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Cases that Test Your Skills

Afraid to leave home

Clozapine alleviates Mr. B’s schizophrenia symptoms, but he develops anxieties that leave him virtually homebound. Is the antipsychotic to blame?

Vol. 8, No. 6 / June 2009

CASE: Disabling anxiety

Mr. B, age 35, has a history of schizophrenia, chronic paranoid type and has been hospitalized more than 12 times since its onset 10 years ago. He received clozapine during his most recent hospitalization approximately 5 years ago and experienced full symptom response without the motor side effects he developed in response to other medications. He visits a psychiatrist monthly for medications and supportive psychotherapy, and he receives intensive case management and housing from a community mental health center.

When Mr. B is assigned to my (CK) care, his psychotic symptoms are in remission, but he complains of anxiety that leaves him almost homebound. He has intense fear of bridges, upper-floor windows, express buses, subways, riding in speeding vehicles, and having a seizure.

If Mr. B faces any of these triggers, he experiences harmful thoughts—such as jumping out a window or off a bridge—even though he does not endorse suicidality. These thoughts are intrusive, ego-dystonic, and ruminative. He avoids these triggers at all costs, which compromises his housing and employment opportunities. He experienced a single panic attack in the subway 1 year earlier. Mr. B firmly believes that any intense anxiety he experiences will trigger a psychotic episode. When faced with sudden urges, he believes his illness would interfere with his ability to control his impulses.

He reports that these symptoms started when he began clozapine and have worsened. Mr. B says he experiences a feeling of “uneasiness” approximately 2 hours after taking clozapine that is exacerbated if he faces a trigger. He describes the uneasiness as “the feeling of being about to have a seizure” during which he would “lose control” of his body.

When I begin treating Mr. B, he is receiving clozapine, 125 mg bid. In an effort to combat Mr. B’s anxiety, a previous psychiatrist had titrated clonazepam up to 5 mg/d as needed. Mr. B is compliant with his medications and appointments but refuses to change his psychotropic or psychotherapy regimen.

The authors’ observations

Approximately 50% of patients with schizophrenia have at least 1 anxiety disorder, and close to 30% meet criteria for >1 anxiety disorder.1 Social anxiety disorder (SAD), generalized anxiety disorder, panic disorder, posttraumatic stress disorder, and obsessive-compulsive disorder (OCD) have been found comorbid with schizophrenia, with rates as high as 30% for each.1

Possible causes of unusually high rates of anxiety disorders in schizophrenia include trauma history, delusional conviction and inflexibility of abstract thought,2 and passive coping mechanisms.

Schizophrenic illnesses may be linked to anxiety antecedents such as panic or social phobia that:

  • develop into more profound psychopathology
  • or bring about anxiety symptoms, given the severity of the subjective psychotic experience.

In a twin pairs study, the schizophrenic twin had an almost threefold increase in rates of comorbid psychiatric disorders compared with their non-schizophrenic twins; social or environmental factors may not account for this.3

Comorbid OCD, panic disorder, and SAD frequently persist after remission of psychotic symptoms. Comorbid anxiety disorders may play a role in the psychotic symptoms themselves (such as panic and social anxiety related to paranoia, OCD, and bizarre behavior) and negatively impact quality of life.4

In patients with schizophrenia, higher anxiety levels are associated with:

  • increased hallucinations
  • poor psychosocial function
  • hopelessness.5

Accurately assessing and diagnosing anxiety disorders in patients with schizophrenia is challenging because there is inconsistency among clinical interviewers (poor reliability scores), and anxiety scales are not as accurate as we would like them to be (poor construct validity).6 Treatment options for comorbid anxiety and schizophrenia include psychopharmacology and psychotherapy (Table 1).

Table 1

Treatment options for comorbid schizophrenia and anxiety






  • Increase antipsychotic dose
  • Change antipsychotic
  • Add an atypical with serotonergic action (ziprasidone, aripiprazole)

Favor monotherapy at full dose for full trial period before considering adjunct therapy with a second antipsychotic, for which evidence is still equivocal


  • SSRI
  • SNRI

Avoid bupropion because of possible dopamine agonism


Weigh risks of sedation and potential for addiction vs benefits of immediate relief


Use high doses to obtain symptomatic response


CBT (for psychosis and anxiety)
Supportive (for decompensating psychosis)
Activity and vocational

CBT: cognitive-behavioral therapy; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin-norepinephrine reuptake inhibitor

HISTORY: Propensity for violence

Mr. B was born in a large city and raised by his single mother. He denies childhood physical or sexual abuse. Mr. B reports engaging in violent activity since he was an adolescent, but this activity is undocumented because he has never been arrested. Mr. B still belongs to a gang he joined after being assaulted at age 16.

Mr. B was diagnosed with schizophrenia at age 20 following an overt psychotic episode and suicide attempt by hanging. During his psychotic episodes, he thinks groups of people are plotting to kill him. He hears people talking about him or voices telling him about others’ plots against him. Mr. B probably has experienced these symptoms since early childhood, as evidenced by reports of attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and tics.

His health records contain no mention of anxiety symptoms until approximately 3 months after he started clozapine, when he reported brief episodes of unexplained phobia of windows and bridges. Approximately 1 year later, he reported obsessive-compulsive symptoms—ruminating and intrusive thoughts of jumping off a bridge with no suicidal intent. Mr. B’s outpatient therapist at the time believed these symptoms began before Mr. B started clozapine.

Numerous medication trials failed. Antipsychotics were ineffective or poorly tolerated because of motor side effects or intense sedation. Mr. B did not tolerate selective serotonin reuptake inhibitors (SSRIs) because of akathisia or sexual side effects. Mr. B had a history of poor medication compliance until he began clozapine treatment.

