Current Psychiatry

Is your office computer system-and the confidential patient records it contains-safe from hackers?

Maintaining office computer security isn’t just good practice-it’s the law. The Health Insurance Portability and Accountability Act of 1996 (HIPAA) requires physicians to ensure that patient records are kept confidential.^{click here.}

Hardware tokens are pocket-size devices that, when connected to the computer, allow access by entering the proper password. Hardware tokens are suitable for managing off-site remote access and add another layer of security for local access.

Medical records programs. Most software programs allow administrators to restrict access to medical records by setting up levels of ability to access and modifying electronic records for different users. Each user should have a unique password for authentication. The software also should have an audit trail capability, so that each user’s activity with electronic patient records can be reviewed.

Security breaches

An Internet connection-however brief-can invite security breaches that allow hackers to access patient information, delete programs, steal passwords, disrupt other Internet-connected computers, and erase the hard drive. Avoiding Internet connections altogether would increase security, but this is not feasible.

• Viruses reproduce using the host computer, most commonly by infiltrating the e-mail program and making it hard to detect corrupted files.
• Worms are similar to viruses but are self-contained, whereas a virus must attach to another file.
• Trojan horse programs, usually disguised within seemingly legitimate Internet programs, are less common than viruses or worms. They do not replicate but are equally dangerous. You unknowingly start the Trojan horse after downloading what looks like a useful program. The Trojan horse then self-installs silently, giving the hacker who created it access to your computer.
• Port attacks are malicious attempts to connect and eventually take over another computer. A ‘port’ is a software ‘location’ where a program on another computer can connect to a host computer.
• NEVER open e-mails from unfamiliar sources. Viruses are commonly sent as attachments, which you should never open unless you know they are safe.
• Turn off your computer or disconnect from the Internet when not in use.
• Back up your data regularly. Put patient files in one folder or directory, then copy them to a backup medium such as CD-ROM, zip drive, or portable hard drive. Of course, keep the disks in a secure place.

Anti-intrusion programs

Antivirus programs can check for the latest viruses and their variants and remove them. To do this, automatically update the program with new virus signature files- files created by antivirus program vendors to help the software identify viruses. Most antivirus programs will automatically check the vendor’s Web site for updated files if the computer is connected to the Internet.

Virus signature files should be updated daily to provide maximum protection. Most companies provide a 1-year subscription to the updates, which must be renewed upon expiration for new virus definition files.

Manual updating is acceptable but may be too time-consuming for a busy office.

Well-known antivirus programs include Wireless Internet 101,” Psyber Psychiatry, December 2003)

If your computer is connected directly to the DSL or cable modem or a telephone line, you probably need a firewall. The most recent Microsoft Windows XP and Mac OS X versions each include a software firewall, which should be activated upon installation.

Windows-compatible firewall programs include ZoneAlarm, Sygate Personal Firewall, Symantec Norton Personal Firewall, and Tiny Software Personal. Mac OS-compatible firewalls include Intego NetBarrier, Sustainable Softworks IPNetSentryX, and Norton Personal Firewall.

Once your firewall is installed, check it to verify that all ports are protected. Gibson Research Corp. has two excellent (and free) security checks: ShieldsUP! and LeakTest. Run these tests, then follow the listed suggestions to secure your computer.

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of CURRENT PSYCHIATRY.

Is your office computer system-and the confidential patient records it contains-safe from hackers?

Maintaining office computer security isn’t just good practice-it’s the law. The Health Insurance Portability and Accountability Act of 1996 (HIPAA) requires physicians to ensure that patient records are kept confidential.^{click here.}

Hardware tokens are pocket-size devices that, when connected to the computer, allow access by entering the proper password. Hardware tokens are suitable for managing off-site remote access and add another layer of security for local access.

Medical records programs. Most software programs allow administrators to restrict access to medical records by setting up levels of ability to access and modifying electronic records for different users. Each user should have a unique password for authentication. The software also should have an audit trail capability, so that each user’s activity with electronic patient records can be reviewed.

Security breaches

An Internet connection-however brief-can invite security breaches that allow hackers to access patient information, delete programs, steal passwords, disrupt other Internet-connected computers, and erase the hard drive. Avoiding Internet connections altogether would increase security, but this is not feasible.

• Viruses reproduce using the host computer, most commonly by infiltrating the e-mail program and making it hard to detect corrupted files.
• Worms are similar to viruses but are self-contained, whereas a virus must attach to another file.
• Trojan horse programs, usually disguised within seemingly legitimate Internet programs, are less common than viruses or worms. They do not replicate but are equally dangerous. You unknowingly start the Trojan horse after downloading what looks like a useful program. The Trojan horse then self-installs silently, giving the hacker who created it access to your computer.
• Port attacks are malicious attempts to connect and eventually take over another computer. A ‘port’ is a software ‘location’ where a program on another computer can connect to a host computer.
• NEVER open e-mails from unfamiliar sources. Viruses are commonly sent as attachments, which you should never open unless you know they are safe.
• Turn off your computer or disconnect from the Internet when not in use.
• Back up your data regularly. Put patient files in one folder or directory, then copy them to a backup medium such as CD-ROM, zip drive, or portable hard drive. Of course, keep the disks in a secure place.

Anti-intrusion programs

Antivirus programs can check for the latest viruses and their variants and remove them. To do this, automatically update the program with new virus signature files- files created by antivirus program vendors to help the software identify viruses. Most antivirus programs will automatically check the vendor’s Web site for updated files if the computer is connected to the Internet.

Virus signature files should be updated daily to provide maximum protection. Most companies provide a 1-year subscription to the updates, which must be renewed upon expiration for new virus definition files.

Manual updating is acceptable but may be too time-consuming for a busy office.

Well-known antivirus programs include Wireless Internet 101,” Psyber Psychiatry, December 2003)

If your computer is connected directly to the DSL or cable modem or a telephone line, you probably need a firewall. The most recent Microsoft Windows XP and Mac OS X versions each include a software firewall, which should be activated upon installation.

Windows-compatible firewall programs include ZoneAlarm, Sygate Personal Firewall, Symantec Norton Personal Firewall, and Tiny Software Personal. Mac OS-compatible firewalls include Intego NetBarrier, Sustainable Softworks IPNetSentryX, and Norton Personal Firewall.

Once your firewall is installed, check it to verify that all ports are protected. Gibson Research Corp. has two excellent (and free) security checks: ShieldsUP! and LeakTest. Run these tests, then follow the listed suggestions to secure your computer.

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of CURRENT PSYCHIATRY.

Is your office computer system-and the confidential patient records it contains-safe from hackers?

Maintaining office computer security isn’t just good practice-it’s the law. The Health Insurance Portability and Accountability Act of 1996 (HIPAA) requires physicians to ensure that patient records are kept confidential.^{click here.}

Hardware tokens are pocket-size devices that, when connected to the computer, allow access by entering the proper password. Hardware tokens are suitable for managing off-site remote access and add another layer of security for local access.

Medical records programs. Most software programs allow administrators to restrict access to medical records by setting up levels of ability to access and modifying electronic records for different users. Each user should have a unique password for authentication. The software also should have an audit trail capability, so that each user’s activity with electronic patient records can be reviewed.

Security breaches

An Internet connection-however brief-can invite security breaches that allow hackers to access patient information, delete programs, steal passwords, disrupt other Internet-connected computers, and erase the hard drive. Avoiding Internet connections altogether would increase security, but this is not feasible.

• Viruses reproduce using the host computer, most commonly by infiltrating the e-mail program and making it hard to detect corrupted files.
• Worms are similar to viruses but are self-contained, whereas a virus must attach to another file.
• Trojan horse programs, usually disguised within seemingly legitimate Internet programs, are less common than viruses or worms. They do not replicate but are equally dangerous. You unknowingly start the Trojan horse after downloading what looks like a useful program. The Trojan horse then self-installs silently, giving the hacker who created it access to your computer.
• Port attacks are malicious attempts to connect and eventually take over another computer. A ‘port’ is a software ‘location’ where a program on another computer can connect to a host computer.
• NEVER open e-mails from unfamiliar sources. Viruses are commonly sent as attachments, which you should never open unless you know they are safe.
• Turn off your computer or disconnect from the Internet when not in use.
• Back up your data regularly. Put patient files in one folder or directory, then copy them to a backup medium such as CD-ROM, zip drive, or portable hard drive. Of course, keep the disks in a secure place.

Anti-intrusion programs

Antivirus programs can check for the latest viruses and their variants and remove them. To do this, automatically update the program with new virus signature files- files created by antivirus program vendors to help the software identify viruses. Most antivirus programs will automatically check the vendor’s Web site for updated files if the computer is connected to the Internet.

Virus signature files should be updated daily to provide maximum protection. Most companies provide a 1-year subscription to the updates, which must be renewed upon expiration for new virus definition files.

Manual updating is acceptable but may be too time-consuming for a busy office.

Well-known antivirus programs include Wireless Internet 101,” Psyber Psychiatry, December 2003)

If your computer is connected directly to the DSL or cable modem or a telephone line, you probably need a firewall. The most recent Microsoft Windows XP and Mac OS X versions each include a software firewall, which should be activated upon installation.

Windows-compatible firewall programs include ZoneAlarm, Sygate Personal Firewall, Symantec Norton Personal Firewall, and Tiny Software Personal. Mac OS-compatible firewalls include Intego NetBarrier, Sustainable Softworks IPNetSentryX, and Norton Personal Firewall.

Once your firewall is installed, check it to verify that all ports are protected. Gibson Research Corp. has two excellent (and free) security checks: ShieldsUP! and LeakTest. Run these tests, then follow the listed suggestions to secure your computer.

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of CURRENT PSYCHIATRY.

When nothing else works, desperate clinicians are resorting to progressively more-tenuous and unpredictable treatments, trying to improve the lives of patients with refractory schizophrenia. High-dose antipsychotics is a common strategy.

Does boosting antipsychotic doses beyond the recommended range—but short of the neuroleptic threshold—enhance efficacy? This article attempts to answer that question by presenting the evidence on higher-than-recommended doses of atypical antipsychotics.

Lessons from neuroleptics

Up to 30% of patients with schizophrenia do not respond to antipsychotics and are considered “treatment refractory.”¹ Even among those who do respond, improving symptoms by 20%—as research defines “treatment response”—does not necessarily yield clinical or functional improvement. Clozapine is the only atypical antipsychotic with well-established efficacy in these chronically ill patients,² but its daunting side effects greatly curtail its use.

Before atypical antipsychotics, patients who did not respond to usual dosages of the typical neuroleptics were treated with higher dosages or switched to another drug class. Although many clinicians embraced high-dose neuroleptics, subsequent research discredited “rapid neuroleptization” in any clinical circumstance and showed that exceeding an antipsychotic’s neuroleptic threshold—the dose at which extrapyramidal side effects (EPS) occur—reduces its efficacy (Figure 1).^3-5 In some instances, reducing neuroleptic dosages improves treatment-resistant patients’ symptoms and reduces druginduced side effects.⁶

Figure 1 Typical antipsychotics’ dose-response curve

Narrow therapeutic window between antipsychotic effect and neuroleptic threshold. Dotted line indicates declining efficacy.

Figure 2 Atypical antipsychotics’ dose-response curve

Wider therapeutic window with atypicals, compared with typical antipsychotics, as neuroleptic threshold (dotted line) moves right.Atypical antipsychotics are defined by their relative lack of EPS at recommended dosages (Figure 2). Because these agents can cause EPS if dosed too high, however, our historical habit of testing this dose limit risks losing “atypicality” and encountering other untoward events (Figure 3).

What is the safest, most effective dosage? Consider the evidence for each atypical antipsychotic.

