The proportion of older adults in the world population is growing rapidly. In the next 10 to 15 years, the population age >60 will grow 3.5 times more rapidly than the general population.¹ As a result, there is an increased urgency in examining benefits vs risks of antipsychotics in older individuals. In a 2010 U.S. nationally representative observational study, antipsychotic use was observed to rise slowly during early and middle adulthood, peaking at approximately age 55, declining slightly between ages 55 and 65, and then rising again after age 65, with >2% of individuals ages 80 to 84 receiving an anti­psychotic.² This is likely due to the chronology of psychotic, mood, and neurocognitive disorders across the life span. In this large national study, long-term antipsychotic treatment was common, and older patients were more likely to receive their prescriptions from non-psychiatrist physicians than from psychiatrists.² Among patients receiving an antipsychotic, the proportion of those receiving it for >120 days was 54% for individuals ages 70 to 74; 49% for individuals ages 75 to 79; and 46% for individuals ages 80 to 84.

This 3-part review summarizes findings and risk–benefit considerations when prescribing antipsychotics to older individuals. Part 1 focused on those with chronic psychotic disorders, such as schizophrenia or bipolar disorder,³ and part 3 will cover patients with dementia. This review (part 2) aims to:

• briefly summarize the results of randomized controlled trials (RCTs) of second-generation antipsychotics (SGAs) and other major studies and analyses in older patients with major depressive disorder (MDD)
• provide a summative opinion on the relative risks and benefits associated with using antipsychotics in older adults with MDD
• highlight the gaps in the evidence base and areas that need additional research.

Summary of benefits, place in treatment armamentarium

The prevalence of MDD and clinically significant depressive symptoms in community­dwelling older adults is 3% to 4% and 15%, respectively, and as high as 16% and 50%, respectively, in nursing home residents.⁴ Because late-life depression is associated with suffering, disability, and excessive mortality, it needs to be recognized and treated aggressively.⁵ Antidepressants are the mainstay of pharmacotherapy for late-life depression. Guidelines and expert opinion informed by the current evidence recommend using selective serotonin reuptake inhibitors, such as escitalopram or sertraline, as a first-line treatment; serotonin norepinephrine reuptake inhibitors, such as duloxetine or venlafaxine, as a second-line treatment; and other antidepressants, such as bupropion or nortriptyline, as a third-line treatment.^5,6 However, antipsychotics also have a role in treating late-life depression.

Over the past decade, several anti­psychotics have been FDA-approved for treating MDD: aripiprazole and brexpiprazole as adjunctive treatment of MDD in adults; olanzapine-fluoxetine combination for acute and maintenance treatment of treatment-resistant depression in adults and geriatric adults; and quetiapine extended-release (XR) as monotherapy for MDD in adults and as adjunctive treatment of MDD in adults and geriatric adults who have had an inadequate response to antidepressants alone (Table 1). However, “black-box” warnings for all first-generation antipsychotics (FGAs) and SGAs alert clinicians that these medications have been associated with serious adverse events in older adults with dementia, including “deaths […] due to heart-related events (eg, heart failure, sudden death) or infections (mostly pneumonia),” with 15 of 17 placebo-controlled trials showing a higher number of deaths with an antipsychotic compared with placebo.⁷ Although similar controlled data on the mortality risk of antipsychotics in older adults with mood disorders do not exist, most experts limit their use to 2 groups of older patients: those with MDD and psychotic features (“psychotic depression”) and those with treatment-resistant depression.

Clinical trials

Olanzapine plus sertraline as first-line pharmacotherapy for MDD with psychotic features. Meyers et al¹¹ reported on a double-blind randomized comparison of olanzapine plus placebo vs olanzapine plus sertraline in 259 patients with MDD with psychotic features. An unusual feature of this trial is that it included a similar number of younger and older participants (ages 18 to 93): 117 participants were age <60 (mean age [standard deviation (SD)]: 41.3 [10.8]) and 142 were age ≥60 (mean age [SD]: 71.7 [7.8]). The same dose titration schedules based on efficacy and tolerability were used in both younger and older participants. At the end of the study, the mean dose (SD) of sertraline (or placebo) did not differ significantly in younger (174.3 mg/d [34.1]) and older participants (165.7 mg/d [43.4]). However, the mean dose (SD) of olanzapine was significantly higher in younger patients (15.7 mg/d [4.7]) than in older participants (13.4 mg/d [5.1]).

