Current Psychiatry

Discuss this article at www.facebook.com/CurrentPsychiatry

Long-acting injectable antipsychotics (LAIs) are a pharmacotherapeutic option to help clinicians individualize schizophrenia treatment. LAIs have been available since the 1960s, starting with fluphenazine and later haloperidol; however, second-generation antipsychotics were not available in the United States until 2007^1,2 and more are in development (Box).^3,4

Box

Up to one-half of patients with schizophrenia do not adhere to their medications.⁵ LAI use may mitigate relapse in acute schizophrenia that is caused by poor adherence to oral medications. LAIs may have a lower risk of dose-related adverse effects because of lower peak antipsychotic plasma levels and less variation between peak and trough plasma levels. LAIs may decrease the financial burden of schizophrenia and increase individual quality of life because patients spend fewer days hospitalized due to acute exacerbations.⁶

Some widely used schizophrenia treatment algorithms, such as the Harvard Schizophrenia Algorithm, neglect LAIs. Also, LAIs have not been well studied for maintenance treatment of bipolar disorder (BD) even though nonadherence is a substantial problem in these patients. Patients, families, and legal guardians may choose LAI antipsychotics over oral formulations to decrease the frequency and severity of psychotic relapse or for convenience because patients who receive LAIs do not need to take a medication every day.

Understanding the similarities and differences among LAIs⁷ and potential interpatient variability of each LAI allows prescribers to tailor the dosing regimen to the patient more safely and efficiently (Table).^1,8-11 All LAI antipsychotic formulations rely on absorption pharmacokinetics (PK) rather than elimination PK, which generally is true for sustained-release oral formulations as well. Absorption half-life duration and absorption half-life variability are key concepts in LAI dosing.

Table

Characteristics of long-acting injectable antipsychotics

Clinical pearls

Before prescribing an LAI, check that your patient has no known contraindications to the active drug or delivery method. Peak-related adverse effects typically are not contraindications, although they may prompt you to start at a lower dose.

Ensure that your patient will have long-term outpatient access to the LAI and the entire treatment team—inpatient and outpatient—is committed to LAI treatment.

Do not rule out first-generation LAIs such as haloperidol and fluphenazine. The Clinical Antipsychotic Trials of Intervention Effectiveness study, Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, and other published data suggest older antipsychotics are not inferior to newer medications.^12,13

Verify that your patient has had an oral trial of the active drug—ideally in the last 12 months—that resulted in at least partial positive response and no serious adverse drug effects (ADEs). Oral medications’ shorter duration of action may help identify ADEs before administering an LAI.¹

Discontinue the oral medication as quickly as evidence, guidance, and good clinical judgment allow. Develop a plan to transition from oral to LAI that you will follow unless the patient develops intolerable ADEs or other problems. There is no evidence to suggest that patients who receive partial LAI therapy decompensate less frequently or less severely than those who take oral medication.

If antipsychotic polypharmacy is necessary, document your rationale.

In patients who are naïve to a specific LAI dosage form, ensure that the first dose does not exceed FDA and evidence-based guidelines for the initial dose (eg, 100 mg intramuscular [IM] for haloperidol decanoate).¹

Consider a loading dose strategy to minimize the time a patient has to take an oral and LAI antipsychotic combination.¹⁴

Ensure that the total volume injected intramuscularly is not >3 ml per injection site per dose.

Use the recommended injection technique for the particular LAI (eg, Z-tract).^1,15

Individualize the dose and dosing interval based on patient response, peak-related adverse effects (time to peak is approximately 5 half-lives for most drugs), and possible reduced symptom control at the end of the dosing interval.⁸

If your patient does not respond as expected, taking an antipsychotic plasma level to assess drug metabolism and other PK factors and characteristics may be useful.

LAI options

Fluphenazine decanoate is an older, inexpensive LAI with considerable interpatient variability in absorption rate and peak effects, and a relatively short duration of action. Dosing every 7 days may be necessary to avoid peak plasma level adverse effects or symptom recurrence. Variable PK make it difficult to accurately calculate an empiric conversion dose from oral to LAI; therefore, start at the low end (eg, 1.2 to 1.6 times the total daily oral dose) or 12.5 or 25 mg for the initial IM fluphenazine decanoate dose. A short overlap period—usually 1 to 2 weeks—may be necessary. Successful subcutaneous administration is possible.²

Haloperidol decanoate. A 28-day dosing interval is effective for most patients. It is possible to administer a loading dose so that no overlapping taper is required. My team has had good results using an initial loading dose 15 to 20 times the effective oral dose and a second dose 28 days later of 10 times the oral daily maintenance dose, with the same dose every month thereafter. If a patient is receiving his or her first haloperidol decanoate injection, the initial dose should not exceed 100 mg. The remainder of the loading dose may be administered 3 to 7 days later if no adverse effects occur. Similar to fluphenazine decanoate, haloperidol decanoate is relatively inexpensive. When considering giving a haloperidol decanoate loading dose >400 mg or a maintenance dose >200 mg every 28 days, carefully document the rationale (eg, rapid metabolism).¹⁶

Olanzapine pamoate. Clinicians who administer olanzapine pamoate must enroll in a national registry that documents the incidence of rare but serious ADEs, particularly hypotension, orthostatis, and post-injection delirium/sedation syndrome (0.1% incidence) at every injection, not just for drug-naïve patients. Patients should be observed for 3 hours after every dose and oral medication overlap may be necessary in some cases.¹⁰ Similar to clozapine, these monitoring difficulties and the expense may have inhibited olanzapine LAI use, even in patients who are likely to benefit.

Risperidone microspheres. This agent has been evolutionary, if not revolutionary, in schizophrenia treatment and data on its efficacy for BD will be available soon. Its 2-week dosing interval, necessity of oral overlap, and anecdotal reports of “dose dumping” possibly because of fragility of the microsphere formulation suggest the need for an improved version, which was addressed by the introduction of paliperidone palmitate.^10,17,18

Paliperidone palmitate has a 28-day dosing interval. No overlapping oral taper is necessary. Details of a week-long, 2-dose loading dose strategy is provided in the package insert.¹¹ It may be safe to use a more aggressive loading dose strategy.^15,19

Related Resources

• Rothschild AJ. The evidence-based guide to antipsychotic medications. Arlington, VA: American Psychiatric Publishing, Inc.; 2010.
• Cañas F, Möller HJ. Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review. Expert Opin Drug Saf. 2010;9(5):683-697.

Drug Brand Names

• Aripiprazole • Abilify
• Fluphenazine deconoate • Prolixin Deconoate
• Haloperidol deconoate • Haldol Deconoate
• Iloperidone • Fanapt
• Olanzapine pamoate • Zyprexa Relprevv
• Paliperidone palmitate • Invega Sustenna
• Risperidone • Risperdal Consta

Disclosures

Dr. Kennedy receives grant or research support from Janssen and Johnson and Johnson.

Discuss this article at www.facebook.com/CurrentPsychiatry

Long-acting injectable antipsychotics (LAIs) are a pharmacotherapeutic option to help clinicians individualize schizophrenia treatment. LAIs have been available since the 1960s, starting with fluphenazine and later haloperidol; however, second-generation antipsychotics were not available in the United States until 2007^1,2 and more are in development (Box).^3,4

Box

Up to one-half of patients with schizophrenia do not adhere to their medications.⁵ LAI use may mitigate relapse in acute schizophrenia that is caused by poor adherence to oral medications. LAIs may have a lower risk of dose-related adverse effects because of lower peak antipsychotic plasma levels and less variation between peak and trough plasma levels. LAIs may decrease the financial burden of schizophrenia and increase individual quality of life because patients spend fewer days hospitalized due to acute exacerbations.⁶

Some widely used schizophrenia treatment algorithms, such as the Harvard Schizophrenia Algorithm, neglect LAIs. Also, LAIs have not been well studied for maintenance treatment of bipolar disorder (BD) even though nonadherence is a substantial problem in these patients. Patients, families, and legal guardians may choose LAI antipsychotics over oral formulations to decrease the frequency and severity of psychotic relapse or for convenience because patients who receive LAIs do not need to take a medication every day.

Understanding the similarities and differences among LAIs⁷ and potential interpatient variability of each LAI allows prescribers to tailor the dosing regimen to the patient more safely and efficiently (Table).^1,8-11 All LAI antipsychotic formulations rely on absorption pharmacokinetics (PK) rather than elimination PK, which generally is true for sustained-release oral formulations as well. Absorption half-life duration and absorption half-life variability are key concepts in LAI dosing.

Table

Characteristics of long-acting injectable antipsychotics

Clinical pearls

Before prescribing an LAI, check that your patient has no known contraindications to the active drug or delivery method. Peak-related adverse effects typically are not contraindications, although they may prompt you to start at a lower dose.

Ensure that your patient will have long-term outpatient access to the LAI and the entire treatment team—inpatient and outpatient—is committed to LAI treatment.