Risperidone

Recommended dosage too high? When using atypicals at recommended doses, you are most likely to encounter the neuroleptic threshold with risperidone, with EPS risk increasing substantially at >6 mg/d.⁷ Post-approval studies set the most effective and safest dosage at approximately 4 mg/d, though this dosage was not studied in North American pre-approval trials. Dosages of 2 to 4 mg/d have been associated with more-favorable outcomes, suggesting that the initial recommendation to titrate to 6 mg/d within the first 3 days was ill-advised.⁸

In our study of patients with treatment-refractory schizophrenia,⁹ those treated with risperidone, 6 mg/d, improved significantly more after 4 weeks than did those receiving haloperidol, 15 mg/d, based on Brief Psychiatric Rating Scale (BPRS) scores. No additional benefit was seen after risperidone was increased to >6 mg/d at 8 weeks. Akathisia and tardive dyskinesia occurred significantly more often in the haloperidol group.

Conclusion. Some patients respond to higher-dose risperidone, but emerging EPS suggest the need to reduce the dosage rather than add an antiparkinsonian agent.

Figure 3 Unknown effects of high-dose atypical antipsychotic therapy

Dotted line indicates potential for greater antipsychotic effect with increasing dose.

Olanzapine

Mixed results. Case reports suggest that some patients who did not respond to previous antipsychotic trials or olanzapine, 20 mg/d, improved sig-nificantly—without substanial side effects—when olanzapine was increased up to 60 mg/d.^10-14 Other case studies, however, report EPS, increased heart rate, increased transaminases, hyperprolactinemia, and prolonged QTc interval with high-dose olanzapine.^14-16

In an open-label trial,¹⁷ 43 patients with schizophrenia received olanzapine, up to 40 mg/d, after inadequate response to neuroleptics and risperidone or clozapine. Olanzapine was titrated to 20 mg/d by week 4 and increased 5 mg every 2 weeks if symptoms did not improve. After 14 weeks, improvement was modest and only 17% of patients met response criteria. However, >20 mg/d reduced symptoms more than did <20 mg/d, suggesting that high-dose olanzapine was more effective.

In a randomized trial,¹⁸ patients who did not respond to at least one atypical antipsychotic then received 8 weeks of fixed, standard-dose treatment with (mean dosages):

• haloperidol, 18.9 mg/d
• risperidone, 7.9 mg/d
• olanzapine, 19.6 mg/d
• clozapine, 401.6 mg/d.

Flexible dosing was then allowed for 6 weeks, and mean dosages were:

• haloperidol, 25.7 mg/d
• risperidone, 11.6 mg/d
• olanzapine, 30.4 mg/d
• clozapine, 526.6 mg/d.

Symptoms improved modestly at best for all medications, although patients taking olanzapine or clozapine improved significantly more than those treated with haloperidol as shown by mean changes in total Positive and Negative Syndrome Scale (PANSS) scores.

PANSS scores for olanzapine-treated patients showed additional improvement at week 14—when higher dosages were used—compared with week 8. This was not the case for the other medications, for which response plateaued. These findings suggest that high-dose risperidone and haloperidol are incrementally ineffective, but high-dose olanzapine could help some patients with refractory symptoms.

Results were different in a randomized, double-blind, 16-week, crossover study,¹⁹ when 13 patients with inadequate response to neuroleptics, risperidone, or conventional-dose olanzapine then received olanzapine, 50 mg/d, or clozapine, 450 mg/d. No olanzapine-treated patients and 20% of clozapine-treated patients met criteria for treatment response (20% improvement in BPRS score and final BPRS score <35 or 1-point improvement on Clinical Global Impressions-Severity of Illness scale).

Box

Subjects switching from clozapine to olanzapine tended to worsen, whereas those switching from olanzapine to clozapine tended to improve. Olanzapine-treated patients experienced more anticholinergic side effects and more weight gain than did clozapine-treated subjects.²⁰

Conclusion. These mixed findings on high-dose olanzapine suggest questionable efficacy in patients with treatment-resistant schizophrenia and an uncertain risk of increased toxicity.

Quetiapine

Early placebo-controlled studies of quetiapine in schizophrenia concluded that statistically significant improvement begins at 150 mg/d and falls off after 600 mg/d.²¹ Although few high-dose quetiapine cases have been presented, clinical opinion holds that:

• most patients with chronic schizophrenia require 400 to 800 mg/d
• some treatment-refractory patients might benefit from >800 mg/d.

One patient responded to quetiapine, 1,600 mg/d, after not responding to olanzapine, 40 mg/d, and quetiapine, 800 mg/d. Constipation was the only reported side effect.²²

Our group²³ reported a series of 7 patients who responded (by clinician report) to quetiapine, 1,200 to 2,400 mg/d, after not responding to quetiapine, 800 mg/d, or to neuroleptics, risperidone, or olanzapine. Six responded to high-dose quetiapine and 1 to high-dose quetiapine plus risperidone, 2 mg/d; 4 received adjunctive dival-proex sodium, 1,500 to 3,000 mg/d. Psychopathology, violence, and behavioral disturbances were reduced throughout 5 to 14 months of monitoring. Side effects included sedation, orthostasis, and dysphagia.

When Nelson et al²⁴ treated 13 subjects for 14 weeks with quetiapine, 1,000 to 1,400 mg/d, mean weight, glucose, total cholesterol, prolactin, and QTc interval duration did not change significantly. Heart rate increased significantly (though not to tachycardia), and headache, constipation, and lethargy were the most frequent side effects.

Summary. Although encouraging, these reports are preliminary, unpublished, and lack peer review. Controlled trials of high-dose quetiapine’s efficacy and safety are needed.

Ziprasidone and aripiprazole

No studies of high-dose ziprasidone or aripiprazole have been published. In premarketing trials:

• ziprasidone was studied at 200 mg/d and released with a maximum recommended dosage of 160 mg/d
• aripiprazole, 30 mg/d, was not more effective than 15 mg/d.²⁵

Deutschman et al²⁶ reviewed the charts of 31 patients who received ziprasidone, 240 to 320 mg/d, after an “incomplete” response to 160 mg/d. At the higher dosing:

• psychosis, affective symptoms, or anxiety improved in nearly one-half of patients
• 15% reported sedation, but most reported no side effects
• none developed QTc intervals >500 msec.

Caveats and precautions

These uncontrolled case reports and open-label studies do not “prove” efficacy or safety but reflect clinical practice. More than anything, they show that we need controlled trials to gauge high-dose antipsychotic therapy’s efficacy and safety and to curb our collective habit of relying on anecdotal experience and idiosyncratic beliefs.

Despite its side-effect profile, clozapine remains the treatment of choice for refractory schizophrenia. Given high-dose antipsychotic therapy’s uncertain efficacy and unknown risks, the evidence supports a clozapine trial before higher-than-recommended dosing is attempted.

Because educated guesswork plays a role in premarketing dosing studies, a medication’s optimal dose may be:

• overestimated (as with risperidone)
• underestimated (as perhaps with olanzapine and quetiapine).

Keep in mind some important caveats when you consider giving a patient high-dose antipsychotic therapy (Box).²⁷ Of course, nonadherence is often the cause of apparent medication nonresponse. Increasing the dosage of a medication a patient is not taking rarely improves adherence. Interventions to enhance adherence—careful assessment, psychoeducation, and using longacting intramuscular medication—may be useful.

Related resources

• Marder SR, Essock SM, Miller AL, et al. The Mount Sinai Conference on the pharmacotherapy of schizophrenia. Schizophrenia Bull 2002;28:5-16.
• Practice guideline for the treatment of patients with schizophrenia (2nd ed). Am J Psychiatry 2004;161(suppl):1-56.
• Texas Medication Algorithm Project antipsychotic algorithm. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/timascz1algo.pdf

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Pierre receives research support from Cephalon Inc., and is a consultant to and/or speaker for Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.

Dr. Donna Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.

Dr. William Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals.

When nothing else works, desperate clinicians are resorting to progressively more-tenuous and unpredictable treatments, trying to improve the lives of patients with refractory schizophrenia. High-dose antipsychotics is a common strategy.

Does boosting antipsychotic doses beyond the recommended range—but short of the neuroleptic threshold—enhance efficacy? This article attempts to answer that question by presenting the evidence on higher-than-recommended doses of atypical antipsychotics.

Lessons from neuroleptics

Up to 30% of patients with schizophrenia do not respond to antipsychotics and are considered “treatment refractory.”¹ Even among those who do respond, improving symptoms by 20%—as research defines “treatment response”—does not necessarily yield clinical or functional improvement. Clozapine is the only atypical antipsychotic with well-established efficacy in these chronically ill patients,² but its daunting side effects greatly curtail its use.

Before atypical antipsychotics, patients who did not respond to usual dosages of the typical neuroleptics were treated with higher dosages or switched to another drug class. Although many clinicians embraced high-dose neuroleptics, subsequent research discredited “rapid neuroleptization” in any clinical circumstance and showed that exceeding an antipsychotic’s neuroleptic threshold—the dose at which extrapyramidal side effects (EPS) occur—reduces its efficacy (Figure 1).^3-5 In some instances, reducing neuroleptic dosages improves treatment-resistant patients’ symptoms and reduces druginduced side effects.⁶

Figure 1 Typical antipsychotics’ dose-response curve

Narrow therapeutic window between antipsychotic effect and neuroleptic threshold. Dotted line indicates declining efficacy.

Figure 2 Atypical antipsychotics’ dose-response curve

Wider therapeutic window with atypicals, compared with typical antipsychotics, as neuroleptic threshold (dotted line) moves right.Atypical antipsychotics are defined by their relative lack of EPS at recommended dosages (Figure 2). Because these agents can cause EPS if dosed too high, however, our historical habit of testing this dose limit risks losing “atypicality” and encountering other untoward events (Figure 3).

What is the safest, most effective dosage? Consider the evidence for each atypical antipsychotic.

Risperidone

Recommended dosage too high? When using atypicals at recommended doses, you are most likely to encounter the neuroleptic threshold with risperidone, with EPS risk increasing substantially at >6 mg/d.⁷ Post-approval studies set the most effective and safest dosage at approximately 4 mg/d, though this dosage was not studied in North American pre-approval trials. Dosages of 2 to 4 mg/d have been associated with more-favorable outcomes, suggesting that the initial recommendation to titrate to 6 mg/d within the first 3 days was ill-advised.⁸

In our study of patients with treatment-refractory schizophrenia,⁹ those treated with risperidone, 6 mg/d, improved significantly more after 4 weeks than did those receiving haloperidol, 15 mg/d, based on Brief Psychiatric Rating Scale (BPRS) scores. No additional benefit was seen after risperidone was increased to >6 mg/d at 8 weeks. Akathisia and tardive dyskinesia occurred significantly more often in the haloperidol group.

Conclusion. Some patients respond to higher-dose risperidone, but emerging EPS suggest the need to reduce the dosage rather than add an antiparkinsonian agent.

Figure 3 Unknown effects of high-dose atypical antipsychotic therapy

Dotted line indicates potential for greater antipsychotic effect with increasing dose.

Olanzapine

Mixed results. Case reports suggest that some patients who did not respond to previous antipsychotic trials or olanzapine, 20 mg/d, improved sig-nificantly—without substanial side effects—when olanzapine was increased up to 60 mg/d.^10-14 Other case studies, however, report EPS, increased heart rate, increased transaminases, hyperprolactinemia, and prolonged QTc interval with high-dose olanzapine.^14-16

In an open-label trial,¹⁷ 43 patients with schizophrenia received olanzapine, up to 40 mg/d, after inadequate response to neuroleptics and risperidone or clozapine. Olanzapine was titrated to 20 mg/d by week 4 and increased 5 mg every 2 weeks if symptoms did not improve. After 14 weeks, improvement was modest and only 17% of patients met response criteria. However, >20 mg/d reduced symptoms more than did <20 mg/d, suggesting that high-dose olanzapine was more effective.