In both age groups, olanzapine plus sertraline was more efficacious than olanzapine plus placebo, and there was no statistical interaction between age, time, and treatment group (ie, the trajectories of improvement were similar in older and younger patients receiving either olanzapine or olanzapine plus sertraline). Similarly, drop-out rates because of poor tolerability did not differ significantly in younger (4.3%) and older participants (5.6%). However, in a multinomial regression, older participants were more likely to discontinue treatment because of poor tolerability.²² Older participants were significantly less likely to experience weight gain (mean [SD]: +3.3 [4.9] vs +6.5 [6.6] kg) or an increase in fasting glucose and more likely to experience a fall, pedal edema, or extrapyramidal symptoms.^11,22-24 Cholesterol and triglyceride increased significantly and similarly in both age groups. The incidence of symptoms of tardive dyskinesia (TD) over the 12-week trial was low (<5%) in both younger and older participants, and clinically diagnosed TD was reported in only 1 (older) participant.²⁵

Venlafaxine plus aripiprazole for treatment-resistant MDD. In the largest double-blind randomized study of augmentation pharmacotherapy for late-life treatment-resistant depression published to date, Lenze et al²¹ compared venlafaxine plus aripiprazole vs venlafaxine plus placebo in 181 patients age >60 (mean age 66, with 49 participants age >70) with MDD who did not remit after 12 weeks of treatment with venlafaxine (up to 300 mg/d). After 12 weeks of augmentation, remission rates were significantly higher with aripiprazole than with placebo: 40 (44%) vs 26 (29%); odds ratio (95% confidence interval [CI]): 2.0 (1.1 to 3.7). The median final aripiprazole dose was 7 mg/d (range 2 to 15 mg/d) in remitters and 10 mg/d (range 2 to 15 mg/d) in nonremitters.

Five of 90 participants (5%) discontinued aripiprazole (1 each: suicide, jitteriness/akathisia, worsening parkinsonism; and 2 withdrew consent); 8 of 90 (9%) discontinued placebo (2 each: lack of efficacy, headache; 1: worsening parkinsonism; and 3 withdrew consent). The completed suicide occurred after 5 weeks of treatment with aripiprazole and was judged to be “neither due to emergent suicidal ideation nor to aripiprazole side-effects, but was concluded by investigators to be a result of the individual’s persisting and long-standing suicidal ideation.”²¹ Including the suicide, there were 4 serious adverse events (5%) in those receiving aripiprazole (1 each: suicide, congestive heart failure, mild stroke, and diverticulitis) and 2 (2%) in those receiving placebo (1 each: myocardial infarction, hospitalized for vomiting due to accidentally taking extra venlafaxine). In 86 participants receiving aripiprazole and 87 receiving placebo, the most frequently reported adverse effects were increased dream activity (aripiprazole: 23 [27%] vs placebo: 12 [14%]), weight gain (17 [20%] vs 8 [9%]), and tremor (5 [6%] vs 0). Akathisia and parkinsonism were observed more frequently with aripiprazole than with placebo (akathisia: 24 [26%] of 91 vs 11 [12%] of 90; parkinsonism: 15 [17%] of 86 vs 2 [2%] of 81). Akathisia was generally mild and resolved with dose adjustment; however, it was associated with a transient increase in suicidality in 3 (3%) participants receiving aripiprazole vs 0 receiving placebo and persisted at the end of the trial in 5 (5%) participants receiving aripiprazole vs 2 (2%) receiving placebo. Participants receiving aripiprazole had a significantly larger increase in weight (mean [SD]: +1.93 [3.00] vs +0.01 [3.15] kg), but there were no differences between aripiprazole and placebo in changes in body fat, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, insulin concentration, or QTc.