Do not rule out first-generation LAIs such as haloperidol and fluphenazine. The Clinical Antipsychotic Trials of Intervention Effectiveness study, Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, and other published data suggest older antipsychotics are not inferior to newer medications.^12,13

Verify that your patient has had an oral trial of the active drug—ideally in the last 12 months—that resulted in at least partial positive response and no serious adverse drug effects (ADEs). Oral medications’ shorter duration of action may help identify ADEs before administering an LAI.¹

Discontinue the oral medication as quickly as evidence, guidance, and good clinical judgment allow. Develop a plan to transition from oral to LAI that you will follow unless the patient develops intolerable ADEs or other problems. There is no evidence to suggest that patients who receive partial LAI therapy decompensate less frequently or less severely than those who take oral medication.

If antipsychotic polypharmacy is necessary, document your rationale.

In patients who are naïve to a specific LAI dosage form, ensure that the first dose does not exceed FDA and evidence-based guidelines for the initial dose (eg, 100 mg intramuscular [IM] for haloperidol decanoate).¹

Consider a loading dose strategy to minimize the time a patient has to take an oral and LAI antipsychotic combination.¹⁴

Ensure that the total volume injected intramuscularly is not >3 ml per injection site per dose.

Use the recommended injection technique for the particular LAI (eg, Z-tract).^1,15

Individualize the dose and dosing interval based on patient response, peak-related adverse effects (time to peak is approximately 5 half-lives for most drugs), and possible reduced symptom control at the end of the dosing interval.⁸

If your patient does not respond as expected, taking an antipsychotic plasma level to assess drug metabolism and other PK factors and characteristics may be useful.

LAI options

Fluphenazine decanoate is an older, inexpensive LAI with considerable interpatient variability in absorption rate and peak effects, and a relatively short duration of action. Dosing every 7 days may be necessary to avoid peak plasma level adverse effects or symptom recurrence. Variable PK make it difficult to accurately calculate an empiric conversion dose from oral to LAI; therefore, start at the low end (eg, 1.2 to 1.6 times the total daily oral dose) or 12.5 or 25 mg for the initial IM fluphenazine decanoate dose. A short overlap period—usually 1 to 2 weeks—may be necessary. Successful subcutaneous administration is possible.²

Haloperidol decanoate. A 28-day dosing interval is effective for most patients. It is possible to administer a loading dose so that no overlapping taper is required. My team has had good results using an initial loading dose 15 to 20 times the effective oral dose and a second dose 28 days later of 10 times the oral daily maintenance dose, with the same dose every month thereafter. If a patient is receiving his or her first haloperidol decanoate injection, the initial dose should not exceed 100 mg. The remainder of the loading dose may be administered 3 to 7 days later if no adverse effects occur. Similar to fluphenazine decanoate, haloperidol decanoate is relatively inexpensive. When considering giving a haloperidol decanoate loading dose >400 mg or a maintenance dose >200 mg every 28 days, carefully document the rationale (eg, rapid metabolism).¹⁶

Olanzapine pamoate. Clinicians who administer olanzapine pamoate must enroll in a national registry that documents the incidence of rare but serious ADEs, particularly hypotension, orthostatis, and post-injection delirium/sedation syndrome (0.1% incidence) at every injection, not just for drug-naïve patients. Patients should be observed for 3 hours after every dose and oral medication overlap may be necessary in some cases.¹⁰ Similar to clozapine, these monitoring difficulties and the expense may have inhibited olanzapine LAI use, even in patients who are likely to benefit.

Risperidone microspheres. This agent has been evolutionary, if not revolutionary, in schizophrenia treatment and data on its efficacy for BD will be available soon. Its 2-week dosing interval, necessity of oral overlap, and anecdotal reports of “dose dumping” possibly because of fragility of the microsphere formulation suggest the need for an improved version, which was addressed by the introduction of paliperidone palmitate.^10,17,18

Paliperidone palmitate has a 28-day dosing interval. No overlapping oral taper is necessary. Details of a week-long, 2-dose loading dose strategy is provided in the package insert.¹¹ It may be safe to use a more aggressive loading dose strategy.^15,19

Related Resources

• Rothschild AJ. The evidence-based guide to antipsychotic medications. Arlington, VA: American Psychiatric Publishing, Inc.; 2010.
• Cañas F, Möller HJ. Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review. Expert Opin Drug Saf. 2010;9(5):683-697.

Drug Brand Names

• Aripiprazole • Abilify
• Fluphenazine deconoate • Prolixin Deconoate
• Haloperidol deconoate • Haldol Deconoate
• Iloperidone • Fanapt
• Olanzapine pamoate • Zyprexa Relprevv
• Paliperidone palmitate • Invega Sustenna
• Risperidone • Risperdal Consta

Disclosures

Dr. Kennedy receives grant or research support from Janssen and Johnson and Johnson.

Discuss this article at www.facebook.com/CurrentPsychiatry

Long-acting injectable antipsychotics (LAIs) are a pharmacotherapeutic option to help clinicians individualize schizophrenia treatment. LAIs have been available since the 1960s, starting with fluphenazine and later haloperidol; however, second-generation antipsychotics were not available in the United States until 2007^1,2 and more are in development (Box).^3,4

Box

Up to one-half of patients with schizophrenia do not adhere to their medications.⁵ LAI use may mitigate relapse in acute schizophrenia that is caused by poor adherence to oral medications. LAIs may have a lower risk of dose-related adverse effects because of lower peak antipsychotic plasma levels and less variation between peak and trough plasma levels. LAIs may decrease the financial burden of schizophrenia and increase individual quality of life because patients spend fewer days hospitalized due to acute exacerbations.⁶

Some widely used schizophrenia treatment algorithms, such as the Harvard Schizophrenia Algorithm, neglect LAIs. Also, LAIs have not been well studied for maintenance treatment of bipolar disorder (BD) even though nonadherence is a substantial problem in these patients. Patients, families, and legal guardians may choose LAI antipsychotics over oral formulations to decrease the frequency and severity of psychotic relapse or for convenience because patients who receive LAIs do not need to take a medication every day.

Understanding the similarities and differences among LAIs⁷ and potential interpatient variability of each LAI allows prescribers to tailor the dosing regimen to the patient more safely and efficiently (Table).^1,8-11 All LAI antipsychotic formulations rely on absorption pharmacokinetics (PK) rather than elimination PK, which generally is true for sustained-release oral formulations as well. Absorption half-life duration and absorption half-life variability are key concepts in LAI dosing.

Table

Characteristics of long-acting injectable antipsychotics

Clinical pearls

Before prescribing an LAI, check that your patient has no known contraindications to the active drug or delivery method. Peak-related adverse effects typically are not contraindications, although they may prompt you to start at a lower dose.

Ensure that your patient will have long-term outpatient access to the LAI and the entire treatment team—inpatient and outpatient—is committed to LAI treatment.

Do not rule out first-generation LAIs such as haloperidol and fluphenazine. The Clinical Antipsychotic Trials of Intervention Effectiveness study, Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, and other published data suggest older antipsychotics are not inferior to newer medications.^12,13

Verify that your patient has had an oral trial of the active drug—ideally in the last 12 months—that resulted in at least partial positive response and no serious adverse drug effects (ADEs). Oral medications’ shorter duration of action may help identify ADEs before administering an LAI.¹

Discontinue the oral medication as quickly as evidence, guidance, and good clinical judgment allow. Develop a plan to transition from oral to LAI that you will follow unless the patient develops intolerable ADEs or other problems. There is no evidence to suggest that patients who receive partial LAI therapy decompensate less frequently or less severely than those who take oral medication.

If antipsychotic polypharmacy is necessary, document your rationale.

In patients who are naïve to a specific LAI dosage form, ensure that the first dose does not exceed FDA and evidence-based guidelines for the initial dose (eg, 100 mg intramuscular [IM] for haloperidol decanoate).¹

Consider a loading dose strategy to minimize the time a patient has to take an oral and LAI antipsychotic combination.¹⁴

Ensure that the total volume injected intramuscularly is not >3 ml per injection site per dose.

Use the recommended injection technique for the particular LAI (eg, Z-tract).^1,15

Individualize the dose and dosing interval based on patient response, peak-related adverse effects (time to peak is approximately 5 half-lives for most drugs), and possible reduced symptom control at the end of the dosing interval.⁸

If your patient does not respond as expected, taking an antipsychotic plasma level to assess drug metabolism and other PK factors and characteristics may be useful.

