82% within 5 years.9

The strongest modifiable predictor of relapse is medication non-adherence, which has been shown to increase the risk of relapse five-fold.7 The first treatment experience provides a window of opportunity to help the patient accept taking medications as a normal part of life.



Mr. C, a 19-year-old college student, was brought for psychiatric admission after he told his roommates he was a new messiah who “needed to starve himself during the sunlight to enhance his holiness.” Approximately 7 months earlier he had become socially withdrawn and less able to do his college work. Two months later, he started using cannabis frequently. About 5 weeks prior to admission, he developed paranoid ideas involving his roommates and immersed himself in Eastern religions.

History and work-up. Mr. C was overweight and presented with mild dehydration. He did not report relevant signs of depression or mania and had no history of medical or psychiatric problems. Admission work-up included physical and neurologic exams, head CT, and blood work, which were unremarkable except for a positive cannabis toxicology. Family history was significant for one grandfather with alcohol abuse and one uncle who required psychiatric hospitalization in his 20s and never recovered functionally.

Family concerns. Mr. C’s parents were convinced a new diet was causing his symptoms and demanded that he be admitted to a medical ward. His brother insisted the symptoms were secondary to some “bad weed” and that everything would clear up in a few days. Although a brief medication-free observation period was considered to rule out substance-induced psychosis, the prodromal pattern of functional decline for more than 6 months and the bizarre quality of his delusions led to the diagnosis of a first episode of schizophrenia.

Treatment strategy. The treatment team met with Mr. C and his family to educate them about psychotic illness, the risks and benefits of novel antipsychotics, and the need to begin immediate treatment. With the patient’s and family’s consent, risperidone was initiated at 0.5 mg at bedtime and slowly increased over 1 week to 3 mg/d, with only mild and transient sedation. Within 3 weeks, Mr. C responded robustly and was discharged back to his family. Over the next 7 months, he continued taking risperidone, 3 mg/d, with some residual negative symptoms (social isolation without depression) and full remission of positive symptoms, which enabled him to return to college.

Therapeutic alliance. Your approach is key to building a therapeutic alliance with a person whose reality often is clouded by paranoia and referential thinking. Trust begins with the first clinical contact—during history-taking, ordering of tests, answering questions about the diagnosis, and discussing treatment options. Patients and their families must be informed about:

  • target symptoms
  • medication side effects
  • predictors of response and relapse
  • lack of certainty about how or when a patient will respond to any antipsychotic
  • and the importance of rapid and uninterrupted treatment.

Supportive therapy. Support groups for the patient and family can help destigmatize the illness and reduce stress. Information about schizophrenia’s nature and course is available from the National Alliance for the Mentally Ill, National Mental Health Association, and other sources (see “Related resources”). 10

CBT. Adjunctive cognitive-behavioral therapy (CBT) may speed up acute symptom response,11,12 reduce rates of nonresponse, and shorten hospital stays13 by helping patients deal with uncertainty about outer and inner realities. CBT approaches are understudied but so far have not been found to reduce relapse rates.

A moving target. As treatment moves from acute to consolidation and maintenance, target symptoms may change, side effects can limit the preferred approach, and partial or nonresponse may require drug or dosing adjustments. It is prudent to be prepared to re-evaluate the initial diagnosis as new symptoms emerge, response patterns develop, additional test or historical data become available, or as the illness’ course becomes more clear. To improve outcome, address comorbid or concurrent diseases—such as substance abuse or dependence, mood disorders, anxiety and obsessive-compulsive symptoms, or eating disorders.

Diagnostic work-up

As in Mr. C’s case (Box), a first psychotic episode is characterized by DSM-IV diagnostic criteria for schizophrenia, including hallucinations, delusions, disorganized thoughts or speech, disorganized behavior(s), or negative symptoms (such as anhedonia, amotivation, asociality, alogia, or affective flattening). The work-up is more comprehensive than that for subsequent episodes and includes a thorough history, complete physical examination, and brain imaging (Table 1) to explore other possible medical and psychiatric diagnoses (Table 2).

Table 1



Mode of evaluation


Symptoms, time course, medical conditions, current/previous medications, herbs, drugs
Medical and neurologic exam
Blood work: CBC with differential, complete metabolic panel, thyroid and liver function tests, syphilis serology, pregnancy test, toxicology
Urinalysis, toxicology


Fasting glucose and lipid profile (ideally before starting atypical antipsychotic)
Head CT (especially if history of recent trauma) or brain MRI


Erythrocyte sedimentation rate, antinuclear antibodies, lumbar puncture, sleep-deprived EEG

The history—ideally gathered from the patient and others—includes:

  • medical and psychiatric diagnoses
  • medications (prescribed and over-the-counter remedies)
  • presence of stressors/triggers
  • chronology of symptoms
  • potential for the episode to endanger the patient or others.

Imaging. Despite a relatively low yield, we recommend that every patient with a first psychotic episode undergo a brain CT or MRI to rule out a potentially treatable organic cause for the psychosis. 14

Other tests. Because of the increased risk of hyperglycemia, dyslipidemia, and possible cardiac conduction abnormalities with atypical antipsychotics, obtain a baseline fasting blood glucose, lipid profile, and ECG. A sleep-deprived EEG is recommended for patients with unclear motor movements or family history of epilepsy.

Choosing medications

Medication choices for the patient with first-episode schizophrenia are influenced by:

  • target symptoms
  • whether the symptoms endanger the patient or others
  • the patient’s personal or family history of medication response or side effects
  • a generally increased sensitivity to side effects in patients who have never been exposed to antipsychotics
  • concurrent medical and/or psychiatric disorders
  • prescriber, patient, and family preferences.