Citalopram plus risperidone for treatment-resistant MDD. Alexopoulos et al²⁶ reported an analysis of data from 110 patients age ≥55 years (mean age [SD]: 63.4 [4.8]), among 489 mixed-age patients with MDD. Participants (n = 110) who did not respond to 1 to 3 antidepressants (venlafaxine, sertraline, mirtazapine, fluoxetine, paroxetine, or bupropion in >90%) during their current depressive episode completed 4 to 6 weeks of treatment with citalopram up to 40 mg/d; 93 did not respond and were treated with open-label risperidone (0.25 to 1 mg/d) augmentation for 4 to 6 weeks. Sixty-three (68%) of these 93 patients remitted and were randomized to 24 weeks of double-blind continuation treatment with citalopram plus risperidone vs citalopram plus placebo. Neither the median times to relapse (105 vs 57 days) nor the relapse rates (risperidone: 18 of 32 [56%] vs placebo: 20 of 31 [65%]) differed significantly. During the open-label risperidone augmentation, the most common adverse events were dizziness and dry mouth (n = 9 each, 9.7% of 93). During the continuation phase, headache (n = 3; 9.1% of 32) was observed with risperidone but not with placebo (n = 0). There was no incident parkinsonism or abnormal movements noted, but risperidone was associated with weight gain during both the open-label risperidone augmentation phase (mean [SD]: +0.9 [2.1] kg) and the continuation phase (risperidone: +0.8 [3.5] vs placebo: −0.3 [2.8] kg).

Quetiapine XR monotherapy for MDD. Katila et al²⁷ reported on a placebo-controlled RCT of quetiapine XR (median dose, 158.7 mg/d; range, 50 to 300 mg/d) in 338 patients age ≥66 years (mean age [SD], 71.3 [7.5]) presenting with MDD and a major depressive episode with a duration <1 year and no history of failed antidepressants trials from 2 classes (more than two-thirds of participants had not received treatment). After 9 weeks, the reduction in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale was significantly larger with quetiapine XR than with placebo (mean [SD]: −16.0 [9.3] vs −9.0 [9.9]). There were congruent, significant differences between quetiapine and placebo in terms of response rate (quetiapine XR: 105 of 164 [64%] vs placebo: 52 of 171 [30.4%]) and remission rate (92 of 164 [56.1%] vs placebo: 40 of 171 [23.4%]). The drop-out rates for all causes were similar, but the drop-out rate attributed to adverse events was higher with quetiapine than placebo (16 of 166 [9.6%] vs 7 of 172 [4.1%]). Most quetiapine drop-outs were attributable to dizziness, headache, and somnolence (n = 4 each), and placebo drop-outs were because of headache (n = 2). Consistent with the profile of quetiapine, adverse events with a rate that was at least 5% higher with quetiapine than with placebo included somnolence (64 of 166 [38.6%] vs 16 of 172 [9.3%]), dry mouth (34 [20.5%] vs 18 [10.5%]), and extrapyramidal symptoms (12 [7.2%] vs 4 [2.3%]). Changes in weight and laboratory test results (eg, glucose, lipid profile) were minimal and not clinically meaningful.

Other clinical data. The efficacy and relatively good tolerability of aripiprazole in older patients with treatment-resistant depression observed in the RCT by Lenze et al²¹ is congruent with the earlier results of 2 small (N = 20 and 24) pilot studies.^18,19 In both studies, the remission rate was 50%, and the most prevalent adverse effects were agitation/restlessness/akathisia or drowsiness/sedation. Similarly, in a post hoc pooled analysis of 409 participants ages 50 to 67 from 3 placebo-controlled randomized trials, the remission rate was significantly higher with aripiprazole than with placebo (32.5% vs 17.1%), and the most common adverse effects were akathisia or restlessness (64 of 210 [30.4%]), somnolence (18 [8.6%]), and insomnia (17 [8.1%]).²⁰