LAI options

Fluphenazine decanoate is an older, inexpensive LAI with considerable interpatient variability in absorption rate and peak effects, and a relatively short duration of action. Dosing every 7 days may be necessary to avoid peak plasma level adverse effects or symptom recurrence. Variable PK make it difficult to accurately calculate an empiric conversion dose from oral to LAI; therefore, start at the low end (eg, 1.2 to 1.6 times the total daily oral dose) or 12.5 or 25 mg for the initial IM fluphenazine decanoate dose. A short overlap period—usually 1 to 2 weeks—may be necessary. Successful subcutaneous administration is possible.²

Haloperidol decanoate. A 28-day dosing interval is effective for most patients. It is possible to administer a loading dose so that no overlapping taper is required. My team has had good results using an initial loading dose 15 to 20 times the effective oral dose and a second dose 28 days later of 10 times the oral daily maintenance dose, with the same dose every month thereafter. If a patient is receiving his or her first haloperidol decanoate injection, the initial dose should not exceed 100 mg. The remainder of the loading dose may be administered 3 to 7 days later if no adverse effects occur. Similar to fluphenazine decanoate, haloperidol decanoate is relatively inexpensive. When considering giving a haloperidol decanoate loading dose >400 mg or a maintenance dose >200 mg every 28 days, carefully document the rationale (eg, rapid metabolism).¹⁶

Olanzapine pamoate. Clinicians who administer olanzapine pamoate must enroll in a national registry that documents the incidence of rare but serious ADEs, particularly hypotension, orthostatis, and post-injection delirium/sedation syndrome (0.1% incidence) at every injection, not just for drug-naïve patients. Patients should be observed for 3 hours after every dose and oral medication overlap may be necessary in some cases.¹⁰ Similar to clozapine, these monitoring difficulties and the expense may have inhibited olanzapine LAI use, even in patients who are likely to benefit.

Risperidone microspheres. This agent has been evolutionary, if not revolutionary, in schizophrenia treatment and data on its efficacy for BD will be available soon. Its 2-week dosing interval, necessity of oral overlap, and anecdotal reports of “dose dumping” possibly because of fragility of the microsphere formulation suggest the need for an improved version, which was addressed by the introduction of paliperidone palmitate.^10,17,18

Paliperidone palmitate has a 28-day dosing interval. No overlapping oral taper is necessary. Details of a week-long, 2-dose loading dose strategy is provided in the package insert.¹¹ It may be safe to use a more aggressive loading dose strategy.^15,19

Related Resources

• Rothschild AJ. The evidence-based guide to antipsychotic medications. Arlington, VA: American Psychiatric Publishing, Inc.; 2010.
• Cañas F, Möller HJ. Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review. Expert Opin Drug Saf. 2010;9(5):683-697.

Drug Brand Names

• Aripiprazole • Abilify
• Fluphenazine deconoate • Prolixin Deconoate
• Haloperidol deconoate • Haldol Deconoate
• Iloperidone • Fanapt
• Olanzapine pamoate • Zyprexa Relprevv
• Paliperidone palmitate • Invega Sustenna
• Risperidone • Risperdal Consta

Disclosures

Dr. Kennedy receives grant or research support from Janssen and Johnson and Johnson.

According to DSM-IV-TR, the minimal duration of a hypomanic episode is 4 days.¹ Should we treat patients for hypomanic symptoms that last <4 days? Could antidepressants’ high failure rate² be because many depressed patients have untreated “subthreshold hypomanic episodes”? Aripiprazole, quetiapine, and lithium all have been shown to alleviate depression when added to an antidepressant.^3-5 Is it possible that these medications are treating subthreshold hypomanic episodes rather than depression?

The literature does not answer these questions. To further confuse matters, a subthreshold hypomanic episode may not be a discrete episode. In such episodes, hypomanic symptoms may overlap at some point and the duration of each symptom may vary.

When I administer the Mood Disorder Questionnaire,^6,7 I ask patients about 13 hypomanic symptoms. Patient responses to questions about 7 of these symptoms—increased energy, irritability, talking, and activity, feeling “hyper,” racing thoughts, and decreased need for sleep—can help demonstrate the variability of symptom duration. For example, a patient may complain of increased energy and irritability for 3 days, increased activity and feeling “hyper” for 2 days, increased talking and a decreased need to sleep for 1 day, and racing thoughts every day.

Alternative criteria

Considering this variation, I often use the following criteria when considering whether to treat subthreshold hypomanic symptoms:

• ≥4 symptoms must last ≥2 consecutive days
• ≥3 symptoms must overlap at some point, and
• ≥2 of the symptoms must be increased energy, increased activity, or racing thoughts.

However, some patients have hypomanic symptoms that do not meet these relaxed criteria but require treatment.⁸ I also need to know when these episodes started, how frequently they occur, and how much of a problem they cause in the patient’s life. I often treat subthreshold hypomanic episodes with an antipsychotic or a mood stabilizer. As with all patients I see, I consider the patient’s reliability, substance abuse history, and mental status during the interview.

According to DSM-IV-TR, the minimal duration of a hypomanic episode is 4 days.¹ Should we treat patients for hypomanic symptoms that last <4 days? Could antidepressants’ high failure rate² be because many depressed patients have untreated “subthreshold hypomanic episodes”? Aripiprazole, quetiapine, and lithium all have been shown to alleviate depression when added to an antidepressant.^3-5 Is it possible that these medications are treating subthreshold hypomanic episodes rather than depression?

The literature does not answer these questions. To further confuse matters, a subthreshold hypomanic episode may not be a discrete episode. In such episodes, hypomanic symptoms may overlap at some point and the duration of each symptom may vary.

When I administer the Mood Disorder Questionnaire,^6,7 I ask patients about 13 hypomanic symptoms. Patient responses to questions about 7 of these symptoms—increased energy, irritability, talking, and activity, feeling “hyper,” racing thoughts, and decreased need for sleep—can help demonstrate the variability of symptom duration. For example, a patient may complain of increased energy and irritability for 3 days, increased activity and feeling “hyper” for 2 days, increased talking and a decreased need to sleep for 1 day, and racing thoughts every day.

Alternative criteria

Considering this variation, I often use the following criteria when considering whether to treat subthreshold hypomanic symptoms:

• ≥4 symptoms must last ≥2 consecutive days
• ≥3 symptoms must overlap at some point, and
• ≥2 of the symptoms must be increased energy, increased activity, or racing thoughts.

However, some patients have hypomanic symptoms that do not meet these relaxed criteria but require treatment.⁸ I also need to know when these episodes started, how frequently they occur, and how much of a problem they cause in the patient’s life. I often treat subthreshold hypomanic episodes with an antipsychotic or a mood stabilizer. As with all patients I see, I consider the patient’s reliability, substance abuse history, and mental status during the interview.

According to DSM-IV-TR, the minimal duration of a hypomanic episode is 4 days.¹ Should we treat patients for hypomanic symptoms that last <4 days? Could antidepressants’ high failure rate² be because many depressed patients have untreated “subthreshold hypomanic episodes”? Aripiprazole, quetiapine, and lithium all have been shown to alleviate depression when added to an antidepressant.^3-5 Is it possible that these medications are treating subthreshold hypomanic episodes rather than depression?

The literature does not answer these questions. To further confuse matters, a subthreshold hypomanic episode may not be a discrete episode. In such episodes, hypomanic symptoms may overlap at some point and the duration of each symptom may vary.

When I administer the Mood Disorder Questionnaire,^6,7 I ask patients about 13 hypomanic symptoms. Patient responses to questions about 7 of these symptoms—increased energy, irritability, talking, and activity, feeling “hyper,” racing thoughts, and decreased need for sleep—can help demonstrate the variability of symptom duration. For example, a patient may complain of increased energy and irritability for 3 days, increased activity and feeling “hyper” for 2 days, increased talking and a decreased need to sleep for 1 day, and racing thoughts every day.

Alternative criteria

Considering this variation, I often use the following criteria when considering whether to treat subthreshold hypomanic symptoms:

• ≥4 symptoms must last ≥2 consecutive days
• ≥3 symptoms must overlap at some point, and
• ≥2 of the symptoms must be increased energy, increased activity, or racing thoughts.

However, some patients have hypomanic symptoms that do not meet these relaxed criteria but require treatment.⁸ I also need to know when these episodes started, how frequently they occur, and how much of a problem they cause in the patient’s life. I often treat subthreshold hypomanic episodes with an antipsychotic or a mood stabilizer. As with all patients I see, I consider the patient’s reliability, substance abuse history, and mental status during the interview.

Psychiatrists recognize that schizophrenia is a disorder in which the highest mental functions, such as thought, language, emotions, conation, and cognition, are drastically disrupted. However, the most serious impairment in schizophrenia is a global malfunction in self-integration and personal identity that includes a deficit in self-recognition.