In a randomized trial,¹⁸ patients who did not respond to at least one atypical antipsychotic then received 8 weeks of fixed, standard-dose treatment with (mean dosages):

• haloperidol, 18.9 mg/d
• risperidone, 7.9 mg/d
• olanzapine, 19.6 mg/d
• clozapine, 401.6 mg/d.

Flexible dosing was then allowed for 6 weeks, and mean dosages were:

• haloperidol, 25.7 mg/d
• risperidone, 11.6 mg/d
• olanzapine, 30.4 mg/d
• clozapine, 526.6 mg/d.

Symptoms improved modestly at best for all medications, although patients taking olanzapine or clozapine improved significantly more than those treated with haloperidol as shown by mean changes in total Positive and Negative Syndrome Scale (PANSS) scores.

PANSS scores for olanzapine-treated patients showed additional improvement at week 14—when higher dosages were used—compared with week 8. This was not the case for the other medications, for which response plateaued. These findings suggest that high-dose risperidone and haloperidol are incrementally ineffective, but high-dose olanzapine could help some patients with refractory symptoms.

Results were different in a randomized, double-blind, 16-week, crossover study,¹⁹ when 13 patients with inadequate response to neuroleptics, risperidone, or conventional-dose olanzapine then received olanzapine, 50 mg/d, or clozapine, 450 mg/d. No olanzapine-treated patients and 20% of clozapine-treated patients met criteria for treatment response (20% improvement in BPRS score and final BPRS score <35 or 1-point improvement on Clinical Global Impressions-Severity of Illness scale).

Box

Subjects switching from clozapine to olanzapine tended to worsen, whereas those switching from olanzapine to clozapine tended to improve. Olanzapine-treated patients experienced more anticholinergic side effects and more weight gain than did clozapine-treated subjects.²⁰

Conclusion. These mixed findings on high-dose olanzapine suggest questionable efficacy in patients with treatment-resistant schizophrenia and an uncertain risk of increased toxicity.

Quetiapine

Early placebo-controlled studies of quetiapine in schizophrenia concluded that statistically significant improvement begins at 150 mg/d and falls off after 600 mg/d.²¹ Although few high-dose quetiapine cases have been presented, clinical opinion holds that:

• most patients with chronic schizophrenia require 400 to 800 mg/d
• some treatment-refractory patients might benefit from >800 mg/d.

One patient responded to quetiapine, 1,600 mg/d, after not responding to olanzapine, 40 mg/d, and quetiapine, 800 mg/d. Constipation was the only reported side effect.²²

Our group²³ reported a series of 7 patients who responded (by clinician report) to quetiapine, 1,200 to 2,400 mg/d, after not responding to quetiapine, 800 mg/d, or to neuroleptics, risperidone, or olanzapine. Six responded to high-dose quetiapine and 1 to high-dose quetiapine plus risperidone, 2 mg/d; 4 received adjunctive dival-proex sodium, 1,500 to 3,000 mg/d. Psychopathology, violence, and behavioral disturbances were reduced throughout 5 to 14 months of monitoring. Side effects included sedation, orthostasis, and dysphagia.

When Nelson et al²⁴ treated 13 subjects for 14 weeks with quetiapine, 1,000 to 1,400 mg/d, mean weight, glucose, total cholesterol, prolactin, and QTc interval duration did not change significantly. Heart rate increased significantly (though not to tachycardia), and headache, constipation, and lethargy were the most frequent side effects.

Summary. Although encouraging, these reports are preliminary, unpublished, and lack peer review. Controlled trials of high-dose quetiapine’s efficacy and safety are needed.

Ziprasidone and aripiprazole

No studies of high-dose ziprasidone or aripiprazole have been published. In premarketing trials:

• ziprasidone was studied at 200 mg/d and released with a maximum recommended dosage of 160 mg/d
• aripiprazole, 30 mg/d, was not more effective than 15 mg/d.²⁵

Deutschman et al²⁶ reviewed the charts of 31 patients who received ziprasidone, 240 to 320 mg/d, after an “incomplete” response to 160 mg/d. At the higher dosing:

• psychosis, affective symptoms, or anxiety improved in nearly one-half of patients
• 15% reported sedation, but most reported no side effects
• none developed QTc intervals >500 msec.

Caveats and precautions

These uncontrolled case reports and open-label studies do not “prove” efficacy or safety but reflect clinical practice. More than anything, they show that we need controlled trials to gauge high-dose antipsychotic therapy’s efficacy and safety and to curb our collective habit of relying on anecdotal experience and idiosyncratic beliefs.

Despite its side-effect profile, clozapine remains the treatment of choice for refractory schizophrenia. Given high-dose antipsychotic therapy’s uncertain efficacy and unknown risks, the evidence supports a clozapine trial before higher-than-recommended dosing is attempted.

Because educated guesswork plays a role in premarketing dosing studies, a medication’s optimal dose may be:

• overestimated (as with risperidone)
• underestimated (as perhaps with olanzapine and quetiapine).

Keep in mind some important caveats when you consider giving a patient high-dose antipsychotic therapy (Box).²⁷ Of course, nonadherence is often the cause of apparent medication nonresponse. Increasing the dosage of a medication a patient is not taking rarely improves adherence. Interventions to enhance adherence—careful assessment, psychoeducation, and using longacting intramuscular medication—may be useful.

Related resources

• Marder SR, Essock SM, Miller AL, et al. The Mount Sinai Conference on the pharmacotherapy of schizophrenia. Schizophrenia Bull 2002;28:5-16.
• Practice guideline for the treatment of patients with schizophrenia (2nd ed). Am J Psychiatry 2004;161(suppl):1-56.
• Texas Medication Algorithm Project antipsychotic algorithm. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/timascz1algo.pdf

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Pierre receives research support from Cephalon Inc., and is a consultant to and/or speaker for Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.

Dr. Donna Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.

Dr. William Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals.

When nothing else works, desperate clinicians are resorting to progressively more-tenuous and unpredictable treatments, trying to improve the lives of patients with refractory schizophrenia. High-dose antipsychotics is a common strategy.

Does boosting antipsychotic doses beyond the recommended range—but short of the neuroleptic threshold—enhance efficacy? This article attempts to answer that question by presenting the evidence on higher-than-recommended doses of atypical antipsychotics.

Lessons from neuroleptics

Up to 30% of patients with schizophrenia do not respond to antipsychotics and are considered “treatment refractory.”¹ Even among those who do respond, improving symptoms by 20%—as research defines “treatment response”—does not necessarily yield clinical or functional improvement. Clozapine is the only atypical antipsychotic with well-established efficacy in these chronically ill patients,² but its daunting side effects greatly curtail its use.

Before atypical antipsychotics, patients who did not respond to usual dosages of the typical neuroleptics were treated with higher dosages or switched to another drug class. Although many clinicians embraced high-dose neuroleptics, subsequent research discredited “rapid neuroleptization” in any clinical circumstance and showed that exceeding an antipsychotic’s neuroleptic threshold—the dose at which extrapyramidal side effects (EPS) occur—reduces its efficacy (Figure 1).^3-5 In some instances, reducing neuroleptic dosages improves treatment-resistant patients’ symptoms and reduces druginduced side effects.⁶

Figure 1 Typical antipsychotics’ dose-response curve

Narrow therapeutic window between antipsychotic effect and neuroleptic threshold. Dotted line indicates declining efficacy.

Figure 2 Atypical antipsychotics’ dose-response curve

Wider therapeutic window with atypicals, compared with typical antipsychotics, as neuroleptic threshold (dotted line) moves right.Atypical antipsychotics are defined by their relative lack of EPS at recommended dosages (Figure 2). Because these agents can cause EPS if dosed too high, however, our historical habit of testing this dose limit risks losing “atypicality” and encountering other untoward events (Figure 3).

What is the safest, most effective dosage? Consider the evidence for each atypical antipsychotic.

Risperidone

Recommended dosage too high? When using atypicals at recommended doses, you are most likely to encounter the neuroleptic threshold with risperidone, with EPS risk increasing substantially at >6 mg/d.⁷ Post-approval studies set the most effective and safest dosage at approximately 4 mg/d, though this dosage was not studied in North American pre-approval trials. Dosages of 2 to 4 mg/d have been associated with more-favorable outcomes, suggesting that the initial recommendation to titrate to 6 mg/d within the first 3 days was ill-advised.⁸

In our study of patients with treatment-refractory schizophrenia,⁹ those treated with risperidone, 6 mg/d, improved significantly more after 4 weeks than did those receiving haloperidol, 15 mg/d, based on Brief Psychiatric Rating Scale (BPRS) scores. No additional benefit was seen after risperidone was increased to >6 mg/d at 8 weeks. Akathisia and tardive dyskinesia occurred significantly more often in the haloperidol group.

Conclusion. Some patients respond to higher-dose risperidone, but emerging EPS suggest the need to reduce the dosage rather than add an antiparkinsonian agent.

Figure 3 Unknown effects of high-dose atypical antipsychotic therapy

Dotted line indicates potential for greater antipsychotic effect with increasing dose.

Olanzapine

Mixed results. Case reports suggest that some patients who did not respond to previous antipsychotic trials or olanzapine, 20 mg/d, improved sig-nificantly—without substanial side effects—when olanzapine was increased up to 60 mg/d.^10-14 Other case studies, however, report EPS, increased heart rate, increased transaminases, hyperprolactinemia, and prolonged QTc interval with high-dose olanzapine.^14-16

In an open-label trial,¹⁷ 43 patients with schizophrenia received olanzapine, up to 40 mg/d, after inadequate response to neuroleptics and risperidone or clozapine. Olanzapine was titrated to 20 mg/d by week 4 and increased 5 mg every 2 weeks if symptoms did not improve. After 14 weeks, improvement was modest and only 17% of patients met response criteria. However, >20 mg/d reduced symptoms more than did <20 mg/d, suggesting that high-dose olanzapine was more effective.

In a randomized trial,¹⁸ patients who did not respond to at least one atypical antipsychotic then received 8 weeks of fixed, standard-dose treatment with (mean dosages):

• haloperidol, 18.9 mg/d
• risperidone, 7.9 mg/d
• olanzapine, 19.6 mg/d
• clozapine, 401.6 mg/d.

Flexible dosing was then allowed for 6 weeks, and mean dosages were:

• haloperidol, 25.7 mg/d
• risperidone, 11.6 mg/d
• olanzapine, 30.4 mg/d
• clozapine, 526.6 mg/d.

Symptoms improved modestly at best for all medications, although patients taking olanzapine or clozapine improved significantly more than those treated with haloperidol as shown by mean changes in total Positive and Negative Syndrome Scale (PANSS) scores.

PANSS scores for olanzapine-treated patients showed additional improvement at week 14—when higher dosages were used—compared with week 8. This was not the case for the other medications, for which response plateaued. These findings suggest that high-dose risperidone and haloperidol are incrementally ineffective, but high-dose olanzapine could help some patients with refractory symptoms.

Results were different in a randomized, double-blind, 16-week, crossover study,¹⁹ when 13 patients with inadequate response to neuroleptics, risperidone, or conventional-dose olanzapine then received olanzapine, 50 mg/d, or clozapine, 450 mg/d. No olanzapine-treated patients and 20% of clozapine-treated patients met criteria for treatment response (20% improvement in BPRS score and final BPRS score <35 or 1-point improvement on Clinical Global Impressions-Severity of Illness scale).