Clinical considerations

When assessing the relative benefits and risks of antipsychotics in older patients, it is important to remember that conclusions and summative opinions are necessarily influenced by the source of the data. Because much of what we know about the use of antipsychotics in geriatric adults is from clinical trials, we know more about their acute efficacy and tolerability than their long-term effectiveness and safety.²⁸ There are similar issues regarding the role of antipsychotics in treating MDD in late life. Based on the results of several RCTs,^8,11 a combination of an antidepressant plus an antipsychotic is the recommended pharmacotherapy for the acute treatment of MDD with psychotic features (Table 2).^{8,11,12,19-21,23-27} However, there are no published data to guide how long the antipsychotic should be continued.²⁹

In older patients with MDD without psychotic features, 1 relatively large placebo-controlled RCT,²¹ 2 smaller open studies,^18,19 and a post hoc analysis of a large placebo-controlled RCT in mixed-age adults²⁰ support the efficacy and relatively good tolerability of aripiprazole augmentation of an antidepressant for treatment-resistant MDD. Similarly, 1 large placebo-controlled RCT supports the efficacy and relatively good tolerability of quetiapine for non–treatment-resistant MDD. However, there are no comparative data assessing the relative merits of using these antipsy­chotics vs other pharmacologic strategies (eg, switching to another antidepressant, lithium augmentation, or combination of 2 antidepressants). Because older patients are more likely to experience adverse effects that may have more serious consequences (Table 3), many prudent clinicians reserve using antipsychotics as a third-line treatment in older patients with MDD without psychotic features and limit the duration of their use to a few months.³⁰

The proportion of older adults in the world population is growing rapidly. In the next 10 to 15 years, the population age >60 will grow 3.5 times more rapidly than the general population.¹ As a result, there is an increased urgency in examining benefits vs risks of antipsychotics in older individuals. In a 2010 U.S. nationally representative observational study, antipsychotic use was observed to rise slowly during early and middle adulthood, peaking at approximately age 55, declining slightly between ages 55 and 65, and then rising again after age 65, with >2% of individuals ages 80 to 84 receiving an anti­psychotic.² This is likely due to the chronology of psychotic, mood, and neurocognitive disorders across the life span. In this large national study, long-term antipsychotic treatment was common, and older patients were more likely to receive their prescriptions from non-psychiatrist physicians than from psychiatrists.² Among patients receiving an antipsychotic, the proportion of those receiving it for >120 days was 54% for individuals ages 70 to 74; 49% for individuals ages 75 to 79; and 46% for individuals ages 80 to 84.

This 3-part review summarizes findings and risk–benefit considerations when prescribing antipsychotics to older individuals. Part 1 focused on those with chronic psychotic disorders, such as schizophrenia or bipolar disorder,³ and part 3 will cover patients with dementia. This review (part 2) aims to:

• briefly summarize the results of randomized controlled trials (RCTs) of second-generation antipsychotics (SGAs) and other major studies and analyses in older patients with major depressive disorder (MDD)
• provide a summative opinion on the relative risks and benefits associated with using antipsychotics in older adults with MDD
• highlight the gaps in the evidence base and areas that need additional research.

Summary of benefits, place in treatment armamentarium

The prevalence of MDD and clinically significant depressive symptoms in community­dwelling older adults is 3% to 4% and 15%, respectively, and as high as 16% and 50%, respectively, in nursing home residents.⁴ Because late-life depression is associated with suffering, disability, and excessive mortality, it needs to be recognized and treated aggressively.⁵ Antidepressants are the mainstay of pharmacotherapy for late-life depression. Guidelines and expert opinion informed by the current evidence recommend using selective serotonin reuptake inhibitors, such as escitalopram or sertraline, as a first-line treatment; serotonin norepinephrine reuptake inhibitors, such as duloxetine or venlafaxine, as a second-line treatment; and other antidepressants, such as bupropion or nortriptyline, as a third-line treatment.^5,6 However, antipsychotics also have a role in treating late-life depression.