This distorted sense of self leads persons with schizophrenia to fail to recognize what is or is not part of their own mind, which can produce clinical symptoms of schizophrenia, including bizarre delusions, hallucinations, thought disorder, social deficits, and information processing.¹

Just as intact physical proprioception enables a healthy person to be continuously aware of where his body and its parts are located in space, allowing sensory-motor integration, mental proprioception enables one to be fully aware of his identity and self-boundaries, and that his thoughts and actions are generated from within his own sphere of consciousness, not from an external source. In schizophrenia, the coherent sense of self is shattered and fragmented, a frightening experience patients describe after emerging from psychosis.² A person affected by schizophrenia feels lost, as if his “self no longer belong[s]” to him. He feels alienated from his “real self” and refers to himself in the third person. He feels “disconnected, disintegrated, and diminished,” with a sense of “emptiness, a painful void of existence,” of being disembodied with no clear demarcation between self and others.²

Not surprisingly, false beliefs (delusions) and perceptual aberrations (hallucinations) emerge from a fragmented sense of self. Patients fail to recognize that their actions, thoughts, or feelings are initiated from within the self, leading to delusions of passivity and being controlled by an outside force. One’s impulses are misperceived as being imposed by an alien. One’s thoughts, fantasies, and memories become external hallucinations instead of internal recollections. It is not surprising that depersonalization and derealization are common in schizophrenia and in the prodrome stage. Phencyclidine and ketamine, which can produce schizophrenia-like psychoses, are known to trigger dissociative phenomena and a loss of a coherent sense of self.

What causes the disintegration of the mind (self) in schizophrenia? The leading neurobiologic explanation is well-documented white matter pathology.³ Numerous studies have demonstrated that the myelinated axons and fibers that connect various brain regions are abnormal in patients with schizophrenia. The evidence for the breakdown of white matter—and, consequently, brain connectedness and integration—includes several lines of evidence, such as: a) in vivo neuroimaging studies using diffusion tensor imaging (DTI) that show abnormal water mobility in the myelin; b) genetic aberrations in myelin genes; c) postmortem evidence of reduced oligodendrocytes, the glial cells that manufacture myelin; and d) biochemical markers such as the calcium-binding protein S100B, which is released by compromised glial cells.³

Therefore, it is reasonable to think that the disruption of the sense of self and its proprioception may be due to the extensive disconnectivity of brain regions caused by myelin pathology.⁴ However, grey matter abnormality also may play a role in loss of mental proprioceptive functions, which causes a failure to properly recognize one’s self. The inferior parietal cortex, which controls body image, concept of self, sensory integration, and executive function, has been reported to be structurally impaired in patients with schizophrenia.⁵ Damage to the parietal cortex can alter awareness in healthy persons that they are initiating a voluntary action as they do it.⁶ Furthermore, refractory auditory hallucinations can be suppressed with repetitive transcranial magnetic stimulation (rTMS) or with transcranial direct current stimulation (tDCS) over the left parietotemporal area.⁷

More than 25 years ago, I published a hypothesis⁸ postulating that the delusions of passivity and external control may be caused by an abnormality in the corpus callosum—the largest white matter bundle in the brain, comprised of approximately 200 million myelinated fibers connecting homologous regions in the left and right cerebral hemispheres. I proposed that failed inter- hemispheric connectivity across the corpus callosum would disrupt the unified sense of self that integrates the 2 hemispheres, each of which has its own sphere of consciousness, producing hallucinations and delusions of alien control. The discovery of multiple white matter abnormalities over the past decade and acceptance of disconnectivity in schizophrenia confirms the model I proposed in 1985 as a possible mechanism for schizophrenia.⁹

Finally, it is interesting that DSM-IV-TR does not contain any reference to self disorder or fragmentation in schizophrenia, and diagnostic criteria do not include any reference to loss of self-identity in schizophrenia despite the extensive literature. The term “self” does not even appear in the index. Perhaps now is an opportune time to incorporate this new knowledge in DSM-5 and even consider a new name for schizophrenia. How about “self-proprioception disorder”?

Psychiatrists recognize that schizophrenia is a disorder in which the highest mental functions, such as thought, language, emotions, conation, and cognition, are drastically disrupted. However, the most serious impairment in schizophrenia is a global malfunction in self-integration and personal identity that includes a deficit in self-recognition.

This distorted sense of self leads persons with schizophrenia to fail to recognize what is or is not part of their own mind, which can produce clinical symptoms of schizophrenia, including bizarre delusions, hallucinations, thought disorder, social deficits, and information processing.¹

Just as intact physical proprioception enables a healthy person to be continuously aware of where his body and its parts are located in space, allowing sensory-motor integration, mental proprioception enables one to be fully aware of his identity and self-boundaries, and that his thoughts and actions are generated from within his own sphere of consciousness, not from an external source. In schizophrenia, the coherent sense of self is shattered and fragmented, a frightening experience patients describe after emerging from psychosis.² A person affected by schizophrenia feels lost, as if his “self no longer belong[s]” to him. He feels alienated from his “real self” and refers to himself in the third person. He feels “disconnected, disintegrated, and diminished,” with a sense of “emptiness, a painful void of existence,” of being disembodied with no clear demarcation between self and others.²

Not surprisingly, false beliefs (delusions) and perceptual aberrations (hallucinations) emerge from a fragmented sense of self. Patients fail to recognize that their actions, thoughts, or feelings are initiated from within the self, leading to delusions of passivity and being controlled by an outside force. One’s impulses are misperceived as being imposed by an alien. One’s thoughts, fantasies, and memories become external hallucinations instead of internal recollections. It is not surprising that depersonalization and derealization are common in schizophrenia and in the prodrome stage. Phencyclidine and ketamine, which can produce schizophrenia-like psychoses, are known to trigger dissociative phenomena and a loss of a coherent sense of self.

What causes the disintegration of the mind (self) in schizophrenia? The leading neurobiologic explanation is well-documented white matter pathology.³ Numerous studies have demonstrated that the myelinated axons and fibers that connect various brain regions are abnormal in patients with schizophrenia. The evidence for the breakdown of white matter—and, consequently, brain connectedness and integration—includes several lines of evidence, such as: a) in vivo neuroimaging studies using diffusion tensor imaging (DTI) that show abnormal water mobility in the myelin; b) genetic aberrations in myelin genes; c) postmortem evidence of reduced oligodendrocytes, the glial cells that manufacture myelin; and d) biochemical markers such as the calcium-binding protein S100B, which is released by compromised glial cells.³

Therefore, it is reasonable to think that the disruption of the sense of self and its proprioception may be due to the extensive disconnectivity of brain regions caused by myelin pathology.⁴ However, grey matter abnormality also may play a role in loss of mental proprioceptive functions, which causes a failure to properly recognize one’s self. The inferior parietal cortex, which controls body image, concept of self, sensory integration, and executive function, has been reported to be structurally impaired in patients with schizophrenia.⁵ Damage to the parietal cortex can alter awareness in healthy persons that they are initiating a voluntary action as they do it.⁶ Furthermore, refractory auditory hallucinations can be suppressed with repetitive transcranial magnetic stimulation (rTMS) or with transcranial direct current stimulation (tDCS) over the left parietotemporal area.⁷

More than 25 years ago, I published a hypothesis⁸ postulating that the delusions of passivity and external control may be caused by an abnormality in the corpus callosum—the largest white matter bundle in the brain, comprised of approximately 200 million myelinated fibers connecting homologous regions in the left and right cerebral hemispheres. I proposed that failed inter- hemispheric connectivity across the corpus callosum would disrupt the unified sense of self that integrates the 2 hemispheres, each of which has its own sphere of consciousness, producing hallucinations and delusions of alien control. The discovery of multiple white matter abnormalities over the past decade and acceptance of disconnectivity in schizophrenia confirms the model I proposed in 1985 as a possible mechanism for schizophrenia.⁹

Finally, it is interesting that DSM-IV-TR does not contain any reference to self disorder or fragmentation in schizophrenia, and diagnostic criteria do not include any reference to loss of self-identity in schizophrenia despite the extensive literature. The term “self” does not even appear in the index. Perhaps now is an opportune time to incorporate this new knowledge in DSM-5 and even consider a new name for schizophrenia. How about “self-proprioception disorder”?

Psychiatrists recognize that schizophrenia is a disorder in which the highest mental functions, such as thought, language, emotions, conation, and cognition, are drastically disrupted. However, the most serious impairment in schizophrenia is a global malfunction in self-integration and personal identity that includes a deficit in self-recognition.

This distorted sense of self leads persons with schizophrenia to fail to recognize what is or is not part of their own mind, which can produce clinical symptoms of schizophrenia, including bizarre delusions, hallucinations, thought disorder, social deficits, and information processing.¹

Just as intact physical proprioception enables a healthy person to be continuously aware of where his body and its parts are located in space, allowing sensory-motor integration, mental proprioception enables one to be fully aware of his identity and self-boundaries, and that his thoughts and actions are generated from within his own sphere of consciousness, not from an external source. In schizophrenia, the coherent sense of self is shattered and fragmented, a frightening experience patients describe after emerging from psychosis.² A person affected by schizophrenia feels lost, as if his “self no longer belong[s]” to him. He feels alienated from his “real self” and refers to himself in the third person. He feels “disconnected, disintegrated, and diminished,” with a sense of “emptiness, a painful void of existence,” of being disembodied with no clear demarcation between self and others.²

Not surprisingly, false beliefs (delusions) and perceptual aberrations (hallucinations) emerge from a fragmented sense of self. Patients fail to recognize that their actions, thoughts, or feelings are initiated from within the self, leading to delusions of passivity and being controlled by an outside force. One’s impulses are misperceived as being imposed by an alien. One’s thoughts, fantasies, and memories become external hallucinations instead of internal recollections. It is not surprising that depersonalization and derealization are common in schizophrenia and in the prodrome stage. Phencyclidine and ketamine, which can produce schizophrenia-like psychoses, are known to trigger dissociative phenomena and a loss of a coherent sense of self.

