Maurizio Pompili, MD, PhD

Findings indicate that more than 50% of patients hospitalized for a first episode of schizophrenia who had threatened others had displayed overt signs of illness for over a year.

Keep in mind the following when working with patients who are agitated:

Violence in patients with schizophrenia can be prevented if the patient is carefully monitored-before, during, and after hospitalization

Collaboration with the patient is crucial

Treatment personnel should be capable of handling difficult situations

Avoid any personal reaction to things that the agitated patient may do or say

When possible, the clinician should ascertain whether there is any substance and/or alcohol abuse

After discharge, there is an increase of violence risk

Medication-nonadherence may run the risk of agitation and possible aggression

Aggression and Impulsivity in Schizophrenia

,” by Maurizio Pompili, MD, PhD and Andrea Fiorillo, MD, PhD, on which this quiz was based.

1. Humphreys MS, Johnstone EC, MacMillan JF, Taylor PJ. Dangerous behavior preceding first admissions for schizophrenia. 

Poll

What percentage of patients hospitalized for a first episode of schizophrenia who had threatened others had displayed overt signs of illness for over a year?

Mini Quiz: Violence and Psychosis

Although the prevalence of violence is similar in psychiatric patients and in the general population, patients suffering from schizophrenia are often portrayed in the media as being unpredictably aggressive and impulsive. The result is increased stigmatization and poorer treatment outcomes. Multiple factors, including insufficient social support, substance abuse, and symptom exacerbations, can precipitate aggressive behavior. Moreover, failure to treat schizophrenic patients adequately is a major risk factor for aggression.

Aggressive behavior and impulsivity are often found in paranoid schizophrenia and can occur during both acute and chronic phases of the illness. Impulsivity is defined as action without planning or reflection, and it seems to be related to a failure of behavioral filtering outside of consciousness.

Patients with schizophrenia may show dysfunctional impulsivity and impulsive aggression. Although the neurobiological aspects of aggression in patients with schizophrenia are still not well understood, impulsivity and aggression may correlate with frontal and temporal brain abnormalities.

 Psychotic symptoms, such as delusions and hallucinations, with subsequent suspiciousness and hostility, may result in aggressive behavior. Or, aggression may be impulsive and caused by an environmental frustrating event. Patients may be more aggressive and violent during acute episodes.

Schizophrenic patients have less insight, experience greater thought disorder, and have poorer control of their aggressive impulses. Comorbidity with alcohol or other substances of abuse is frequent and complicates the agitation and the impulsivity. Among patients with schizophrenia, MDD, and bipolar disorder, the risk for homicide was found to be increased with comorbid alcohol abuse or dependence.

 categorized the risk factors for aggression into 4 sets of variables:

: history of violence, violent threats or fantasies, age, sex, history of child abuse

: diagnosis, relevant symptoms, treatment adherence

: social support, availability of weapons

: the nature of the alliance with the patient, the potential cognitive bias of the evaluator

Assessment through clinical history still remains the most important way to gauge potential violent behavior in patients with schizophrenia, although it is still impossible to predict with any certainty whether a patient will become aggressive. Dysfunctional impulsivity can be assessed with many self-report questionnaires and several tests of cognitive ability (

Because of the multidimensional etiology of aggression, making treatment decisions can be difficult. The underlying psychosis, poor impulse control, and comorbid substance use all need to be managed. In addition, the personality traits that may have contributed to the violent behavior need to be recognized. Hostility and aggressive behavior during psychosis can result when patients with a thought disorder or persecutory delusion perceive themselves as threatened. Patients with paranoid schizophrenic manifestations of suspiciousness, mistrust, and anger may be particularly challenging for clinicians who need to abstain from questioning the patient’s delusions.

Clinicians need to ensure that a safe place-for themselves and for the patient-is available where they can meet with the patient. In the emergency department, this can be particularly challenging if no dedicated space is available. A crowded place with many other somatic emergencies can impair proper management of aggressive and impulsive behavior. In such settings, administration of sedative agents is often the first-line approach, whereas when quiet rooms are available, there may be more space for collaboration between physicians and patients, leading to less invasive interventions.

Collaboration with the patient is crucial as is an experienced staff capable of handling difficult situations. Staff should respect protocols and avoid any personal reaction to things that the agitated patient may do or say; in addition, the fewer the stimuli the better. When possible, the clinician should ascertain whether there is any substance and/or alcohol abuse.

Violence by schizophrenic patients can be prevented if the patient is carefully monitored-before, during, and after hospitalization. More than 50% of patients hospitalized for a first episode of schizophrenia who had threatened others had displayed overt signs of illness for over a year.

 After discharge, there is an increase of violence risk: aggressions committed by persons with schizophrenia often occur within the first few months of hospital discharge.