Psychiatrists generally select psychotropic classes by symptom domains (Table 3) and individual agents in each class by side effect profile. Except for clozapine’s superior effectiveness in patients with refractory psychosis, controlled studies have shown no clinically significant differences in efficacy among the drugs in each class—including the antipsychotics. Individual patients, however, may respond differently to different agents.

Principles of prescribing antipsychotics

Antipsychotics are effective in treating most psychotic core symptoms, such as hallucinations, delusions, agitation, aggression, and disorganized thinking and behavior. Other medications can be added to speed up or enhance treatment response or to target other domains.

Dosages. First-episode patients often require lower dosages and slower titration than multi-episode patients. As a rule, antipsychotics are started at about one-half the dosage given to patients with a chronic treatment history, although symptom severity and absence of side effects at lower dosages can help individualize titration.

Side effects. Atypical antipsychotics are preferred because of their reduced risk of extrapyramidal symptoms (EPS), positive effects on depressive and cognitive symptoms, and improved patient satisfaction and adherence, compared with the older antipsychotics. 15-17 Atypicals’ potential side effects include weight gain, hyperglycemia, and dyslipidemia, 18 as well as often-overlooked sexual side effects. 19

Table 2


Possible diagnosis

Key points for differentiation


6 months of psychosis* (including prodromal symptoms); total duration of mood episodes brief relative to active and residual psychotic phases; not directly caused by medical condition or substance

Schizophreniform disorder

Same as above, except symptoms are present 1 to 6 months

Brief psychotic disorder

Same as above, except symptoms are present 1 day to 1 month

Delusional disorder

Apart from non-bizarre delusions, functioning not markedly impaired; total duration of mood episodes brief relative to active and residual psychotic phases; not caused by direct physiologic effects of medical condition or substance

Psychotic disorder NOS

Psychotic symptoms insufficient to make a specific diagnosis

Schizoaffective disorder

Like schizophrenia for at least 2 weeks, but with mania or major depression present for much of the active and residual psychotic periods

Mood disorder with psychosis

Psychotic symptoms occur exclusively during mood disorder episodes

Psychosis due to general medical condition

Psychotic symptoms caused by direct physiologic effects of a general medical condition

Delirium due to general medical condition

Psychotic symptoms associated with a disturbance in consciousness and other cognitive deficits; characterized by a fluctuating course

Dementia due to general medical condition

Psychotic symptoms associated with memory impairment and other cognitive deficits

Substance-induced psychotic disorder

Psychotic symptoms caused by direct physiologic effects of a substance; reaction exceeds that usually encountered with intoxication or withdrawal

Substance-induced psychotic delirium

Similar to above, but associated with a disturbance in consciousness and other cognitive deficits; characterized by a fluctuating course

Substance intoxication or withdrawal

Caused by direct physiologic effects of a substance; reaction is typically encountered with intoxication or withdrawal

Conversion disorder

Contradictory and inconsistent history and presentation; secondary gain


Contradictory and inconsistent history and presentation; primary gain

* Psychotic symptoms must interfere with functioning, and at least two of the following are required: delusions, hallucinations, disorganized thoughts or speech, disorganized behavior, or negative symptoms (avolition, alogia, affective flattening, asociality, or anhedonia), unless delusions are bizarre (impossible), or hallucinations consist of a running commentary or of two or more voices conversing with each other.

Source: Adapted from DSM-IV handbook of differential diagnosis. Washington, DC: American Psychiatric Press, 1995.

Consider the patient’s risk for side effects when choosing an atypical antipsychotic, as each drug has strengths and weaknesses. For example, it may be reasonable to consider:

  • risperidone, ziprasidone, or aripiprazole—rather than olanzapine or quetiapine—for patients at high risk for weight gain or with a family history of diabetes
  • avoiding risperidone for patients with an early indication of sensitivity to EPS or prolactin-related side effects
  • an agent that can be loaded rapidly, such as olanzapine or aripiprazole—rather than an agent that requires titration, such as quetiapine—for a patient presenting with severe agitation.

Clozapine—because of its side effect potential—is generally reserved for patients who have not responded to at least two antipsychotic trials of at least 4 to 6 weeks duration and have a steady-state clozapine level >350 ng/dl.

Acute agitation. Short-acting IM formulations can be used effectively for acute agitation and impulsivity or for patients who refuse oral antipsychotics. Until recently, only first-generation antipsychotics such as haloperidol and fluphenazine were available in IM formulations. Injectable ziprasidone mesylate is now available for acute agitation and has been found to be as safe and effective as haloperidol. Lorazepam may be used to treat agitation or as an adjunct to a patient’s antipsychotic agent.

Adjunctive therapies

When antipsychotic monotherapy is inadequate, adjunctive medications may be considered:

  • to treat catatonia, obsessive-compulsive disorder, or depression
  • to resolve agitation or mania more quickly
  • to control agitation or anxiety while an antipsychotic dosage is being titrated
  • when side effects emerge or residual symptoms remain despite adequate dosage and duration of antipsychotic treatment.

Deciding if and when to add another drug depends on the nature and severity of target symptoms, the degree and time course of response, and whether side effects appear. If you use adjunctive therapies during acute stabilization, attempt to taper and discontinue them after the patient’s symptoms have improved. Avoid combining antipsychotics, as no clinical data support the effectiveness and safety of this practice. 20

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