Box

Subjects switching from clozapine to olanzapine tended to worsen, whereas those switching from olanzapine to clozapine tended to improve. Olanzapine-treated patients experienced more anticholinergic side effects and more weight gain than did clozapine-treated subjects.²⁰

Conclusion. These mixed findings on high-dose olanzapine suggest questionable efficacy in patients with treatment-resistant schizophrenia and an uncertain risk of increased toxicity.

Quetiapine

Early placebo-controlled studies of quetiapine in schizophrenia concluded that statistically significant improvement begins at 150 mg/d and falls off after 600 mg/d.²¹ Although few high-dose quetiapine cases have been presented, clinical opinion holds that:

• most patients with chronic schizophrenia require 400 to 800 mg/d
• some treatment-refractory patients might benefit from >800 mg/d.

One patient responded to quetiapine, 1,600 mg/d, after not responding to olanzapine, 40 mg/d, and quetiapine, 800 mg/d. Constipation was the only reported side effect.²²

Our group²³ reported a series of 7 patients who responded (by clinician report) to quetiapine, 1,200 to 2,400 mg/d, after not responding to quetiapine, 800 mg/d, or to neuroleptics, risperidone, or olanzapine. Six responded to high-dose quetiapine and 1 to high-dose quetiapine plus risperidone, 2 mg/d; 4 received adjunctive dival-proex sodium, 1,500 to 3,000 mg/d. Psychopathology, violence, and behavioral disturbances were reduced throughout 5 to 14 months of monitoring. Side effects included sedation, orthostasis, and dysphagia.

When Nelson et al²⁴ treated 13 subjects for 14 weeks with quetiapine, 1,000 to 1,400 mg/d, mean weight, glucose, total cholesterol, prolactin, and QTc interval duration did not change significantly. Heart rate increased significantly (though not to tachycardia), and headache, constipation, and lethargy were the most frequent side effects.

Summary. Although encouraging, these reports are preliminary, unpublished, and lack peer review. Controlled trials of high-dose quetiapine’s efficacy and safety are needed.

Ziprasidone and aripiprazole

No studies of high-dose ziprasidone or aripiprazole have been published. In premarketing trials:

• ziprasidone was studied at 200 mg/d and released with a maximum recommended dosage of 160 mg/d
• aripiprazole, 30 mg/d, was not more effective than 15 mg/d.²⁵

Deutschman et al²⁶ reviewed the charts of 31 patients who received ziprasidone, 240 to 320 mg/d, after an “incomplete” response to 160 mg/d. At the higher dosing:

• psychosis, affective symptoms, or anxiety improved in nearly one-half of patients
• 15% reported sedation, but most reported no side effects
• none developed QTc intervals >500 msec.

Caveats and precautions

These uncontrolled case reports and open-label studies do not “prove” efficacy or safety but reflect clinical practice. More than anything, they show that we need controlled trials to gauge high-dose antipsychotic therapy’s efficacy and safety and to curb our collective habit of relying on anecdotal experience and idiosyncratic beliefs.

Despite its side-effect profile, clozapine remains the treatment of choice for refractory schizophrenia. Given high-dose antipsychotic therapy’s uncertain efficacy and unknown risks, the evidence supports a clozapine trial before higher-than-recommended dosing is attempted.

Because educated guesswork plays a role in premarketing dosing studies, a medication’s optimal dose may be:

• overestimated (as with risperidone)
• underestimated (as perhaps with olanzapine and quetiapine).

Keep in mind some important caveats when you consider giving a patient high-dose antipsychotic therapy (Box).²⁷ Of course, nonadherence is often the cause of apparent medication nonresponse. Increasing the dosage of a medication a patient is not taking rarely improves adherence. Interventions to enhance adherence—careful assessment, psychoeducation, and using longacting intramuscular medication—may be useful.

Related resources

• Marder SR, Essock SM, Miller AL, et al. The Mount Sinai Conference on the pharmacotherapy of schizophrenia. Schizophrenia Bull 2002;28:5-16.
• Practice guideline for the treatment of patients with schizophrenia (2nd ed). Am J Psychiatry 2004;161(suppl):1-56.
• Texas Medication Algorithm Project antipsychotic algorithm. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/timascz1algo.pdf

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Pierre receives research support from Cephalon Inc., and is a consultant to and/or speaker for Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.

Dr. Donna Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.

Dr. William Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals.

Often we encounter patients who are angry about having been “forced” to see a psychiatrist:

• In the emergency room or inpatient setting, patients who present with an apparent medical problem may become upset after learning that a psychiatric evaluation has been ordered without their knowledge or against their wishes.
• In outpatient clinics, patients who arrive under “coercion” from parents, spouses, or employers can also be hostile.

Defusing the hostility and engaging the patient are critical first steps toward a therapeutic alliance. When faced with a hostile patient, take a deep breath, control your emotions, and follow the PEACE principle: presence, empathy, acceptance, collaboration, and empowerment.

Presence. From the outset, make it clear that the patient has your undivided attention. Nonverbal cues such as sitting down, maintaining comfortable eye contact, and not writing notes during the interview’s initial stages give this impression.

Empathy. As you sit quietly and attentively, encourage the patient to vent his or her anger over being “forced” to see a psychiatrist. Most of us can empathize with a person who feels powerless, patronized, or coerced.

Acceptance. Acknowledging the patient’s distress can go far toward diminishing or defusing the anger. For example, tell the patient, “I understand that this is unsettling for you,” or “I, too, wish the circumstances were different because this is obviously difficult for you.”

Collaboration. Tell the patient you only want to help him, to be his partner in a therapeutic alliance.

Empower. Never force the evaluation. Rather, let the patient decide whether to proceed. Tell her, “I want to help you with what’s been going on in your life, but it’s totally up to you to continue. I cannot—and don’t want to—force you to do something you choose not to do.”

Then offer alternatives such as:

• a follow-up appointment
• a visit the next day if the patient is hospitalized
• or telling the emergency physician that the patient declined the psychiatric evaluation.

I find that when using this approach the patient usually agrees to a therapeutic assessment.

Often we encounter patients who are angry about having been “forced” to see a psychiatrist:

• In the emergency room or inpatient setting, patients who present with an apparent medical problem may become upset after learning that a psychiatric evaluation has been ordered without their knowledge or against their wishes.
• In outpatient clinics, patients who arrive under “coercion” from parents, spouses, or employers can also be hostile.

Defusing the hostility and engaging the patient are critical first steps toward a therapeutic alliance. When faced with a hostile patient, take a deep breath, control your emotions, and follow the PEACE principle: presence, empathy, acceptance, collaboration, and empowerment.

Presence. From the outset, make it clear that the patient has your undivided attention. Nonverbal cues such as sitting down, maintaining comfortable eye contact, and not writing notes during the interview’s initial stages give this impression.

Empathy. As you sit quietly and attentively, encourage the patient to vent his or her anger over being “forced” to see a psychiatrist. Most of us can empathize with a person who feels powerless, patronized, or coerced.

Acceptance. Acknowledging the patient’s distress can go far toward diminishing or defusing the anger. For example, tell the patient, “I understand that this is unsettling for you,” or “I, too, wish the circumstances were different because this is obviously difficult for you.”

Collaboration. Tell the patient you only want to help him, to be his partner in a therapeutic alliance.

Empower. Never force the evaluation. Rather, let the patient decide whether to proceed. Tell her, “I want to help you with what’s been going on in your life, but it’s totally up to you to continue. I cannot—and don’t want to—force you to do something you choose not to do.”

Then offer alternatives such as:

• a follow-up appointment
• a visit the next day if the patient is hospitalized
• or telling the emergency physician that the patient declined the psychiatric evaluation.

I find that when using this approach the patient usually agrees to a therapeutic assessment.

Often we encounter patients who are angry about having been “forced” to see a psychiatrist:

• In the emergency room or inpatient setting, patients who present with an apparent medical problem may become upset after learning that a psychiatric evaluation has been ordered without their knowledge or against their wishes.
• In outpatient clinics, patients who arrive under “coercion” from parents, spouses, or employers can also be hostile.

Defusing the hostility and engaging the patient are critical first steps toward a therapeutic alliance. When faced with a hostile patient, take a deep breath, control your emotions, and follow the PEACE principle: presence, empathy, acceptance, collaboration, and empowerment.

Presence. From the outset, make it clear that the patient has your undivided attention. Nonverbal cues such as sitting down, maintaining comfortable eye contact, and not writing notes during the interview’s initial stages give this impression.

Empathy. As you sit quietly and attentively, encourage the patient to vent his or her anger over being “forced” to see a psychiatrist. Most of us can empathize with a person who feels powerless, patronized, or coerced.

Acceptance. Acknowledging the patient’s distress can go far toward diminishing or defusing the anger. For example, tell the patient, “I understand that this is unsettling for you,” or “I, too, wish the circumstances were different because this is obviously difficult for you.”

Collaboration. Tell the patient you only want to help him, to be his partner in a therapeutic alliance.

Empower. Never force the evaluation. Rather, let the patient decide whether to proceed. Tell her, “I want to help you with what’s been going on in your life, but it’s totally up to you to continue. I cannot—and don’t want to—force you to do something you choose not to do.”

Then offer alternatives such as:

• a follow-up appointment
• a visit the next day if the patient is hospitalized
• or telling the emergency physician that the patient declined the psychiatric evaluation.

I find that when using this approach the patient usually agrees to a therapeutic assessment.

Like you, I always worry about being sued for malpractice. I comfort myself by knowing that not every psychiatrist—or even the majority—has to agree with the way I practice. To meet the “standard of care” and fulfill my duty to patients, my practice just needs to be endorsed by a respectable minority of practitioners.

Two articles in this issue illustrate the legitimate diversity of opinion within psychiatry. Drs. Joseph Pierre, Donna Wirshing, and William Wirshing at UCLA provide an excellent review on higher-than-recommended antipsychotic dosages for patients with treatment-refractory schizophrenia. They conclude that:

• there is very little evidence that high dosages are more effective than usual dosages
• patients who do not respond to usual dosages should be switched to clozapine before high-dose therapy is tried.

We invited Sheldon Preskorn, MD—a Current Psychiatry associate editor—to review the article. Based on his research in clinical psychopharmacology, he wrote a commentary to explain the variables that determine patient response to drug therapy. He suggests that:

• some patients may need higher antipsychotic dosages, which might be tried before switching medications
• plasma levels should be considered before changing treatments.

We’ll let you decide which approach or synthesis of approaches works for you. Whichever you choose will be supported by at least a respectable minority of practitioners.

Like you, I always worry about being sued for malpractice. I comfort myself by knowing that not every psychiatrist—or even the majority—has to agree with the way I practice. To meet the “standard of care” and fulfill my duty to patients, my practice just needs to be endorsed by a respectable minority of practitioners.

Two articles in this issue illustrate the legitimate diversity of opinion within psychiatry. Drs. Joseph Pierre, Donna Wirshing, and William Wirshing at UCLA provide an excellent review on higher-than-recommended antipsychotic dosages for patients with treatment-refractory schizophrenia. They conclude that:

• there is very little evidence that high dosages are more effective than usual dosages
• patients who do not respond to usual dosages should be switched to clozapine before high-dose therapy is tried.

We invited Sheldon Preskorn, MD—a Current Psychiatry associate editor—to review the article. Based on his research in clinical psychopharmacology, he wrote a commentary to explain the variables that determine patient response to drug therapy. He suggests that:

• some patients may need higher antipsychotic dosages, which might be tried before switching medications
• plasma levels should be considered before changing treatments.