 Once a patient with schizophrenia is discharged, he or she may become medication-nonadherent, resulting in symptom recurrence and an increased risk of agitation, impulse discontrol, and possible aggression.

In an acute setting, pharmacological interventions may be necessary, and the clinician may be challenged by the need to administer the maximum dose and at the same time not harm the patient. It is important to monitor vital signs, provide close observation, and assess agitation for at least 24 hours. Adverse events from otherwise good sedative agents can occur because different compounds are administered simultaneously or in addition to previously administered medications.

In the long-term management of aggressive behavior, ascertain whether the potential for violence can be managed with psychotherapy before proceeding with medications. It is important to convey empathy and authenticity: if the agitated patient feels that he is understood and a good therapeutic relationship is in process, he may be less suspicious and defensive.

Although pharmacological treatment may help manage aggressive behavior in schizophrenic patients, it may be difficult to establish the direct effect of each medicine. Drugs are usually used to maintain impulse control and reduce aggressive behavior. Although they may induce paradoxic disinhibition, benzodiazepines, especially lorazepam, are well tolerated and not associated with the extrapyramidal adverse effects typically associated with antipsychotics. Benzodiazepines are very useful in combination therapy with typical or atypical antipsychotics.

In patients with acute psychosis, the use of typical antipsychotics, especially haloperidol, is supported by their strong evidence base and the long and safe history of their intramuscular formulation. Atypical antipsychotics may decrease hostility over the long term. They also are associated with a lower risk of acute extrapyramidal adverse effects, such as dystonia and akathisia, as well as a lower risk of cardiovascular adverse effects, such as QTc prolongation.

Clozapine, olanzapine, risperidone, aripiprazole, ziprasidone, and asenapine are the atypical antipsychotics most often used in the long-term treatment of hostility, impulsivity, and aggression in patients with schizophrenia. Those available in oral dissolving form are particularly useful for ease of administration (avoiding swallowing). Intramuscular formulations of atypical antipsychotics are also beneficial for treating aggressive and impulsive behavior in schizophrenic patients. Long-acting injectable formulations of antipsychotics are available for long-term treatment of patients with schizophrenia and schizoaffective disorder.

 These formulations are particularly beneficial for patients who might have trouble with medication adherence.

Clozapine decreases hostile, aggressive, and violent behavior in the treatment of persistent aggression in patients with schizophrenia. It represents the best long-term medication choice. In one study, after treatment with clozapine, the scores on the hostility item of the Positive and Negative Syndrome Scale were reduced in 157 patients with treatment-resistant schizophrenia.

 However, clozapine is not used for acute episodes because the dose must be titrated slowly during the first 3 weeks of treatment and it is likely that its anti-aggressive effect is not related to its antipsychotic effects.

Mood stabilizers-anticonvulsants and lithium-are often also prescribed in combination with antipsychotics. Substance abuse comorbidity increases the risk of violent behavior. Atypical antipsychotics and benzodiazepines are recommended for schizophrenic patients with substance abuse comorbidity. (Benzodiazepines are safe and effective sedative agents that do not create problems with addiction in the acute phase, especially when the patient is closely monitored.) Of note is loxapine, a typical antipsychotic, now available to treat agitation in inhalation form. According to preliminary evidence, agitation is reduced within 2 minutes of administration and the effects of a single dose last up to 24 hours.

Aggressive and impulsive behaviors in schizophrenia pose many clinical challenges. The best way to reduce the risk of aggression is with adequate treatment of schizophrenia.

) to assess a patient’s agitation/hostility can help psychiatrists make treatment decisions that will reduce the risk of aggression. Proper training of staff and a structured, calming environment can easily reduce the risk of violence and improve outcomes, ensuring safety for both staff and patients. Understanding treatment protocols provides clinicians with the knowledge for proper management and gives patients better solutions with possibly less invasive interventions.

Dr Pompili is Professor of Suicidology in the department of neurosciences, mental health, and sensory organs at Sapienza University of Rome, and Director of the Suicide Prevention Center at Sant’Andrea Hospital in Rome. Dr Fiorillo is Associate Professor in the department of psychiatry at the University of Naples SUN, Naples, Italy. The authors report no conflicts of interest concerning the subject matter of this article.

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Articles

Suicide may be the culmination of a complex combination of psychological, biological, social, and cultural factors, and it is particularly likely to occur during periods of individual, family, and socioeconomic crises associated with loss and shame. Psychiatric disorders, especially depression, bipolar disorder, and substance abuse, are most often associated with suicide.

In bipolar disorder, mixed manic-depressive states are often associated with increased suicide risk.

 Suicide rates are also surprisingly high among persons who have anxiety disorders, and severe anxiety may accompany suicidal behavior. However, evidence of the efficacy of antianxiety medications in lowering suicide risk is limited.