What causes the disintegration of the mind (self) in schizophrenia? The leading neurobiologic explanation is well-documented white matter pathology.³ Numerous studies have demonstrated that the myelinated axons and fibers that connect various brain regions are abnormal in patients with schizophrenia. The evidence for the breakdown of white matter—and, consequently, brain connectedness and integration—includes several lines of evidence, such as: a) in vivo neuroimaging studies using diffusion tensor imaging (DTI) that show abnormal water mobility in the myelin; b) genetic aberrations in myelin genes; c) postmortem evidence of reduced oligodendrocytes, the glial cells that manufacture myelin; and d) biochemical markers such as the calcium-binding protein S100B, which is released by compromised glial cells.³

Therefore, it is reasonable to think that the disruption of the sense of self and its proprioception may be due to the extensive disconnectivity of brain regions caused by myelin pathology.⁴ However, grey matter abnormality also may play a role in loss of mental proprioceptive functions, which causes a failure to properly recognize one’s self. The inferior parietal cortex, which controls body image, concept of self, sensory integration, and executive function, has been reported to be structurally impaired in patients with schizophrenia.⁵ Damage to the parietal cortex can alter awareness in healthy persons that they are initiating a voluntary action as they do it.⁶ Furthermore, refractory auditory hallucinations can be suppressed with repetitive transcranial magnetic stimulation (rTMS) or with transcranial direct current stimulation (tDCS) over the left parietotemporal area.⁷

More than 25 years ago, I published a hypothesis⁸ postulating that the delusions of passivity and external control may be caused by an abnormality in the corpus callosum—the largest white matter bundle in the brain, comprised of approximately 200 million myelinated fibers connecting homologous regions in the left and right cerebral hemispheres. I proposed that failed inter- hemispheric connectivity across the corpus callosum would disrupt the unified sense of self that integrates the 2 hemispheres, each of which has its own sphere of consciousness, producing hallucinations and delusions of alien control. The discovery of multiple white matter abnormalities over the past decade and acceptance of disconnectivity in schizophrenia confirms the model I proposed in 1985 as a possible mechanism for schizophrenia.⁹

Finally, it is interesting that DSM-IV-TR does not contain any reference to self disorder or fragmentation in schizophrenia, and diagnostic criteria do not include any reference to loss of self-identity in schizophrenia despite the extensive literature. The term “self” does not even appear in the index. Perhaps now is an opportune time to incorporate this new knowledge in DSM-5 and even consider a new name for schizophrenia. How about “self-proprioception disorder”?

Discuss this article at www.facebook.com/CurrentPsychiatry

Mrs. G is a 52-year-old mother and teacher with a 20-year history of recurrent depressive episodes for which she has been treated with various antidepressants, including sertraline, fluoxetine, and citalopram. For some of her depressive recurrences, she also received adjunctive second-generation antipsychotics (SGAs), including quetiapine and olanzapine.

She describes feelings of “being defeated,” hopelessness, and boredom and frustration with her teaching. It takes her approximately 30 minutes to go to sleep each night, but she wakes up after 2 to 3 hours, and the remainder of her night’s sleep is markedly disrupted. Because of her hopeless feelings, she has given up on dieting and going to the gym. When feeling down she has donuts and coffee. She has gained 45 lbs over the past 10 years and now weighs 175 lbs. In addition to her disrupted mood, she complains of frequent headaches and sore muscles.

Mrs. G’s psychiatrist refers her to her primary care physician for evaluation of her physical complaints and recommendations regarding her weight gain. Her waistline measures 90 cm and her body mass index (BMI) is 29.1 kg/m²; a BMI of ≥30 is considered obese. Her blood pressure is 145/85 mmHg. Laboratory work reveals a total cholesterol level of 235 mg/dL, low-density lipoprotein of 146 mg/dL, and fasting blood sugar, 135 mg/dL.

Mrs. G’s case illustrates many of the issues psychiatrists face when caring for overweight or obese patients with depression (OW/OB-D). Both conditions can be challenging to manage, and may be especially difficult to treat when they co-occur. When depression and obesity co-occur, their capacity to inflict psychological and physical harm likely is greater than either condition alone. Data point to a “2-way street” of mutually destructive effects of being overweight/obese on depression and vice versa.¹

This article summarizes ways that depression and obesity aggravate each other, and highlights research that suggests depression and obesity are manifestations of inflammatory processes. It also suggests a stepwise approach to treating OW/OB-D patients.

Mutually destructive processes

Self-esteem and body image. Lowered self-esteem is a hallmark of depression. In popular culture, “you can’t be too rich or too thin,” and the pressure to be slim is great. Therefore, OW/OB-D patients have 2 reasons to feel a depleted sense of self-worth: their psychiatric illness and their weight. Observant clinicians will recognize these dual sources of self-deprecation and tailor treatment to address both.

Increasing numbers of celebrities, performers, and prominent politicians are overweight or obese. Increased social acceptance of OW/OB individuals in our culture may be legitimizing weight gain and obesity. When OW/OB-D patients justify their weight by pointing to overweight celebrities, clinicians can counter this argument with data on the hazards of obesity on health and well-being, such as premature death, coronary artery disease, diabetes, arthritis, and some forms of cancer.

OW/OB patients tend to interact with other OW/OB individuals. Christakis et al² reported that adults with obese friends were more likely to become obese than individuals without obese friends. Valente et al³ found that overweight teens were twice as likely to have overweight friends as non-overweight teens. This power of social connectedness can be harnessed when treating OW/OB-D patients, where therapeutic groups can help patients address both depression and weight gain.

Inactivity. OW/OB-D patients with psychomotor retardation or reduced activity may gain weight because they consume more calories than their body requires. Depressed patients may say they “have no energy” to participate in a clinician-recommended exercise program or that “it won’t do any good anyway.”

These tendencies are best dealt with by incorporating an exercise program into the comprehensive plan for OW/OB-D patients from the start of treatment. Several studies suggest that in addition to helping manage weight, exercise may have antidepressant effects. In a large, well-controlled trial of patients with major depressive disorder (MDD), Blumenthal et al⁴ found that an exercise program was as effective as fluoxetine, 20 mg/d, and the antidepressant effects persisted at 10-month follow-up for patients who continued to exercise.⁵ In a review of studies of exercise in depressed patients, Helmich et al⁶ concluded that in most studies exercise was beneficial. However, Mead et al⁷ found that nearly all trials of exercise and depression had substantial design flaws. Based on the 3 well-designed studies they reviewed, Mead et al concluded that the efficacy of exercise was comparable to that of cognitive therapy.

Although the evidence on exercise for treating depression is inconclusive, an exercise program is essential for OW/OB-D patients because it can help manage weight and improve cardiovascular fitness. Motivation is a key ingredient of successful programs.⁸ Encourage patients to make exercise enjoyable, perhaps by using video games or other interactive computer-based programs.⁹

Sleep disturbances. Disrupted sleep— another hallmark of depression—appears to be a risk factor for weight gain.¹⁰ Although the basis for this relationship is still under investigation, one possibility is that some patients with insomnia get up to eat more often than those without sleep disturbances. Research has shown that when sleep is curtailed in a sleep laboratory, patients consume approximately 20% more calories from snacks (1,086 calories) than non-sleep-deprived patients (866 calories).¹¹ Although this 220-calorie increase may seem small, it would amount to approximately 2 lbs of additional weight per month.

Appetite. Although weight loss is a cardinal sign of MDD, increased appetite and weight gain can be seen in many depressed patients who do not meet diagnostic criteria for MDD as well as those with seasonal affective disorder and metabolic syndrome, a condition characterized by insulin resistance, glucose intolerance, atherogenic dyslipidemia, visceral adiposity, hypercoagulation, chronic inflammation, oxidative stress, and hypertension.¹²

Emerging information about the neuroendocrinology of appetite regulation may lead to a better understanding of weight management in OW/OB-D patients. Leptin, a hormone released by adipose tissue, increases when fat stores are high, leading to reduced appetite and fat stores. Conversely, when fat stores are low, plasma leptin levels decrease, producing increased appetite and reduced energy expenditure.¹³

Researchers have suggested that leptin insufficiency and/or leptin resistance may contribute to vulnerability to depression, and leptin may have antidepressant effects.¹⁴ Lawson et al¹⁵ found that leptin levels were inversely associated with Hamilton Depression Rating Scale scores in normal-weight (BMI ≤25) women.