We’ll let you decide which approach or synthesis of approaches works for you. Whichever you choose will be supported by at least a respectable minority of practitioners.

Like you, I always worry about being sued for malpractice. I comfort myself by knowing that not every psychiatrist—or even the majority—has to agree with the way I practice. To meet the “standard of care” and fulfill my duty to patients, my practice just needs to be endorsed by a respectable minority of practitioners.

Two articles in this issue illustrate the legitimate diversity of opinion within psychiatry. Drs. Joseph Pierre, Donna Wirshing, and William Wirshing at UCLA provide an excellent review on higher-than-recommended antipsychotic dosages for patients with treatment-refractory schizophrenia. They conclude that:

• there is very little evidence that high dosages are more effective than usual dosages
• patients who do not respond to usual dosages should be switched to clozapine before high-dose therapy is tried.

We invited Sheldon Preskorn, MD—a Current Psychiatry associate editor—to review the article. Based on his research in clinical psychopharmacology, he wrote a commentary to explain the variables that determine patient response to drug therapy. He suggests that:

• some patients may need higher antipsychotic dosages, which might be tried before switching medications
• plasma levels should be considered before changing treatments.

We’ll let you decide which approach or synthesis of approaches works for you. Whichever you choose will be supported by at least a respectable minority of practitioners.

Psychiatrists may consider using higher than usually recommended dosages of antipsychotics when faced with nonresponse. In this issue , Pierre et al¹ carefully and thoughtfully discuss the pros and cons of this practice in patients with schizophrenia. Having reviewed that article, I thought CURRENT PSYCHIATRY’s readers might benefit from a theoretical framework for analyzing drug response.

‘Usual’ vs ‘unusual’ patients

A clinical trial for drug registration is, in essence, a population pharmacokinetic study whose goal is to determine the usual dosage for the usual patient in the trial. Many patients seen in clinical practice, such as those with treatment-refractory psychotic disorders, are typically excluded from registration trials. Thus, the usual registration trial patient may be an unusual patient in a clinician’s practice, and the trial’s usual dosage may not produce an adequate response for the clinician’s usual patient. How, then, might a clinician approach inadequate response, except by:

• blindly exceeding the usually recommended dosage
• switching among available drugs
• adding drugs to create a complex cocktail?

This commentary dissects why a patient might not benefit from the usual recommended dosage and how that could lead to different courses of action.

Equation 1. Three variables (Table) determine response to any drug:

• affinity for and intrinsic action on a regulatory protein (such as a receptor)
• concentration (amount of drug reaching the site of action)
• biological variance, which can shift an individual’s dose-response curve relative to that of the “usual” patient, making that individual more or less sensitive to the drug’s effects.²

Table

3 variables that determine patient response to any drug

Equation 2. Drug concentration is dosing rate divided by clearance in a given patient. Dosing rate and clearance are equally important in determining drug concentration—which, in turn, determines the site of action engaged, to what degree, and the patient’s response to the drug.

Causes of inadequate response. Nonadherence is a common cause of inadequate response. When a patient repeatedly misses doses or stops taking the drug, the true dosing rate is lower than the prescribed dosing rate, resulting in reduced drug concentration and effect.

Pierre and colleagues focus on the “unusual” patient who does not respond optimally to antipsychotic dosages established in registration trials.¹ As in Equation 1, sources of biological variance—genetics, age, disease, and environment (internal)—may distinguish the treatment-refractory patient from the responsive patient. The mnemonic GADE captures these variables:

Genetic variation refers to mutations in regulatory proteins that:

• determine the drug’s action (such mutations may change the drug’s binding affinity, so that a higher concentration is needed to adequately engage the site)
• determine what drug concentration reaches the site of action (such as drug-metabolizing enzymes that regulate clearance, or transporter proteins that prevent or facilitate the drug’s ability to reach the site of action).

Age refers to physiologic changes (pharmacodynamic or pharmacokinetic) that make the patient more or less sensitive to the drug’s effects.

Disease refers to differences in organ function related to pathophysiology. Patients with the same clinical presentation (in this case, psychosis) may respond differently to the same drug because they have different underlying pathophysiologies (such as schizophrenic syndrome due to differing genetic causes or to toxins or slow viruses).

Environment (internal) refers to exogenous substances in the body—such as drugs and dietary substances—that can interact with and influence response to other drugs.

Nonpsychiatric disease also can alter response to medication. For example, impaired hepatic, renal, or cardiac function can impair drug clearance, leading to greater-than-usual accumulation. Such a patient can be “sensitive” to the drug and experience a greater effect than is usually seen with the dosage given.

Dosing for clinical effect

Psychiatrists commonly titrate dosages based on clinical assessment of response.³ The clinician increases the dosage if a patient does not improve and has no obvious rate-limiting adverse effects.

Perhaps without realizing it, the clinician is assuming that the dosage is inadequate for a given patient because the concentration is inadequate due to rapid clearance. Other reasons are possible, however, such as:

• the drug is not reaching the site of action a mutation at the site of action is altering
• the drug’s binding affinity
• the concentration may be too high, but the resulting adverse effects resemble worsening of the disease being treated. For example, akathisia due to dopamine-2 receptor blockade can present as agitation, and the clinician may increase the dosage when it should be decreased.

In the first two instances, escalating the dosage may be beneficial or cause toxicity. High levels in a peripheral compartment can cause adverse effects that may be silent until they become deadly (such as torsades de pointes). In the third instance, dosage escalation is the wrong step because the level is already too high.

Recommended dosage range

Principal goals of phase I studies in drug development are to establish the optimal dosage range and a maximum tolerated dosage. This upper limit is rarely, if ever, exceeded in later trials. Because phase I trial results are rarely published, the prescriber often does not know the rationale for a recommended dosing range’s upper limit.

Clinicians who escalate a drug’s dosage above the recommended range are using an n=1 paradigm, in which the patient is his or her own control. Unfortunately, treating one patient at a time cannot detect infrequent (much less rare) adverse events.

Using higher-than-recommended dosages thus exposes patients to unknown risks, with less monitoring than in a typical phase I trial in which subjects are confined to a research unit before, during, and after drug exposure. During the study, participants undergo serial ECGs, laboratory tests, and plasma drug level monitoring.

Therapeutic drug monitoring (TDM) is based on the concept that a meaningful relationship exists between a drug’s plasma concentration and its concentration at the site of action. Clinicians can measure the drug’s plasma concentration relative to the presumed dosage a patient is taking.

When nonadherence is the reason for nonresponse to usual dosing, TDM measurements of drug concentration would be lower than expected—or nonexistent with complete nonadherence. Rapid clearance, however, can also cause lower-than-expected levels on a given dosage.

So, how can the clinician determine whether the problem is rapid clearance or noncompliance? One way is to repeat the plasma level after arranging for supervised dosing for at least five times the half-life of the drug being measured. A higher level on follow-up would indicate that noncompliance is the likely problem. If the repeat level remains low, then the problem is most likely rapid clearance. In the latter case, the patient would need a higher dosage to achieve the concentrations associated with response in clinical trials.

Although TDM’s results are often conceptualized as being relative to a therapeutic range, TDM is fundamentally a means of measuring a patient’s ability to clear the drug. If the dosing rate and plasma drug level are known, then the clinician can solve for clearance by rearranging Equation 2. Rather than formally solving for clearance, results can be considered as within, below, or above the expected range for the dosage given. The clinician can then adjust the dosage to compensate for clearance that is faster or slower than usual. Thus, TDM allows clinicians to individualize dosages, taking into account the biological variances (Equation 1) that affect a patient’s ability to clear a specific drug.

TDM has limitations. It cannot assess whether a genetic mutation may be altering a drug’s binding affinity at the receptor site or whether the drug is not reaching the target compartment because of an abnormality in distribution mechanisms. Those possibilities would need to be assessed by techniques not available to most clinicians today.

Many psychiatrists think the inability to show a correlation between plasma drug levels and response is a limitation of TDM. That is not a limitation of TDM as much as a reflection on clinical trials of psychiatric drugs. Many such trials fail because of poor “signal-to-noise ratio”—defined as the true specific response to the treatment versus either placebo response or nonresponse due to not having an illness that is responsive to the drug.

Consider instead that the usually effective dosage defines a usually expected plasma drug concentration range associated with response. Further discussion of this topic is beyond the scope of this commentary, but the interested reader is referred to articles at www.preskorn.com, including Clinical pharmacology of serotonin selective re-uptake inhibitors (chapter 5); the column, Understanding dose-response curves in psychiatry; and the discussion, Finding the signal through the noise.

Summary

Based on the review by Pierre et al, the evidence for high-dose atypical antipsychotics’ safety and tolerability is not encouraging. These authors found only a modest body of evidence, and most study designs were not rigorous enough to eliminate erroneous conclusions. My intent here is not to advocate the use of higher-than-recommended dosages but to explain reasons why the patient may not respond and to call for more research.

Investigators designing future studies of nonresponse could consider including procedures to first rule out noncompliance and then divide participants into two groups:

• patients who achieved usual plasma drug levels on the usual recommended dosages (normal clearance)
• those who achieved levels below the usual expected range, despite good compliance (rapid clearance).

These two groups could then be randomized to continued exposure to the usual dosing range or higher-than-usual dosing. Patients with rapid clearance would be predicted to have a greater response to higher-than-usual dosing, compared with those with usual clearance.

In the absence of such trials, the clinician should proceed cautiously—if at all—to use higher-than usual antipsychotic dosages in his or her patients. The prescriber must always consider whether the risks outweigh the potential benefits, taking into account:

• the drug’s therapeutic index
• evidence of safety and tolerability problems in the individual patient as the dosage is escalated.

Related resources

• Preskorn SH. The recommended dosage range: How is it established and why would it ever be exceeded? J Psychiatry Pract 2004;10(4):249-54.

Psychiatrists may consider using higher than usually recommended dosages of antipsychotics when faced with nonresponse. In this issue , Pierre et al¹ carefully and thoughtfully discuss the pros and cons of this practice in patients with schizophrenia. Having reviewed that article, I thought CURRENT PSYCHIATRY’s readers might benefit from a theoretical framework for analyzing drug response.

‘Usual’ vs ‘unusual’ patients

A clinical trial for drug registration is, in essence, a population pharmacokinetic study whose goal is to determine the usual dosage for the usual patient in the trial. Many patients seen in clinical practice, such as those with treatment-refractory psychotic disorders, are typically excluded from registration trials. Thus, the usual registration trial patient may be an unusual patient in a clinician’s practice, and the trial’s usual dosage may not produce an adequate response for the clinician’s usual patient. How, then, might a clinician approach inadequate response, except by:

• blindly exceeding the usually recommended dosage
• switching among available drugs
• adding drugs to create a complex cocktail?

This commentary dissects why a patient might not benefit from the usual recommended dosage and how that could lead to different courses of action.

Equation 1. Three variables (Table) determine response to any drug:

• affinity for and intrinsic action on a regulatory protein (such as a receptor)
• concentration (amount of drug reaching the site of action)
• biological variance, which can shift an individual’s dose-response curve relative to that of the “usual” patient, making that individual more or less sensitive to the drug’s effects.²

Table

3 variables that determine patient response to any drug

Equation 2. Drug concentration is dosing rate divided by clearance in a given patient. Dosing rate and clearance are equally important in determining drug concentration—which, in turn, determines the site of action engaged, to what degree, and the patient’s response to the drug.

Causes of inadequate response. Nonadherence is a common cause of inadequate response. When a patient repeatedly misses doses or stops taking the drug, the true dosing rate is lower than the prescribed dosing rate, resulting in reduced drug concentration and effect.