Mr. B used cannabis daily until 10 years ago. He smokes cigarettes and reports occasional alcohol use. He has no history of chronic substance or alcohol use, withdrawal symptoms, or complications from intoxication.

Mr. B is unemployed and receives Supplemental Security Income. He has never married or had children.

Medical comorbidities include a white blood cell count and absolute neutrophil count that have been chronically in the lower limit range, and dyslipidemia and diabetes, for which Mr. B receives statins and oral hypoglycemics. He has no history of seizures or brain trauma. His family history includes substance dependence on his mother’s side and schizophrenia in 2 paternal cousins.

The authors’ observations

Mr. B’s anxiety disorder has not been clearly elucidated. He does not seem to meet criteria for:

  • panic disorder (only 1 panic attack)
  • OCD (no compulsions to diminish anxiety)
  • specific phobia (phobias were too broad and lacked fear of an object itself).


Clozapine and OCD: The jury’s still out

Clozapine has been associated with the emergence or worsening of obsessive-compulsive symptoms, although conclusions of studies that investigated this link are equivocal.7 Most of the literature consists of isolated case reports, some of which advocate clozapine for treating obsessive-compulsive disorder rather than for its role as a causative agent.

A case report has associated clozapine with the development of panic disorder in a 34-year-old woman receiving 400 mg/d for paranoid schizophrenia.8 She developed daily attacks of sudden chest compression, dizziness, fear of dying, and intense anxiety. These symptoms progressively improved and eventually resolved after she was switched to olanzapine, 10 mg/d. Clozapine also has been associated with cardiomyopathy presenting as panic attacks.9

In addition, he does not seem to have residual paranoia, akathisia, or drug-seeking behavior. Based on numerous evaluations, Mr. B’s anxiety symptoms seem most consistent with agoraphobia without panic (Table 2).

The phenomenology of his symptoms appears to be linked to his psychodynamic development, but previous therapists had not explored this. In addition, his relationships with his therapists, illness, and medications are complex. Mr. B is poorly engaged, lacks motivation toward recovery goals, and does not trust me. However, he holds high expectations of the potential damage or benefits of medication.

Table 2

Anxiety: How to differentiate disorders and symptoms


Keys to differential diagnosis

Panic disorder

≥2 panic attacks


Fear of ‘no escape,’ ‘no options,’ ‘loss of control’

Generalized anxiety disorder

Constant worriers

Specific phobias

Fear of an object itself, not the response it will elicit within the patient

Obsessive-compulsive disorder

Patterns of intrusive thoughts followed by an action to undo or avoid anxiety

Residual paranoia

Feeling of insecurity associated with episodes of decompensation that have remained inter-episode

Drug-seeking behaviors

Secondary gain, in direct relationship to request for medication

Akathisia, other side effects

Inner restlessness that is constant, without trigger

Mr. B’s pharmacologic management is complicated by several relative contraindications. Clozapine may be associated with or increase the incidence of OCD, panic, and agoraphobia (Box).79 Combining clonazepam with clozapine is not recommended because of the possibility of intense sedation. Even so, in a patient with a history of substance use and illegal activity—such as Mr. B—cautious use of benzodiazepines is warranted to avoid addiction or drug diversion.

Mr. B was taking clonazepam when our work began, and discontinuing it would have increased his risk for seizures and the possibility of him seeking illicit benzodiazepines. Furthermore, discontinuing clonazepam might have thwarted an emerging therapeutic relationship that would become key to enhancing his motivation and exploring the antisocial and narcissistic traits that were limiting his recovery.

I slowly increase the frequency of my sessions with Mr. B from monthly to biweekly to weekly. We focus on strengthening the therapeutic alliance, motivational enhancement, emotional expression, and verbal identification of feeling states. We explore anxiety symptoms and psychosis using cognitive-behavioral therapy techniques informed by psychodynamic aspects of his experience, with the goal of resuming his prior level of functionality, including employment.

I carefully and slowly change Mr. B’s medications. First I increase his clozapine to 300 mg/d in 150 mg divided doses in an attempt to cover the possibility of residual paranoia, and for anxiolytic sedation without introducing a new medication. However, Mr. B’s anxiety symptoms worsen, so I resume the baseline dosage (125 mg bid). I choose not to switch to another antipsychotic because the risk for psychotic decompensation outweighs the potential benefits. I lower clonazepam to 2 mg/d in split doses. I teach Mr. B anxiety management techniques, including distraction, exposure, and anxiety tolerance training.

Because Mr. B refuses to start an SSRI for his anxiety symptoms, I prescribe bupropion and monitor him closely for dopamine agonism as evidenced by a re-emergence of psychosis. Once again, his anxiety symptoms worsen.

I stop bupropion and switch Mr. B to gabapentin, titrated to 400 mg tid. I chose this medication because of its sedation properties and relatively safe side effect profile. Mr. B was willing to try gabapentin—which was first approved to treat epilepsy—because he was afraid of having a seizure and also because it is not associated with sexual side effects. Furthermore, its GABA-mimetic actions made it a plausible alternative to replicate the benefits he was getting from clonazepam.

TREATMENT: An effective drug

Mr. B tolerates gabapentin well and his anxiety symptoms are much more sporadic, shorter, and more easily controlled by conscious exercise. The content of his thoughts is less disastrous and less ego-dystonic. He feels less dysphoria associated with clozapine and does not need as much clonazepam. He overcomes his avoidance of all fear-provoking triggers except walking across bridges.

Mr. B and I explore issues of object relationships and intimacy, establishing emotionally significant relationships with others, and the association between these and his distrust and paranoia. We also investigate the relationship between his criminal activity and feelings of loneliness or lack of control. Mr. B is able to verbalize positive and negative feelings and to feel in cognitive control of them.

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