Leptin levels also are significantly associated with comorbid depressed mood and sleep disturbance.¹⁶ In healthy volunteers, shortening sleep duration to 4 hours produced an approximately 20% reduction in leptin release compared with normal sleep duration.¹⁷ Because of the relationship between sleep disorders and depression, leptin may act on sleep regulatory mechanisms, depressogenic pathways, or both. But studies of leptin’s role in obesity, depression, and sleep have not yet found a single role for leptin that ties all 3 conditions to this hormone’s known physiological functions.

Nonadherence. Compared with non-depressed patients, depressed patients are 76% more likely to not adhere to treatment.¹⁸ Patients may report that they are not interested in the treatment program or lack hope that it will be successful. Furthermore, OW/OB-D patients may consider exercise programs to be too strenuous and diet programs too depriving.¹⁹

OW/OB-D patients may require special care in monitoring adherence. The presence of depression in patients enrolled in weight loss programs may prompt the treatment staff to modify the usual protocol by including the patient in an active depression treatment module.²⁰

Effects of pharmacologic agents

Many antidepressant agents are associated with weight gain.²¹Tables 1 and 2 summarize the effects antidepressants and adjunctive medications used to treat depression have on weight.^22,23 SGAs such as clozapine and olanzapine, which frequently are used as augmenting agents in patients with treatment-resistant depression (TRD), are associated with weight gain.²² Lamotrigine also is an effective adjunctive medication for TRD and is not associated with significant weight gain.²⁴

Bupropion has antidepressant and weight-loss effects and may be a suitable primary medication for OW/OB-D patients.

Early weight gain with olanzapine/fluoxetine combination may be a strong indicator of substantial weight gain with longer-term treatment. A weight gain of >2 kg (4.4 lbs) during the first 2 weeks of treatment is a strong predictor of weight gain of ≥10 kg (22 lbs) at 26 weeks.²⁵

Antidepressants may be associated with an increased risk of obesity, and strategies to offset this risk may be useful in clinical practice, particularly patient education on the risks of weight gain and early introduction of a diet and exercise program.

Evidence suggests that depression and obesity are associated with alterations in immune activity (Box). This suggests that anti-inflammatory agents might have a role in treating depression by reducing the release of cytokines that may lead to depressive symptoms.

Table 1

Pharmacotherapy and weight gain: Antidepressants

Table 2

Pharmacotherapy and weight gain: Adjunctive agents

Box

Cognitive/behavioral approaches

Although large, well-designed studies of OW/OB-D patients are in the planning or pilot phases,^26-28 a substantial database supports incorporating behavioral or cognitive-behavioral therapies when treating these patients.²⁹ Patients in programs that combine behavioral approaches with diet and exercise achieve the greatest weight loss, and frequently show improved depression scores.^30-32

In a randomized trial, 203 obese women with moderate to severe depression showed significant weight loss and decreased depression scores whether they were in a behavioral weight-loss program or one that combined behavioral weigh loss with cognitive-behavioral depression management.³³ This study raises important questions: Did the behavioral weight-loss program effectively treat depression? Did patients’ depressive symptoms improve because of their improved sense of well-being as they lost weight? Did a putative reduction in cytokine production by fat cells improve their mood?

Treatment implications

Mrs. G has TRD, a BMI that borders on obesity, sleep problems, and lab values that suggest she may have metabolic syndrome. To best manage patients such as Mrs. G, consider the following steps:

1. Select an antidepressant that is unlikely to cause further weight gain, such as bupropion, duloxetine, or fluoxetine.
2. If necessary, add an augmenting agent that is not associated with weight gain, such as bupropion, aripiprazole, or lamotrigine.
3. Verify that your patient is getting adequate sleep. Begin by reviewing the principles of sleep hygiene and, if necessary, prescribe a sedative or hypnotic medication.
4. Although controlled clinical trials are lacking, consider including an anti-inflammatory agent such as aspirin to the pharmacologic armamentarium.
5. Institute an exercise and diet program at the beginning of treatment. Exercise can begin with 20 to 30 minutes a day of walking. Tell patients that exercising in groups is a good way to address nonadherence and social isolation and reinforce positive lifestyle changes. Recommend that patients combine aerobic exercise to burn calories with resistance training to build muscle. Suggest that patients try to make exercising fun using video games or interactive computer-based programs.
6. Encourage your patient to keep a journal to record his or her weight, amount and type of exercise, medication taken, and dietary intake. Review this information at every session to reinforce the importance of this integrated exercise and diet program.

Related Resources

• Markowitz S, Friedman MA, Arent SM. Understanding the relation between obesity and depression: causal mechanisms and implications for treatment. Clinical Psychology: Science and Practice. 2008:15(1):1-20.
• Burke LE, Wang J, Sevick MA. Self-monitoring in weight loss: a systematic review of the literature. J Am Diet Assoc. 2011;111(1):92-102.

Drug Brand Names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Selegiline • Emsam
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Ziprasidone • Geodon

Disclosure

Dr. Crayton reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mrs. G is a 52-year-old mother and teacher with a 20-year history of recurrent depressive episodes for which she has been treated with various antidepressants, including sertraline, fluoxetine, and citalopram. For some of her depressive recurrences, she also received adjunctive second-generation antipsychotics (SGAs), including quetiapine and olanzapine.

She describes feelings of “being defeated,” hopelessness, and boredom and frustration with her teaching. It takes her approximately 30 minutes to go to sleep each night, but she wakes up after 2 to 3 hours, and the remainder of her night’s sleep is markedly disrupted. Because of her hopeless feelings, she has given up on dieting and going to the gym. When feeling down she has donuts and coffee. She has gained 45 lbs over the past 10 years and now weighs 175 lbs. In addition to her disrupted mood, she complains of frequent headaches and sore muscles.

Mrs. G’s psychiatrist refers her to her primary care physician for evaluation of her physical complaints and recommendations regarding her weight gain. Her waistline measures 90 cm and her body mass index (BMI) is 29.1 kg/m²; a BMI of ≥30 is considered obese. Her blood pressure is 145/85 mmHg. Laboratory work reveals a total cholesterol level of 235 mg/dL, low-density lipoprotein of 146 mg/dL, and fasting blood sugar, 135 mg/dL.

Mrs. G’s case illustrates many of the issues psychiatrists face when caring for overweight or obese patients with depression (OW/OB-D). Both conditions can be challenging to manage, and may be especially difficult to treat when they co-occur. When depression and obesity co-occur, their capacity to inflict psychological and physical harm likely is greater than either condition alone. Data point to a “2-way street” of mutually destructive effects of being overweight/obese on depression and vice versa.¹

This article summarizes ways that depression and obesity aggravate each other, and highlights research that suggests depression and obesity are manifestations of inflammatory processes. It also suggests a stepwise approach to treating OW/OB-D patients.

Mutually destructive processes

Self-esteem and body image. Lowered self-esteem is a hallmark of depression. In popular culture, “you can’t be too rich or too thin,” and the pressure to be slim is great. Therefore, OW/OB-D patients have 2 reasons to feel a depleted sense of self-worth: their psychiatric illness and their weight. Observant clinicians will recognize these dual sources of self-deprecation and tailor treatment to address both.

Increasing numbers of celebrities, performers, and prominent politicians are overweight or obese. Increased social acceptance of OW/OB individuals in our culture may be legitimizing weight gain and obesity. When OW/OB-D patients justify their weight by pointing to overweight celebrities, clinicians can counter this argument with data on the hazards of obesity on health and well-being, such as premature death, coronary artery disease, diabetes, arthritis, and some forms of cancer.

OW/OB patients tend to interact with other OW/OB individuals. Christakis et al² reported that adults with obese friends were more likely to become obese than individuals without obese friends. Valente et al³ found that overweight teens were twice as likely to have overweight friends as non-overweight teens. This power of social connectedness can be harnessed when treating OW/OB-D patients, where therapeutic groups can help patients address both depression and weight gain.

Inactivity. OW/OB-D patients with psychomotor retardation or reduced activity may gain weight because they consume more calories than their body requires. Depressed patients may say they “have no energy” to participate in a clinician-recommended exercise program or that “it won’t do any good anyway.”

These tendencies are best dealt with by incorporating an exercise program into the comprehensive plan for OW/OB-D patients from the start of treatment. Several studies suggest that in addition to helping manage weight, exercise may have antidepressant effects. In a large, well-controlled trial of patients with major depressive disorder (MDD), Blumenthal et al⁴ found that an exercise program was as effective as fluoxetine, 20 mg/d, and the antidepressant effects persisted at 10-month follow-up for patients who continued to exercise.⁵ In a review of studies of exercise in depressed patients, Helmich et al⁶ concluded that in most studies exercise was beneficial. However, Mead et al⁷ found that nearly all trials of exercise and depression had substantial design flaws. Based on the 3 well-designed studies they reviewed, Mead et al concluded that the efficacy of exercise was comparable to that of cognitive therapy.