Pierre and colleagues focus on the “unusual” patient who does not respond optimally to antipsychotic dosages established in registration trials.¹ As in Equation 1, sources of biological variance—genetics, age, disease, and environment (internal)—may distinguish the treatment-refractory patient from the responsive patient. The mnemonic GADE captures these variables:

Genetic variation refers to mutations in regulatory proteins that:

• determine the drug’s action (such mutations may change the drug’s binding affinity, so that a higher concentration is needed to adequately engage the site)
• determine what drug concentration reaches the site of action (such as drug-metabolizing enzymes that regulate clearance, or transporter proteins that prevent or facilitate the drug’s ability to reach the site of action).

Age refers to physiologic changes (pharmacodynamic or pharmacokinetic) that make the patient more or less sensitive to the drug’s effects.

Disease refers to differences in organ function related to pathophysiology. Patients with the same clinical presentation (in this case, psychosis) may respond differently to the same drug because they have different underlying pathophysiologies (such as schizophrenic syndrome due to differing genetic causes or to toxins or slow viruses).

Environment (internal) refers to exogenous substances in the body—such as drugs and dietary substances—that can interact with and influence response to other drugs.

Nonpsychiatric disease also can alter response to medication. For example, impaired hepatic, renal, or cardiac function can impair drug clearance, leading to greater-than-usual accumulation. Such a patient can be “sensitive” to the drug and experience a greater effect than is usually seen with the dosage given.

Dosing for clinical effect

Psychiatrists commonly titrate dosages based on clinical assessment of response.³ The clinician increases the dosage if a patient does not improve and has no obvious rate-limiting adverse effects.

Perhaps without realizing it, the clinician is assuming that the dosage is inadequate for a given patient because the concentration is inadequate due to rapid clearance. Other reasons are possible, however, such as:

• the drug is not reaching the site of action a mutation at the site of action is altering
• the drug’s binding affinity
• the concentration may be too high, but the resulting adverse effects resemble worsening of the disease being treated. For example, akathisia due to dopamine-2 receptor blockade can present as agitation, and the clinician may increase the dosage when it should be decreased.

In the first two instances, escalating the dosage may be beneficial or cause toxicity. High levels in a peripheral compartment can cause adverse effects that may be silent until they become deadly (such as torsades de pointes). In the third instance, dosage escalation is the wrong step because the level is already too high.

Recommended dosage range

Principal goals of phase I studies in drug development are to establish the optimal dosage range and a maximum tolerated dosage. This upper limit is rarely, if ever, exceeded in later trials. Because phase I trial results are rarely published, the prescriber often does not know the rationale for a recommended dosing range’s upper limit.

Clinicians who escalate a drug’s dosage above the recommended range are using an n=1 paradigm, in which the patient is his or her own control. Unfortunately, treating one patient at a time cannot detect infrequent (much less rare) adverse events.

Using higher-than-recommended dosages thus exposes patients to unknown risks, with less monitoring than in a typical phase I trial in which subjects are confined to a research unit before, during, and after drug exposure. During the study, participants undergo serial ECGs, laboratory tests, and plasma drug level monitoring.

Therapeutic drug monitoring (TDM) is based on the concept that a meaningful relationship exists between a drug’s plasma concentration and its concentration at the site of action. Clinicians can measure the drug’s plasma concentration relative to the presumed dosage a patient is taking.

When nonadherence is the reason for nonresponse to usual dosing, TDM measurements of drug concentration would be lower than expected—or nonexistent with complete nonadherence. Rapid clearance, however, can also cause lower-than-expected levels on a given dosage.

So, how can the clinician determine whether the problem is rapid clearance or noncompliance? One way is to repeat the plasma level after arranging for supervised dosing for at least five times the half-life of the drug being measured. A higher level on follow-up would indicate that noncompliance is the likely problem. If the repeat level remains low, then the problem is most likely rapid clearance. In the latter case, the patient would need a higher dosage to achieve the concentrations associated with response in clinical trials.

Although TDM’s results are often conceptualized as being relative to a therapeutic range, TDM is fundamentally a means of measuring a patient’s ability to clear the drug. If the dosing rate and plasma drug level are known, then the clinician can solve for clearance by rearranging Equation 2. Rather than formally solving for clearance, results can be considered as within, below, or above the expected range for the dosage given. The clinician can then adjust the dosage to compensate for clearance that is faster or slower than usual. Thus, TDM allows clinicians to individualize dosages, taking into account the biological variances (Equation 1) that affect a patient’s ability to clear a specific drug.

TDM has limitations. It cannot assess whether a genetic mutation may be altering a drug’s binding affinity at the receptor site or whether the drug is not reaching the target compartment because of an abnormality in distribution mechanisms. Those possibilities would need to be assessed by techniques not available to most clinicians today.

Many psychiatrists think the inability to show a correlation between plasma drug levels and response is a limitation of TDM. That is not a limitation of TDM as much as a reflection on clinical trials of psychiatric drugs. Many such trials fail because of poor “signal-to-noise ratio”—defined as the true specific response to the treatment versus either placebo response or nonresponse due to not having an illness that is responsive to the drug.

Consider instead that the usually effective dosage defines a usually expected plasma drug concentration range associated with response. Further discussion of this topic is beyond the scope of this commentary, but the interested reader is referred to articles at www.preskorn.com, including Clinical pharmacology of serotonin selective re-uptake inhibitors (chapter 5); the column, Understanding dose-response curves in psychiatry; and the discussion, Finding the signal through the noise.

Summary

Based on the review by Pierre et al, the evidence for high-dose atypical antipsychotics’ safety and tolerability is not encouraging. These authors found only a modest body of evidence, and most study designs were not rigorous enough to eliminate erroneous conclusions. My intent here is not to advocate the use of higher-than-recommended dosages but to explain reasons why the patient may not respond and to call for more research.

Investigators designing future studies of nonresponse could consider including procedures to first rule out noncompliance and then divide participants into two groups:

• patients who achieved usual plasma drug levels on the usual recommended dosages (normal clearance)
• those who achieved levels below the usual expected range, despite good compliance (rapid clearance).

These two groups could then be randomized to continued exposure to the usual dosing range or higher-than-usual dosing. Patients with rapid clearance would be predicted to have a greater response to higher-than-usual dosing, compared with those with usual clearance.

In the absence of such trials, the clinician should proceed cautiously—if at all—to use higher-than usual antipsychotic dosages in his or her patients. The prescriber must always consider whether the risks outweigh the potential benefits, taking into account:

• the drug’s therapeutic index
• evidence of safety and tolerability problems in the individual patient as the dosage is escalated.

Related resources

• Preskorn SH. The recommended dosage range: How is it established and why would it ever be exceeded? J Psychiatry Pract 2004;10(4):249-54.

Psychiatrists may consider using higher than usually recommended dosages of antipsychotics when faced with nonresponse. In this issue , Pierre et al¹ carefully and thoughtfully discuss the pros and cons of this practice in patients with schizophrenia. Having reviewed that article, I thought CURRENT PSYCHIATRY’s readers might benefit from a theoretical framework for analyzing drug response.

‘Usual’ vs ‘unusual’ patients

A clinical trial for drug registration is, in essence, a population pharmacokinetic study whose goal is to determine the usual dosage for the usual patient in the trial. Many patients seen in clinical practice, such as those with treatment-refractory psychotic disorders, are typically excluded from registration trials. Thus, the usual registration trial patient may be an unusual patient in a clinician’s practice, and the trial’s usual dosage may not produce an adequate response for the clinician’s usual patient. How, then, might a clinician approach inadequate response, except by:

• blindly exceeding the usually recommended dosage
• switching among available drugs
• adding drugs to create a complex cocktail?

This commentary dissects why a patient might not benefit from the usual recommended dosage and how that could lead to different courses of action.

Equation 1. Three variables (Table) determine response to any drug:

• affinity for and intrinsic action on a regulatory protein (such as a receptor)
• concentration (amount of drug reaching the site of action)
• biological variance, which can shift an individual’s dose-response curve relative to that of the “usual” patient, making that individual more or less sensitive to the drug’s effects.²

Table

3 variables that determine patient response to any drug

Equation 2. Drug concentration is dosing rate divided by clearance in a given patient. Dosing rate and clearance are equally important in determining drug concentration—which, in turn, determines the site of action engaged, to what degree, and the patient’s response to the drug.

Causes of inadequate response. Nonadherence is a common cause of inadequate response. When a patient repeatedly misses doses or stops taking the drug, the true dosing rate is lower than the prescribed dosing rate, resulting in reduced drug concentration and effect.

Pierre and colleagues focus on the “unusual” patient who does not respond optimally to antipsychotic dosages established in registration trials.¹ As in Equation 1, sources of biological variance—genetics, age, disease, and environment (internal)—may distinguish the treatment-refractory patient from the responsive patient. The mnemonic GADE captures these variables:

Genetic variation refers to mutations in regulatory proteins that:

• determine the drug’s action (such mutations may change the drug’s binding affinity, so that a higher concentration is needed to adequately engage the site)
• determine what drug concentration reaches the site of action (such as drug-metabolizing enzymes that regulate clearance, or transporter proteins that prevent or facilitate the drug’s ability to reach the site of action).

Age refers to physiologic changes (pharmacodynamic or pharmacokinetic) that make the patient more or less sensitive to the drug’s effects.

Disease refers to differences in organ function related to pathophysiology. Patients with the same clinical presentation (in this case, psychosis) may respond differently to the same drug because they have different underlying pathophysiologies (such as schizophrenic syndrome due to differing genetic causes or to toxins or slow viruses).

Environment (internal) refers to exogenous substances in the body—such as drugs and dietary substances—that can interact with and influence response to other drugs.

Nonpsychiatric disease also can alter response to medication. For example, impaired hepatic, renal, or cardiac function can impair drug clearance, leading to greater-than-usual accumulation. Such a patient can be “sensitive” to the drug and experience a greater effect than is usually seen with the dosage given.

Dosing for clinical effect

Psychiatrists commonly titrate dosages based on clinical assessment of response.³ The clinician increases the dosage if a patient does not improve and has no obvious rate-limiting adverse effects.

Perhaps without realizing it, the clinician is assuming that the dosage is inadequate for a given patient because the concentration is inadequate due to rapid clearance. Other reasons are possible, however, such as:

• the drug is not reaching the site of action a mutation at the site of action is altering
• the drug’s binding affinity
• the concentration may be too high, but the resulting adverse effects resemble worsening of the disease being treated. For example, akathisia due to dopamine-2 receptor blockade can present as agitation, and the clinician may increase the dosage when it should be decreased.

In the first two instances, escalating the dosage may be beneficial or cause toxicity. High levels in a peripheral compartment can cause adverse effects that may be silent until they become deadly (such as torsades de pointes). In the third instance, dosage escalation is the wrong step because the level is already too high.

Recommended dosage range

Principal goals of phase I studies in drug development are to establish the optimal dosage range and a maximum tolerated dosage. This upper limit is rarely, if ever, exceeded in later trials. Because phase I trial results are rarely published, the prescriber often does not know the rationale for a recommended dosing range’s upper limit.

Clinicians who escalate a drug’s dosage above the recommended range are using an n=1 paradigm, in which the patient is his or her own control. Unfortunately, treating one patient at a time cannot detect infrequent (much less rare) adverse events.

Using higher-than-recommended dosages thus exposes patients to unknown risks, with less monitoring than in a typical phase I trial in which subjects are confined to a research unit before, during, and after drug exposure. During the study, participants undergo serial ECGs, laboratory tests, and plasma drug level monitoring.

Therapeutic drug monitoring (TDM) is based on the concept that a meaningful relationship exists between a drug’s plasma concentration and its concentration at the site of action. Clinicians can measure the drug’s plasma concentration relative to the presumed dosage a patient is taking.