Over the past decade, several anti­psychotics have been FDA-approved for treating MDD: aripiprazole and brexpiprazole as adjunctive treatment of MDD in adults; olanzapine-fluoxetine combination for acute and maintenance treatment of treatment-resistant depression in adults and geriatric adults; and quetiapine extended-release (XR) as monotherapy for MDD in adults and as adjunctive treatment of MDD in adults and geriatric adults who have had an inadequate response to antidepressants alone (Table 1). However, “black-box” warnings for all first-generation antipsychotics (FGAs) and SGAs alert clinicians that these medications have been associated with serious adverse events in older adults with dementia, including “deaths […] due to heart-related events (eg, heart failure, sudden death) or infections (mostly pneumonia),” with 15 of 17 placebo-controlled trials showing a higher number of deaths with an antipsychotic compared with placebo.⁷ Although similar controlled data on the mortality risk of antipsychotics in older adults with mood disorders do not exist, most experts limit their use to 2 groups of older patients: those with MDD and psychotic features (“psychotic depression”) and those with treatment-resistant depression.

Clinical trials

Olanzapine plus sertraline as first-line pharmacotherapy for MDD with psychotic features. Meyers et al¹¹ reported on a double-blind randomized comparison of olanzapine plus placebo vs olanzapine plus sertraline in 259 patients with MDD with psychotic features. An unusual feature of this trial is that it included a similar number of younger and older participants (ages 18 to 93): 117 participants were age <60 (mean age [standard deviation (SD)]: 41.3 [10.8]) and 142 were age ≥60 (mean age [SD]: 71.7 [7.8]). The same dose titration schedules based on efficacy and tolerability were used in both younger and older participants. At the end of the study, the mean dose (SD) of sertraline (or placebo) did not differ significantly in younger (174.3 mg/d [34.1]) and older participants (165.7 mg/d [43.4]). However, the mean dose (SD) of olanzapine was significantly higher in younger patients (15.7 mg/d [4.7]) than in older participants (13.4 mg/d [5.1]).

In both age groups, olanzapine plus sertraline was more efficacious than olanzapine plus placebo, and there was no statistical interaction between age, time, and treatment group (ie, the trajectories of improvement were similar in older and younger patients receiving either olanzapine or olanzapine plus sertraline). Similarly, drop-out rates because of poor tolerability did not differ significantly in younger (4.3%) and older participants (5.6%). However, in a multinomial regression, older participants were more likely to discontinue treatment because of poor tolerability.²² Older participants were significantly less likely to experience weight gain (mean [SD]: +3.3 [4.9] vs +6.5 [6.6] kg) or an increase in fasting glucose and more likely to experience a fall, pedal edema, or extrapyramidal symptoms.^11,22-24 Cholesterol and triglyceride increased significantly and similarly in both age groups. The incidence of symptoms of tardive dyskinesia (TD) over the 12-week trial was low (<5%) in both younger and older participants, and clinically diagnosed TD was reported in only 1 (older) participant.²⁵

Venlafaxine plus aripiprazole for treatment-resistant MDD. In the largest double-blind randomized study of augmentation pharmacotherapy for late-life treatment-resistant depression published to date, Lenze et al²¹ compared venlafaxine plus aripiprazole vs venlafaxine plus placebo in 181 patients age >60 (mean age 66, with 49 participants age >70) with MDD who did not remit after 12 weeks of treatment with venlafaxine (up to 300 mg/d). After 12 weeks of augmentation, remission rates were significantly higher with aripiprazole than with placebo: 40 (44%) vs 26 (29%); odds ratio (95% confidence interval [CI]): 2.0 (1.1 to 3.7). The median final aripiprazole dose was 7 mg/d (range 2 to 15 mg/d) in remitters and 10 mg/d (range 2 to 15 mg/d) in nonremitters.