Although the evidence on exercise for treating depression is inconclusive, an exercise program is essential for OW/OB-D patients because it can help manage weight and improve cardiovascular fitness. Motivation is a key ingredient of successful programs.⁸ Encourage patients to make exercise enjoyable, perhaps by using video games or other interactive computer-based programs.⁹

Sleep disturbances. Disrupted sleep— another hallmark of depression—appears to be a risk factor for weight gain.¹⁰ Although the basis for this relationship is still under investigation, one possibility is that some patients with insomnia get up to eat more often than those without sleep disturbances. Research has shown that when sleep is curtailed in a sleep laboratory, patients consume approximately 20% more calories from snacks (1,086 calories) than non-sleep-deprived patients (866 calories).¹¹ Although this 220-calorie increase may seem small, it would amount to approximately 2 lbs of additional weight per month.

Appetite. Although weight loss is a cardinal sign of MDD, increased appetite and weight gain can be seen in many depressed patients who do not meet diagnostic criteria for MDD as well as those with seasonal affective disorder and metabolic syndrome, a condition characterized by insulin resistance, glucose intolerance, atherogenic dyslipidemia, visceral adiposity, hypercoagulation, chronic inflammation, oxidative stress, and hypertension.¹²

Emerging information about the neuroendocrinology of appetite regulation may lead to a better understanding of weight management in OW/OB-D patients. Leptin, a hormone released by adipose tissue, increases when fat stores are high, leading to reduced appetite and fat stores. Conversely, when fat stores are low, plasma leptin levels decrease, producing increased appetite and reduced energy expenditure.¹³

Researchers have suggested that leptin insufficiency and/or leptin resistance may contribute to vulnerability to depression, and leptin may have antidepressant effects.¹⁴ Lawson et al¹⁵ found that leptin levels were inversely associated with Hamilton Depression Rating Scale scores in normal-weight (BMI ≤25) women.

Leptin levels also are significantly associated with comorbid depressed mood and sleep disturbance.¹⁶ In healthy volunteers, shortening sleep duration to 4 hours produced an approximately 20% reduction in leptin release compared with normal sleep duration.¹⁷ Because of the relationship between sleep disorders and depression, leptin may act on sleep regulatory mechanisms, depressogenic pathways, or both. But studies of leptin’s role in obesity, depression, and sleep have not yet found a single role for leptin that ties all 3 conditions to this hormone’s known physiological functions.

Nonadherence. Compared with non-depressed patients, depressed patients are 76% more likely to not adhere to treatment.¹⁸ Patients may report that they are not interested in the treatment program or lack hope that it will be successful. Furthermore, OW/OB-D patients may consider exercise programs to be too strenuous and diet programs too depriving.¹⁹

OW/OB-D patients may require special care in monitoring adherence. The presence of depression in patients enrolled in weight loss programs may prompt the treatment staff to modify the usual protocol by including the patient in an active depression treatment module.²⁰

Effects of pharmacologic agents

Many antidepressant agents are associated with weight gain.²¹Tables 1 and 2 summarize the effects antidepressants and adjunctive medications used to treat depression have on weight.^22,23 SGAs such as clozapine and olanzapine, which frequently are used as augmenting agents in patients with treatment-resistant depression (TRD), are associated with weight gain.²² Lamotrigine also is an effective adjunctive medication for TRD and is not associated with significant weight gain.²⁴

Bupropion has antidepressant and weight-loss effects and may be a suitable primary medication for OW/OB-D patients.

Early weight gain with olanzapine/fluoxetine combination may be a strong indicator of substantial weight gain with longer-term treatment. A weight gain of >2 kg (4.4 lbs) during the first 2 weeks of treatment is a strong predictor of weight gain of ≥10 kg (22 lbs) at 26 weeks.²⁵

Antidepressants may be associated with an increased risk of obesity, and strategies to offset this risk may be useful in clinical practice, particularly patient education on the risks of weight gain and early introduction of a diet and exercise program.

Evidence suggests that depression and obesity are associated with alterations in immune activity (Box). This suggests that anti-inflammatory agents might have a role in treating depression by reducing the release of cytokines that may lead to depressive symptoms.

Table 1

Pharmacotherapy and weight gain: Antidepressants

Table 2

Pharmacotherapy and weight gain: Adjunctive agents

Box

Cognitive/behavioral approaches

Although large, well-designed studies of OW/OB-D patients are in the planning or pilot phases,^26-28 a substantial database supports incorporating behavioral or cognitive-behavioral therapies when treating these patients.²⁹ Patients in programs that combine behavioral approaches with diet and exercise achieve the greatest weight loss, and frequently show improved depression scores.^30-32

In a randomized trial, 203 obese women with moderate to severe depression showed significant weight loss and decreased depression scores whether they were in a behavioral weight-loss program or one that combined behavioral weigh loss with cognitive-behavioral depression management.³³ This study raises important questions: Did the behavioral weight-loss program effectively treat depression? Did patients’ depressive symptoms improve because of their improved sense of well-being as they lost weight? Did a putative reduction in cytokine production by fat cells improve their mood?

Treatment implications

Mrs. G has TRD, a BMI that borders on obesity, sleep problems, and lab values that suggest she may have metabolic syndrome. To best manage patients such as Mrs. G, consider the following steps:

1. Select an antidepressant that is unlikely to cause further weight gain, such as bupropion, duloxetine, or fluoxetine.
2. If necessary, add an augmenting agent that is not associated with weight gain, such as bupropion, aripiprazole, or lamotrigine.
3. Verify that your patient is getting adequate sleep. Begin by reviewing the principles of sleep hygiene and, if necessary, prescribe a sedative or hypnotic medication.
4. Although controlled clinical trials are lacking, consider including an anti-inflammatory agent such as aspirin to the pharmacologic armamentarium.
5. Institute an exercise and diet program at the beginning of treatment. Exercise can begin with 20 to 30 minutes a day of walking. Tell patients that exercising in groups is a good way to address nonadherence and social isolation and reinforce positive lifestyle changes. Recommend that patients combine aerobic exercise to burn calories with resistance training to build muscle. Suggest that patients try to make exercising fun using video games or interactive computer-based programs.
6. Encourage your patient to keep a journal to record his or her weight, amount and type of exercise, medication taken, and dietary intake. Review this information at every session to reinforce the importance of this integrated exercise and diet program.

Related Resources

• Markowitz S, Friedman MA, Arent SM. Understanding the relation between obesity and depression: causal mechanisms and implications for treatment. Clinical Psychology: Science and Practice. 2008:15(1):1-20.
• Burke LE, Wang J, Sevick MA. Self-monitoring in weight loss: a systematic review of the literature. J Am Diet Assoc. 2011;111(1):92-102.

Drug Brand Names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Selegiline • Emsam
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Ziprasidone • Geodon

Disclosure

Dr. Crayton reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mrs. G is a 52-year-old mother and teacher with a 20-year history of recurrent depressive episodes for which she has been treated with various antidepressants, including sertraline, fluoxetine, and citalopram. For some of her depressive recurrences, she also received adjunctive second-generation antipsychotics (SGAs), including quetiapine and olanzapine.

She describes feelings of “being defeated,” hopelessness, and boredom and frustration with her teaching. It takes her approximately 30 minutes to go to sleep each night, but she wakes up after 2 to 3 hours, and the remainder of her night’s sleep is markedly disrupted. Because of her hopeless feelings, she has given up on dieting and going to the gym. When feeling down she has donuts and coffee. She has gained 45 lbs over the past 10 years and now weighs 175 lbs. In addition to her disrupted mood, she complains of frequent headaches and sore muscles.

Mrs. G’s psychiatrist refers her to her primary care physician for evaluation of her physical complaints and recommendations regarding her weight gain. Her waistline measures 90 cm and her body mass index (BMI) is 29.1 kg/m²; a BMI of ≥30 is considered obese. Her blood pressure is 145/85 mmHg. Laboratory work reveals a total cholesterol level of 235 mg/dL, low-density lipoprotein of 146 mg/dL, and fasting blood sugar, 135 mg/dL.

Mrs. G’s case illustrates many of the issues psychiatrists face when caring for overweight or obese patients with depression (OW/OB-D). Both conditions can be challenging to manage, and may be especially difficult to treat when they co-occur. When depression and obesity co-occur, their capacity to inflict psychological and physical harm likely is greater than either condition alone. Data point to a “2-way street” of mutually destructive effects of being overweight/obese on depression and vice versa.¹

This article summarizes ways that depression and obesity aggravate each other, and highlights research that suggests depression and obesity are manifestations of inflammatory processes. It also suggests a stepwise approach to treating OW/OB-D patients.