When nonadherence is the reason for nonresponse to usual dosing, TDM measurements of drug concentration would be lower than expected—or nonexistent with complete nonadherence. Rapid clearance, however, can also cause lower-than-expected levels on a given dosage.

So, how can the clinician determine whether the problem is rapid clearance or noncompliance? One way is to repeat the plasma level after arranging for supervised dosing for at least five times the half-life of the drug being measured. A higher level on follow-up would indicate that noncompliance is the likely problem. If the repeat level remains low, then the problem is most likely rapid clearance. In the latter case, the patient would need a higher dosage to achieve the concentrations associated with response in clinical trials.

Although TDM’s results are often conceptualized as being relative to a therapeutic range, TDM is fundamentally a means of measuring a patient’s ability to clear the drug. If the dosing rate and plasma drug level are known, then the clinician can solve for clearance by rearranging Equation 2. Rather than formally solving for clearance, results can be considered as within, below, or above the expected range for the dosage given. The clinician can then adjust the dosage to compensate for clearance that is faster or slower than usual. Thus, TDM allows clinicians to individualize dosages, taking into account the biological variances (Equation 1) that affect a patient’s ability to clear a specific drug.

TDM has limitations. It cannot assess whether a genetic mutation may be altering a drug’s binding affinity at the receptor site or whether the drug is not reaching the target compartment because of an abnormality in distribution mechanisms. Those possibilities would need to be assessed by techniques not available to most clinicians today.

Many psychiatrists think the inability to show a correlation between plasma drug levels and response is a limitation of TDM. That is not a limitation of TDM as much as a reflection on clinical trials of psychiatric drugs. Many such trials fail because of poor “signal-to-noise ratio”—defined as the true specific response to the treatment versus either placebo response or nonresponse due to not having an illness that is responsive to the drug.

Consider instead that the usually effective dosage defines a usually expected plasma drug concentration range associated with response. Further discussion of this topic is beyond the scope of this commentary, but the interested reader is referred to articles at www.preskorn.com, including Clinical pharmacology of serotonin selective re-uptake inhibitors (chapter 5); the column, Understanding dose-response curves in psychiatry; and the discussion, Finding the signal through the noise.

Summary

Based on the review by Pierre et al, the evidence for high-dose atypical antipsychotics’ safety and tolerability is not encouraging. These authors found only a modest body of evidence, and most study designs were not rigorous enough to eliminate erroneous conclusions. My intent here is not to advocate the use of higher-than-recommended dosages but to explain reasons why the patient may not respond and to call for more research.

Investigators designing future studies of nonresponse could consider including procedures to first rule out noncompliance and then divide participants into two groups:

• patients who achieved usual plasma drug levels on the usual recommended dosages (normal clearance)
• those who achieved levels below the usual expected range, despite good compliance (rapid clearance).

These two groups could then be randomized to continued exposure to the usual dosing range or higher-than-usual dosing. Patients with rapid clearance would be predicted to have a greater response to higher-than-usual dosing, compared with those with usual clearance.

In the absence of such trials, the clinician should proceed cautiously—if at all—to use higher-than usual antipsychotic dosages in his or her patients. The prescriber must always consider whether the risks outweigh the potential benefits, taking into account:

• the drug’s therapeutic index
• evidence of safety and tolerability problems in the individual patient as the dosage is escalated.

Related resources

• Preskorn SH. The recommended dosage range: How is it established and why would it ever be exceeded? J Psychiatry Pract 2004;10(4):249-54.

One of the most perplexing and shocking aspects of human behavior is the cruelty we can inflict on one another. Infamous events such as the Spanish Inquisition, slavery, lynching, conquest of the native Americans, and Nazi concentration camps are so sickening that many of us can barely tolerate hearing about them. How can people behave this way?

Recently, we’ve been shocked by photographs from the Abu Ghraib military prison in Iraq. American soldiers with unremarkable backgrounds—not Saddam’s henchmen—were shown humiliating and abusing Iraqi prisoners. Most remarkable was the joy on the Americans’ faces (Figure 1).

‘Good’ people, ‘bad’ circumstances

In experiments with college students, psychologists have shown that “regular” people can become sadistic under the right (or wrong) circumstances.¹ One explanation is that it’s not just psychopaths who perpetrate crimes against humanity. Somehow, the psychopath within us all becomes unleashed.

Artificial situations such as the Stanford Prison Experiment (www.prisonexp.org) show that normal people can dissolve into cruelty but don’t explain why. A recent neuroscience experiment suggests a mechanism for this kind of aggression.

Figure 1 Deriving pleasure from abuse?

American soldiers appearing to enjoy themselves as they humiliate Iraqi prisoners in the Abu Ghraib military prison.

Source: Reprinted with permission of The New Yorker, which first published this photo.

Dopamine and aggression

The nucleus accumbens has been called the brain’s “pleasure center,” and dopamine is the neurotransmitter that activates it.² Activities and substances that stimulate dopamine release include sex, gambling, and smoking as well as cocaine and alcohol. The good feeling a person gets from these activities/substances reinforces the behavior that produced the feeling. In some cases, problems develop when people cannot resist the urge for more.

Ferrari et al³ placed micropipettes in rats’ nucleus accumbens to measure extracellular dopamine before, during, and after an aggressive confrontation. When the rats were confronted with an intruder rat for 10 minutes, they attacked and bit the intruder an average of 5 times, despite being implanted, tethered, and sampled. During and after the fight, dopamine was increased in the rats’ nucleus accumbens (Figure 2). Clearly, fighting gave them a “squirt” of pleasure that lasted almost 2 hours.

If we can extrapolate from this study to humans, we may understand why people become aggressive. At some level, they enjoy it. The bully on the playground, the wife beater, the mean boss—they get pleasure from being aggressive. It’s not just serial killers.

It is important to acknowledge that other variables such as poor supervision and too much power affected the actions of American soldiers working as prison guards in Iraq. However, the neuroscientific studies show us that aggression can be pleasurable, and people often have a hard time resisting what feels good. This knowledge may help us treat war veterans struggling not only with traumatic memories of violence but also with socially and personally unacceptable feelings of pleasure.

Figure 2 A ‘squirt’ of dopamine during violence

A 10-minute fight increased extracellular dopamine levels in rats’ nucleus accumbens for approximately 2 hours, suggesting that aggressive behavior produced pleasure.

Source: Adapted and reprinted with permission from reference 3. Copyright 2003, Blackwell Publishing.

One of the most perplexing and shocking aspects of human behavior is the cruelty we can inflict on one another. Infamous events such as the Spanish Inquisition, slavery, lynching, conquest of the native Americans, and Nazi concentration camps are so sickening that many of us can barely tolerate hearing about them. How can people behave this way?

Recently, we’ve been shocked by photographs from the Abu Ghraib military prison in Iraq. American soldiers with unremarkable backgrounds—not Saddam’s henchmen—were shown humiliating and abusing Iraqi prisoners. Most remarkable was the joy on the Americans’ faces (Figure 1).

‘Good’ people, ‘bad’ circumstances

In experiments with college students, psychologists have shown that “regular” people can become sadistic under the right (or wrong) circumstances.¹ One explanation is that it’s not just psychopaths who perpetrate crimes against humanity. Somehow, the psychopath within us all becomes unleashed.

Artificial situations such as the Stanford Prison Experiment (www.prisonexp.org) show that normal people can dissolve into cruelty but don’t explain why. A recent neuroscience experiment suggests a mechanism for this kind of aggression.

Figure 1 Deriving pleasure from abuse?

American soldiers appearing to enjoy themselves as they humiliate Iraqi prisoners in the Abu Ghraib military prison.

Source: Reprinted with permission of The New Yorker, which first published this photo.

Dopamine and aggression

The nucleus accumbens has been called the brain’s “pleasure center,” and dopamine is the neurotransmitter that activates it.² Activities and substances that stimulate dopamine release include sex, gambling, and smoking as well as cocaine and alcohol. The good feeling a person gets from these activities/substances reinforces the behavior that produced the feeling. In some cases, problems develop when people cannot resist the urge for more.

Ferrari et al³ placed micropipettes in rats’ nucleus accumbens to measure extracellular dopamine before, during, and after an aggressive confrontation. When the rats were confronted with an intruder rat for 10 minutes, they attacked and bit the intruder an average of 5 times, despite being implanted, tethered, and sampled. During and after the fight, dopamine was increased in the rats’ nucleus accumbens (Figure 2). Clearly, fighting gave them a “squirt” of pleasure that lasted almost 2 hours.

If we can extrapolate from this study to humans, we may understand why people become aggressive. At some level, they enjoy it. The bully on the playground, the wife beater, the mean boss—they get pleasure from being aggressive. It’s not just serial killers.

It is important to acknowledge that other variables such as poor supervision and too much power affected the actions of American soldiers working as prison guards in Iraq. However, the neuroscientific studies show us that aggression can be pleasurable, and people often have a hard time resisting what feels good. This knowledge may help us treat war veterans struggling not only with traumatic memories of violence but also with socially and personally unacceptable feelings of pleasure.

Figure 2 A ‘squirt’ of dopamine during violence

A 10-minute fight increased extracellular dopamine levels in rats’ nucleus accumbens for approximately 2 hours, suggesting that aggressive behavior produced pleasure.

Source: Adapted and reprinted with permission from reference 3. Copyright 2003, Blackwell Publishing.

One of the most perplexing and shocking aspects of human behavior is the cruelty we can inflict on one another. Infamous events such as the Spanish Inquisition, slavery, lynching, conquest of the native Americans, and Nazi concentration camps are so sickening that many of us can barely tolerate hearing about them. How can people behave this way?

Recently, we’ve been shocked by photographs from the Abu Ghraib military prison in Iraq. American soldiers with unremarkable backgrounds—not Saddam’s henchmen—were shown humiliating and abusing Iraqi prisoners. Most remarkable was the joy on the Americans’ faces (Figure 1).

‘Good’ people, ‘bad’ circumstances

In experiments with college students, psychologists have shown that “regular” people can become sadistic under the right (or wrong) circumstances.¹ One explanation is that it’s not just psychopaths who perpetrate crimes against humanity. Somehow, the psychopath within us all becomes unleashed.

Artificial situations such as the Stanford Prison Experiment (www.prisonexp.org) show that normal people can dissolve into cruelty but don’t explain why. A recent neuroscience experiment suggests a mechanism for this kind of aggression.

Figure 1 Deriving pleasure from abuse?

American soldiers appearing to enjoy themselves as they humiliate Iraqi prisoners in the Abu Ghraib military prison.

Source: Reprinted with permission of The New Yorker, which first published this photo.

Dopamine and aggression

The nucleus accumbens has been called the brain’s “pleasure center,” and dopamine is the neurotransmitter that activates it.² Activities and substances that stimulate dopamine release include sex, gambling, and smoking as well as cocaine and alcohol. The good feeling a person gets from these activities/substances reinforces the behavior that produced the feeling. In some cases, problems develop when people cannot resist the urge for more.

Ferrari et al³ placed micropipettes in rats’ nucleus accumbens to measure extracellular dopamine before, during, and after an aggressive confrontation. When the rats were confronted with an intruder rat for 10 minutes, they attacked and bit the intruder an average of 5 times, despite being implanted, tethered, and sampled. During and after the fight, dopamine was increased in the rats’ nucleus accumbens (Figure 2). Clearly, fighting gave them a “squirt” of pleasure that lasted almost 2 hours.

If we can extrapolate from this study to humans, we may understand why people become aggressive. At some level, they enjoy it. The bully on the playground, the wife beater, the mean boss—they get pleasure from being aggressive. It’s not just serial killers.