The effect of treatment on suicide risk has been a topic of growing research interest in recent years. There is limited evidence that psychiatric treatments reduce suicide risk, although a decrease in the long-term suicide rate for patients with mood disorders treated with lithium, neuroleptics, and antidepressants has been reported in more recent studies.

 Psychiatric treatments as diverse as psychotherapy, rapid hospitalization, and ECT can be lifesaving in acute emergencies, but there are limited data to suggest that any of them decrease suicide risk.

In this article, we review psychopharmacological interventions that have been associated with suicide prevention in patients with major psychiatric illnesses.

The first FDA-approved medication with an antisuicide indication was clozapine for schizophrenia. The regulatory approval in 2003 was largely based on the International Suicide Prevention Trial (InterSePT), a remarkable randomized trial that compared clozapine with olanzapine in patients with schizophrenia and schizoaffective disorder who were at high risk for suicide.

 In that trial, suicidal behavior (measured by suicide attempts, hospitalizations, and rescue interventions) was significantly decreased in patients treated with clozapine.

The efficacy of other antipsychotic drugs in reducing suicide risk has not been adequately tested. However, some evidence suggests that olanzapine may reduce suicidal ideation when given in combination with a mood-stabilizing agent in patients with bipolar I disorder mixed-episode.

Quetiapine (300 to 600 mg) may help prevent suicide in patients with bipolar depression.

8,9 When compared with lithium and paroxetine, quetiapine (600 mg) was associated with a statistically significant reduction in suicidal ideation (as measured by the Montgomery-Asberg Depression Rating Scale [MADRS]).

 Quetiapine may reduce suicidal ideation and may be considered for patients with other diagnoses for which clozapine cannot or should not be used.

One of the most interesting questions in preventive medicine today is the impact of lithium on suicide rates. There are no systematic data available at this time [about its efficacy], although it can be hoped that a well-documented answer will be possible within the next 10 years. Until then, we must rely upon preliminary speculations and clinical observations.

Just a decade later, the first scientific evidence convincingly supported a suicide risk–reducing effect of long-term treatment of bipolar and other manic-depressive disorders with lithium.

A recent meta-analysis of data on long-term lithium treatment in bipolar disorder or a mix of major mood disorders supported a marked reduction (5-fold, or approximately 80%) in risk of suicide attempts and of completed suicides.

 Interestingly, the researchers also found that the proportion of suicide attempts relative to completed suicides during treatment with lithium was more than 2-fold higher, which suggests reduced lethality of suicidal behavior. The evident beneficial effects of lithium in reducing mortality from suicide are all the more remarkable in light of its potentially lethal toxicity in acute overdoses.

What is already known about pharmacotherapy interventions for reducing suicidality? 
? Robust treatment of the underlying psychiatric illness has been the most effective antisuicide approach.

What new information does this article provide? 
? Clozapine appears to be useful in decreasing suicide risk in persons with schizophrenia; lithium appears effective for suicidal bipolar patients.

What are the implications for psychiatric practice? 
? SSRIs are useful in the treatment of suicidal depressed patients. However, patients should be carefully monitored, especially adolescents who receive these agents.

Evidence that antidepressant treatment decreases suicide risk or suicide attempts is mixed. It is often based on data from correlative or “ecological,” pharmacoepidemiological studies that compare suicide rates by regions or years with concurrent rates of prescriptions for antidepressant drugs.

 There have been moderate decreases in overall suicide rates, varying by sex and age-groups, in some Nordic countries and in the US since the 1990s; these decreases are possibly associated with the emergence of the modern, less toxic antidepressants that now dominate current clinical practice.

 Data from observational studies indicate that SSRIs may be associated with a reduced risk of suicide in adults with depression, while their use may increase suicidality in adolescents.

This remains a controversial topic. Findings from a meta-analysis of randomized placebo-controlled studies suggest a modestly increased risk of suicidality associated with the use of antidepressants in pediatric patients.

 However, a more recent review of suicides in adolescents found that only 1.6% of these young people had recently been exposed to SSRIs.

 Most adolescents who died by suicide were not taking antidepressants at the time of their death. Following the introduction of the FDA’s regulatory action on restriction of antidepressants in children and adolescents, there has been an increase in suicides. The decrease in antidepressant prescriptions for children and adolescents paralleled the increase in suicide rates; before the FDA’s warning, the suicide rates had been decreasing.

 These findings support the use of SSRIs as part of a comprehensive treatment plan for adolescents with significant depression.

Medication nonadherence occurs for various reasons and presents risk of relapse of depression with an increase in symptoms. Relational psychopharmacology emphasizes collaboration between patient and pharmacologist toward a shared goal of symptom relief.

 suggests that pharmacologists rely on “informed intuition and close follow-up” as part of an empathic therapeutic relationship that enables the patient to tolerate some amount of adverse effects and delay in achieving therapeutic response.