Mutually destructive processes

Self-esteem and body image. Lowered self-esteem is a hallmark of depression. In popular culture, “you can’t be too rich or too thin,” and the pressure to be slim is great. Therefore, OW/OB-D patients have 2 reasons to feel a depleted sense of self-worth: their psychiatric illness and their weight. Observant clinicians will recognize these dual sources of self-deprecation and tailor treatment to address both.

Increasing numbers of celebrities, performers, and prominent politicians are overweight or obese. Increased social acceptance of OW/OB individuals in our culture may be legitimizing weight gain and obesity. When OW/OB-D patients justify their weight by pointing to overweight celebrities, clinicians can counter this argument with data on the hazards of obesity on health and well-being, such as premature death, coronary artery disease, diabetes, arthritis, and some forms of cancer.

OW/OB patients tend to interact with other OW/OB individuals. Christakis et al² reported that adults with obese friends were more likely to become obese than individuals without obese friends. Valente et al³ found that overweight teens were twice as likely to have overweight friends as non-overweight teens. This power of social connectedness can be harnessed when treating OW/OB-D patients, where therapeutic groups can help patients address both depression and weight gain.

Inactivity. OW/OB-D patients with psychomotor retardation or reduced activity may gain weight because they consume more calories than their body requires. Depressed patients may say they “have no energy” to participate in a clinician-recommended exercise program or that “it won’t do any good anyway.”

These tendencies are best dealt with by incorporating an exercise program into the comprehensive plan for OW/OB-D patients from the start of treatment. Several studies suggest that in addition to helping manage weight, exercise may have antidepressant effects. In a large, well-controlled trial of patients with major depressive disorder (MDD), Blumenthal et al⁴ found that an exercise program was as effective as fluoxetine, 20 mg/d, and the antidepressant effects persisted at 10-month follow-up for patients who continued to exercise.⁵ In a review of studies of exercise in depressed patients, Helmich et al⁶ concluded that in most studies exercise was beneficial. However, Mead et al⁷ found that nearly all trials of exercise and depression had substantial design flaws. Based on the 3 well-designed studies they reviewed, Mead et al concluded that the efficacy of exercise was comparable to that of cognitive therapy.

Although the evidence on exercise for treating depression is inconclusive, an exercise program is essential for OW/OB-D patients because it can help manage weight and improve cardiovascular fitness. Motivation is a key ingredient of successful programs.⁸ Encourage patients to make exercise enjoyable, perhaps by using video games or other interactive computer-based programs.⁹

Sleep disturbances. Disrupted sleep— another hallmark of depression—appears to be a risk factor for weight gain.¹⁰ Although the basis for this relationship is still under investigation, one possibility is that some patients with insomnia get up to eat more often than those without sleep disturbances. Research has shown that when sleep is curtailed in a sleep laboratory, patients consume approximately 20% more calories from snacks (1,086 calories) than non-sleep-deprived patients (866 calories).¹¹ Although this 220-calorie increase may seem small, it would amount to approximately 2 lbs of additional weight per month.

Appetite. Although weight loss is a cardinal sign of MDD, increased appetite and weight gain can be seen in many depressed patients who do not meet diagnostic criteria for MDD as well as those with seasonal affective disorder and metabolic syndrome, a condition characterized by insulin resistance, glucose intolerance, atherogenic dyslipidemia, visceral adiposity, hypercoagulation, chronic inflammation, oxidative stress, and hypertension.¹²

Emerging information about the neuroendocrinology of appetite regulation may lead to a better understanding of weight management in OW/OB-D patients. Leptin, a hormone released by adipose tissue, increases when fat stores are high, leading to reduced appetite and fat stores. Conversely, when fat stores are low, plasma leptin levels decrease, producing increased appetite and reduced energy expenditure.¹³

Researchers have suggested that leptin insufficiency and/or leptin resistance may contribute to vulnerability to depression, and leptin may have antidepressant effects.¹⁴ Lawson et al¹⁵ found that leptin levels were inversely associated with Hamilton Depression Rating Scale scores in normal-weight (BMI ≤25) women.

Leptin levels also are significantly associated with comorbid depressed mood and sleep disturbance.¹⁶ In healthy volunteers, shortening sleep duration to 4 hours produced an approximately 20% reduction in leptin release compared with normal sleep duration.¹⁷ Because of the relationship between sleep disorders and depression, leptin may act on sleep regulatory mechanisms, depressogenic pathways, or both. But studies of leptin’s role in obesity, depression, and sleep have not yet found a single role for leptin that ties all 3 conditions to this hormone’s known physiological functions.

Nonadherence. Compared with non-depressed patients, depressed patients are 76% more likely to not adhere to treatment.¹⁸ Patients may report that they are not interested in the treatment program or lack hope that it will be successful. Furthermore, OW/OB-D patients may consider exercise programs to be too strenuous and diet programs too depriving.¹⁹

OW/OB-D patients may require special care in monitoring adherence. The presence of depression in patients enrolled in weight loss programs may prompt the treatment staff to modify the usual protocol by including the patient in an active depression treatment module.²⁰

Effects of pharmacologic agents

Many antidepressant agents are associated with weight gain.²¹Tables 1 and 2 summarize the effects antidepressants and adjunctive medications used to treat depression have on weight.^22,23 SGAs such as clozapine and olanzapine, which frequently are used as augmenting agents in patients with treatment-resistant depression (TRD), are associated with weight gain.²² Lamotrigine also is an effective adjunctive medication for TRD and is not associated with significant weight gain.²⁴

Bupropion has antidepressant and weight-loss effects and may be a suitable primary medication for OW/OB-D patients.

Early weight gain with olanzapine/fluoxetine combination may be a strong indicator of substantial weight gain with longer-term treatment. A weight gain of >2 kg (4.4 lbs) during the first 2 weeks of treatment is a strong predictor of weight gain of ≥10 kg (22 lbs) at 26 weeks.²⁵

Antidepressants may be associated with an increased risk of obesity, and strategies to offset this risk may be useful in clinical practice, particularly patient education on the risks of weight gain and early introduction of a diet and exercise program.

Evidence suggests that depression and obesity are associated with alterations in immune activity (Box). This suggests that anti-inflammatory agents might have a role in treating depression by reducing the release of cytokines that may lead to depressive symptoms.

Table 1

Pharmacotherapy and weight gain: Antidepressants

Table 2

Pharmacotherapy and weight gain: Adjunctive agents

Box

Cognitive/behavioral approaches

Although large, well-designed studies of OW/OB-D patients are in the planning or pilot phases,^26-28 a substantial database supports incorporating behavioral or cognitive-behavioral therapies when treating these patients.²⁹ Patients in programs that combine behavioral approaches with diet and exercise achieve the greatest weight loss, and frequently show improved depression scores.^30-32

In a randomized trial, 203 obese women with moderate to severe depression showed significant weight loss and decreased depression scores whether they were in a behavioral weight-loss program or one that combined behavioral weigh loss with cognitive-behavioral depression management.³³ This study raises important questions: Did the behavioral weight-loss program effectively treat depression? Did patients’ depressive symptoms improve because of their improved sense of well-being as they lost weight? Did a putative reduction in cytokine production by fat cells improve their mood?

Treatment implications

Mrs. G has TRD, a BMI that borders on obesity, sleep problems, and lab values that suggest she may have metabolic syndrome. To best manage patients such as Mrs. G, consider the following steps:

1. Select an antidepressant that is unlikely to cause further weight gain, such as bupropion, duloxetine, or fluoxetine.
2. If necessary, add an augmenting agent that is not associated with weight gain, such as bupropion, aripiprazole, or lamotrigine.
3. Verify that your patient is getting adequate sleep. Begin by reviewing the principles of sleep hygiene and, if necessary, prescribe a sedative or hypnotic medication.
4. Although controlled clinical trials are lacking, consider including an anti-inflammatory agent such as aspirin to the pharmacologic armamentarium.
5. Institute an exercise and diet program at the beginning of treatment. Exercise can begin with 20 to 30 minutes a day of walking. Tell patients that exercising in groups is a good way to address nonadherence and social isolation and reinforce positive lifestyle changes. Recommend that patients combine aerobic exercise to burn calories with resistance training to build muscle. Suggest that patients try to make exercising fun using video games or interactive computer-based programs.
6. Encourage your patient to keep a journal to record his or her weight, amount and type of exercise, medication taken, and dietary intake. Review this information at every session to reinforce the importance of this integrated exercise and diet program.

Related Resources

• Markowitz S, Friedman MA, Arent SM. Understanding the relation between obesity and depression: causal mechanisms and implications for treatment. Clinical Psychology: Science and Practice. 2008:15(1):1-20.
• Burke LE, Wang J, Sevick MA. Self-monitoring in weight loss: a systematic review of the literature. J Am Diet Assoc. 2011;111(1):92-102.

Drug Brand Names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Selegiline • Emsam
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Ziprasidone • Geodon

Disclosure

Dr. Crayton reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.