It is important to acknowledge that other variables such as poor supervision and too much power affected the actions of American soldiers working as prison guards in Iraq. However, the neuroscientific studies show us that aggression can be pleasurable, and people often have a hard time resisting what feels good. This knowledge may help us treat war veterans struggling not only with traumatic memories of violence but also with socially and personally unacceptable feelings of pleasure.

Figure 2 A ‘squirt’ of dopamine during violence

A 10-minute fight increased extracellular dopamine levels in rats’ nucleus accumbens for approximately 2 hours, suggesting that aggressive behavior produced pleasure.

Source: Adapted and reprinted with permission from reference 3. Copyright 2003, Blackwell Publishing.

We read with interest Dr. Nelson’s and Dr. Krahn’s article on treating chronic pain and comorbid major depression (Current Psychiatry, May 2004).

We treat many patients who present with depression and chronic pain—often as a partial cause of their depression. The article’s recommendations will be most useful.

We have found that two agents—lamotrigine and mirtazapine—have been particularly helpful. The authors, however, did not mention these agents or only briefly referred to them.

Lamotrigine, although not FDA-approved for these uses, has demonstrated efficacy in unipolar depression¹ and chronic pain.² Although the medication has not been studied for treating comorbid depression and chronic pain, we can attest to its usefulness for such patients.

Mirtazapine is FDA-approved for depression and has been compared favorably with selective serotonin reuptake inhibitors^3-4 or venlafaxine.⁵ Fewer data support using mirtazapine for chronic pain, but its sedating effects make it an option for treating any syndrome associated with sleep disturbance—ie, major depression and chronic pain.

Vida Robertson, MD
Michael S. Wilson, II, MD
Department of psychiatry
Louisiana State University Health Sciences Center
New Orleans

References

1. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003;64(4):403–7.
2. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57(3):505–9.
3. Winokur A. DeMartinis NA 3rd, McNally DP, et al. Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia. J Clin Psychiatry 2003;64(10):1224–9.
4. Wade A, Crawford GM, Angus M, et al. A randomized, double-blind, 24-week study comparing the efficacy and tolerability of mirtazapine and paroxetine in depressed patients in primary care. Int Clin Psychopharmacol 2003;18(3):133–41.
5. Guelfi JD, Ansseau M, Timmerman L, Korsgaard S; Mirtazapine-Venlafaxine Study Group. Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features. J Clin Psychopharmacol 2001;21(4):425–31.

We read with interest Dr. Nelson’s and Dr. Krahn’s article on treating chronic pain and comorbid major depression (Current Psychiatry, May 2004).

We treat many patients who present with depression and chronic pain—often as a partial cause of their depression. The article’s recommendations will be most useful.

We have found that two agents—lamotrigine and mirtazapine—have been particularly helpful. The authors, however, did not mention these agents or only briefly referred to them.

Lamotrigine, although not FDA-approved for these uses, has demonstrated efficacy in unipolar depression¹ and chronic pain.² Although the medication has not been studied for treating comorbid depression and chronic pain, we can attest to its usefulness for such patients.

Mirtazapine is FDA-approved for depression and has been compared favorably with selective serotonin reuptake inhibitors^3-4 or venlafaxine.⁵ Fewer data support using mirtazapine for chronic pain, but its sedating effects make it an option for treating any syndrome associated with sleep disturbance—ie, major depression and chronic pain.

Vida Robertson, MD
Michael S. Wilson, II, MD
Department of psychiatry
Louisiana State University Health Sciences Center
New Orleans

References

1. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003;64(4):403–7.
2. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57(3):505–9.
3. Winokur A. DeMartinis NA 3rd, McNally DP, et al. Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia. J Clin Psychiatry 2003;64(10):1224–9.
4. Wade A, Crawford GM, Angus M, et al. A randomized, double-blind, 24-week study comparing the efficacy and tolerability of mirtazapine and paroxetine in depressed patients in primary care. Int Clin Psychopharmacol 2003;18(3):133–41.
5. Guelfi JD, Ansseau M, Timmerman L, Korsgaard S; Mirtazapine-Venlafaxine Study Group. Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features. J Clin Psychopharmacol 2001;21(4):425–31.

We read with interest Dr. Nelson’s and Dr. Krahn’s article on treating chronic pain and comorbid major depression (Current Psychiatry, May 2004).

We treat many patients who present with depression and chronic pain—often as a partial cause of their depression. The article’s recommendations will be most useful.

We have found that two agents—lamotrigine and mirtazapine—have been particularly helpful. The authors, however, did not mention these agents or only briefly referred to them.

Lamotrigine, although not FDA-approved for these uses, has demonstrated efficacy in unipolar depression¹ and chronic pain.² Although the medication has not been studied for treating comorbid depression and chronic pain, we can attest to its usefulness for such patients.

Mirtazapine is FDA-approved for depression and has been compared favorably with selective serotonin reuptake inhibitors^3-4 or venlafaxine.⁵ Fewer data support using mirtazapine for chronic pain, but its sedating effects make it an option for treating any syndrome associated with sleep disturbance—ie, major depression and chronic pain.

Vida Robertson, MD
Michael S. Wilson, II, MD
Department of psychiatry
Louisiana State University Health Sciences Center
New Orleans

References

1. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003;64(4):403–7.
2. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57(3):505–9.
3. Winokur A. DeMartinis NA 3rd, McNally DP, et al. Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia. J Clin Psychiatry 2003;64(10):1224–9.
4. Wade A, Crawford GM, Angus M, et al. A randomized, double-blind, 24-week study comparing the efficacy and tolerability of mirtazapine and paroxetine in depressed patients in primary care. Int Clin Psychopharmacol 2003;18(3):133–41.
5. Guelfi JD, Ansseau M, Timmerman L, Korsgaard S; Mirtazapine-Venlafaxine Study Group. Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features. J Clin Psychopharmacol 2001;21(4):425–31.

“Tardive Dyskinesia: How to prevent and treat a lingering nemesis” (Current Psychiatry, October 2003) was a very good, basic article. The algorithm on managing tardive dyskinesia was particularly helpful, and the information on possible reversible dyskinesias with mood stabilizers and with antihistamines such as Benadryl was a useful refresher.

For MDs such as I who practice in rural clinics, however, more-specific dosage information would be useful—even for experimental agents such as tetrabenazine—since we do not have ready access to higher-level movement disorder clinics. The nearest such clinic to my practice is 2 1/2 hours away, an impossible commute for many of my patients.

Sophia Bezirganian MD
Trumansburg, NY

“Tardive Dyskinesia: How to prevent and treat a lingering nemesis” (Current Psychiatry, October 2003) was a very good, basic article. The algorithm on managing tardive dyskinesia was particularly helpful, and the information on possible reversible dyskinesias with mood stabilizers and with antihistamines such as Benadryl was a useful refresher.

For MDs such as I who practice in rural clinics, however, more-specific dosage information would be useful—even for experimental agents such as tetrabenazine—since we do not have ready access to higher-level movement disorder clinics. The nearest such clinic to my practice is 2 1/2 hours away, an impossible commute for many of my patients.

Sophia Bezirganian MD
Trumansburg, NY

“Tardive Dyskinesia: How to prevent and treat a lingering nemesis” (Current Psychiatry, October 2003) was a very good, basic article. The algorithm on managing tardive dyskinesia was particularly helpful, and the information on possible reversible dyskinesias with mood stabilizers and with antihistamines such as Benadryl was a useful refresher.

For MDs such as I who practice in rural clinics, however, more-specific dosage information would be useful—even for experimental agents such as tetrabenazine—since we do not have ready access to higher-level movement disorder clinics. The nearest such clinic to my practice is 2 1/2 hours away, an impossible commute for many of my patients.

Sophia Bezirganian MD
Trumansburg, NY

Dr John Battaglia’s article about intramuscular (IM) olanzapine (Out of the Pipeline, Current Psychiatry, May 2004) appears biased because of his pharmaceutical company connection. He mentions four studies supporting its use in treating schizophrenia, bipolar type I mania, and dementia.

As a resident eager to learn what constitutes good clinical care, I feel the article does an injustice by mentioning no negative studies or those that recorded no significant change.

Getting all the facts is key to establishing how to best use a treatment. Debate or unbiased commentary should accompany articles on new medications/treatments.

Matthew Sager, MD
Chief resident
Brown University Psychiatry Program
Providence, RI

Dr. Battaglia responds

I appreciate the passion with which Dr. Sager is approaching his education; he might want to learn more about drug development.

For decades, the overwhelming majority of FDA approvals for psychiatric medications have resulted from industry-supported studies. Very few researchers are doing substantial psychopharmacology clinical trials without industry support. It is extremely difficult to publish “negative” studies or those that show “no significant change.” I am not aware of any such published studies with IM olanzapine.

The best “unbiased” commentary on IM olanzapine will occur when it is used widely in clinical practice. For now, we are limited to published studies.

John Battaglia, MD
Medical director, Meriter Hospital adult psychiatry program
Associate professor, department of psychiatry
University of Wisconsin Medical School
Madison

Dr John Battaglia’s article about intramuscular (IM) olanzapine (Out of the Pipeline, Current Psychiatry, May 2004) appears biased because of his pharmaceutical company connection. He mentions four studies supporting its use in treating schizophrenia, bipolar type I mania, and dementia.

As a resident eager to learn what constitutes good clinical care, I feel the article does an injustice by mentioning no negative studies or those that recorded no significant change.

Getting all the facts is key to establishing how to best use a treatment. Debate or unbiased commentary should accompany articles on new medications/treatments.

Matthew Sager, MD
Chief resident
Brown University Psychiatry Program
Providence, RI

Dr. Battaglia responds

I appreciate the passion with which Dr. Sager is approaching his education; he might want to learn more about drug development.

For decades, the overwhelming majority of FDA approvals for psychiatric medications have resulted from industry-supported studies. Very few researchers are doing substantial psychopharmacology clinical trials without industry support. It is extremely difficult to publish “negative” studies or those that show “no significant change.” I am not aware of any such published studies with IM olanzapine.

The best “unbiased” commentary on IM olanzapine will occur when it is used widely in clinical practice. For now, we are limited to published studies.

John Battaglia, MD
Medical director, Meriter Hospital adult psychiatry program
Associate professor, department of psychiatry
University of Wisconsin Medical School
Madison

Dr John Battaglia’s article about intramuscular (IM) olanzapine (Out of the Pipeline, Current Psychiatry, May 2004) appears biased because of his pharmaceutical company connection. He mentions four studies supporting its use in treating schizophrenia, bipolar type I mania, and dementia.

As a resident eager to learn what constitutes good clinical care, I feel the article does an injustice by mentioning no negative studies or those that recorded no significant change.

Getting all the facts is key to establishing how to best use a treatment. Debate or unbiased commentary should accompany articles on new medications/treatments.

Matthew Sager, MD
Chief resident
Brown University Psychiatry Program
Providence, RI

Dr. Battaglia responds

I appreciate the passion with which Dr. Sager is approaching his education; he might want to learn more about drug development.

For decades, the overwhelming majority of FDA approvals for psychiatric medications have resulted from industry-supported studies. Very few researchers are doing substantial psychopharmacology clinical trials without industry support. It is extremely difficult to publish “negative” studies or those that show “no significant change.” I am not aware of any such published studies with IM olanzapine.

The best “unbiased” commentary on IM olanzapine will occur when it is used widely in clinical practice. For now, we are limited to published studies.

John Battaglia, MD
Medical director, Meriter Hospital adult psychiatry program
Associate professor, department of psychiatry
University of Wisconsin Medical School
Madison