Patients who independently interrupt or discontinue treatment without consulting their prescribing physician are at greatly increased risk for recurrence or early relapse. The decision to discontinue medication may provide relief from unpleasant adverse effects; however, there are associated risks related to recurrence of symptoms. These risks appear to be higher if medications with shorter half-lives are abruptly discontinued.

 Furthermore, findings from some studies indicate that antidepressant discontinuation is associated with increased risk of suicide.

The therapeutic alliance may minimize unilateral actions that lead to premature termination or discontinuation of pharmacological treatments. The therapeutic alliance enables the patient to tolerate unpleasant adverse effects.

These agents are receiving increasing attention because of a possible association with suicidal thoughts or behaviors. Recent studies, however, have yielded inconsistent findings regarding suicide risk conferred by specific antiepileptic drugs (AEDs). In patients with epilepsy, heightened suicide risk has also been attributed to comorbid psychiatric conditions.

In 2008, the FDA reported an apparent suicide risk among epileptic patients treated with anticonvulsants. However, questions have been raised about the report; the anticonvulsants grouped together were pharmacodynamically highly heterogeneous. The report also included outcomes of questionable comparability, including suicidal ideation, suicidal acts, and 4 completed suicides. Moreover, the data were acquired as passive and incidental “adverse event reports” of uncertain reliability and completeness.

 Parenthetically, it is curious that epileptic patients would volunteer for potential exposure to placebo treatment.

It is unclear whether the action of AEDs in patients with affective disorders is similar to that in patients with seizure disorders. It is crucial to determine whether suicide risk with anticonvulsants and high-potency benzodiazepines with anticonvulsant activity carries over to psychiatric patients, because these drugs are widely used to treat serious psychiatric disorders.

Two studies have examined this potential association between AEDs and suicide risk, with inconclusive results.

Reported investigations that examined suicide risk and AEDs are strikingly inconsistent in their rankings of relative risks associated with particular drugs. Nevertheless, levetiracetam, lamotrigine, and topiramate were among the top 3 AEDs with the highest observed suicide risks in at least 2 of the 5 reported analyses. Levetiracetam was among the top 3 drugs in all 5 studies that found increased suicide risk. Lamotrigine and topiramate appeared in the top 3 in 3 of the 5 studies. Only topiramate has been associated with clinical depression. These 3 drugs differ in their pharmacodynamics. Thus, it is difficult to conclude which biological mechanisms lead to increased suicide risk.

Lamotrigine monotherapy is an effective and well-tolerated treatment for mania and bipolar depression, and it may be used as an augmentation strategy for unipolar depression.

Some pharmacological challenges go beyond diagnostic categories. There are many clinical challenges in which medications play key roles in reducing generalized symptoms, such as anxiety and insomnia, that worsen during a psychosocial crises and are associated with increased suicide risk. Adequate treatment of insomnia and agitation is important anecdotally in suicidal patients. Although suicide rates are surprisingly high among persons with anxiety disorders and severe anxiety may accompany suicidal behavior, evidence that antianxiety medications may alter suicide risk is limited.

 Acute relief of agitation in suicidal depressed patients may play a significant role in suicide prevention.

Adequate treatment of the underlying psychiatric illness consistently appears to be the most effective use of medication in suicidal patients. Although studies are limited, there are indications that some medications will provide specific antisuicidal protection. The use of illness-specific medication provided through the therapeutic relation-ship is key to decreasing the risk of suicide.

Clozapine has shown some efficacy at reducing suicide risk in schizophrenia, and olanzapine and quetiapine appear promising. Similarly, lithium has been shown to be effective for patients who have bipolar disorder. SSRIs are useful in the treatment of suicidal depressed adults. However, patients who are receiving SSRIs, especially adolescents, should be carefully monitored. Additional research is urgently needed to determine the safety of antiepileptic drugs.

A good therapeutic alliance is key to effective pharmacotherapy. By forging a therapeutic relationship, the prescribing psychiatrist encourages patient adherence and enables physician and patient to monitor suicide risk across the spectrum of diagnoses and possible adverse effects.

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 Barraclough B, Bunch J, Nelson B, Sainsbury P. A hundred cases of suicide: clinical aspects.

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 Baldessarini RJ, Tondo L. Psychopharmacology for suicide prevention. In: Pompili M, ed.

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 Angst J, Angst F, Gerber-Werder R, Gamma A. Suicide in 406 mood-disorder patients with and without long-term medication: 40 to 44 years’ follow-up.

 Meltzer HY, Alphs L, Green AI, et al; International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT) [published correction appears in

Adequate treatment of the underlying psychiatric illness consistently appears to be the most effective use of medication in suicidal patients.

Author | Maurizio Pompili, MD, PhD

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