Five of 90 participants (5%) discontinued aripiprazole (1 each: suicide, jitteriness/akathisia, worsening parkinsonism; and 2 withdrew consent); 8 of 90 (9%) discontinued placebo (2 each: lack of efficacy, headache; 1: worsening parkinsonism; and 3 withdrew consent). The completed suicide occurred after 5 weeks of treatment with aripiprazole and was judged to be “neither due to emergent suicidal ideation nor to aripiprazole side-effects, but was concluded by investigators to be a result of the individual’s persisting and long-standing suicidal ideation.”²¹ Including the suicide, there were 4 serious adverse events (5%) in those receiving aripiprazole (1 each: suicide, congestive heart failure, mild stroke, and diverticulitis) and 2 (2%) in those receiving placebo (1 each: myocardial infarction, hospitalized for vomiting due to accidentally taking extra venlafaxine). In 86 participants receiving aripiprazole and 87 receiving placebo, the most frequently reported adverse effects were increased dream activity (aripiprazole: 23 [27%] vs placebo: 12 [14%]), weight gain (17 [20%] vs 8 [9%]), and tremor (5 [6%] vs 0). Akathisia and parkinsonism were observed more frequently with aripiprazole than with placebo (akathisia: 24 [26%] of 91 vs 11 [12%] of 90; parkinsonism: 15 [17%] of 86 vs 2 [2%] of 81). Akathisia was generally mild and resolved with dose adjustment; however, it was associated with a transient increase in suicidality in 3 (3%) participants receiving aripiprazole vs 0 receiving placebo and persisted at the end of the trial in 5 (5%) participants receiving aripiprazole vs 2 (2%) receiving placebo. Participants receiving aripiprazole had a significantly larger increase in weight (mean [SD]: +1.93 [3.00] vs +0.01 [3.15] kg), but there were no differences between aripiprazole and placebo in changes in body fat, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, insulin concentration, or QTc.

Citalopram plus risperidone for treatment-resistant MDD. Alexopoulos et al²⁶ reported an analysis of data from 110 patients age ≥55 years (mean age [SD]: 63.4 [4.8]), among 489 mixed-age patients with MDD. Participants (n = 110) who did not respond to 1 to 3 antidepressants (venlafaxine, sertraline, mirtazapine, fluoxetine, paroxetine, or bupropion in >90%) during their current depressive episode completed 4 to 6 weeks of treatment with citalopram up to 40 mg/d; 93 did not respond and were treated with open-label risperidone (0.25 to 1 mg/d) augmentation for 4 to 6 weeks. Sixty-three (68%) of these 93 patients remitted and were randomized to 24 weeks of double-blind continuation treatment with citalopram plus risperidone vs citalopram plus placebo. Neither the median times to relapse (105 vs 57 days) nor the relapse rates (risperidone: 18 of 32 [56%] vs placebo: 20 of 31 [65%]) differed significantly. During the open-label risperidone augmentation, the most common adverse events were dizziness and dry mouth (n = 9 each, 9.7% of 93). During the continuation phase, headache (n = 3; 9.1% of 32) was observed with risperidone but not with placebo (n = 0). There was no incident parkinsonism or abnormal movements noted, but risperidone was associated with weight gain during both the open-label risperidone augmentation phase (mean [SD]: +0.9 [2.1] kg) and the continuation phase (risperidone: +0.8 [3.5] vs placebo: −0.3 [2.8] kg).

Quetiapine XR monotherapy for MDD. Katila et al²⁷ reported on a placebo-controlled RCT of quetiapine XR (median dose, 158.7 mg/d; range, 50 to 300 mg/d) in 338 patients age ≥66 years (mean age [SD], 71.3 [7.5]) presenting with MDD and a major depressive episode with a duration <1 year and no history of failed antidepressants trials from 2 classes (more than two-thirds of participants had not received treatment). After 9 weeks, the reduction in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale was significantly larger with quetiapine XR than with placebo (mean [SD]: −16.0 [9.3] vs −9.0 [9.9]). There were congruent, significant differences between quetiapine and placebo in terms of response rate (quetiapine XR: 105 of 164 [64%] vs placebo: 52 of 171 [30.4%]) and remission rate (92 of 164 [56.1%] vs placebo: 40 of 171 [23.4%]). The drop-out rates for all causes were similar, but the drop-out rate attributed to adverse events was higher with quetiapine than placebo (16 of 166 [9.6%] vs 7 of 172 [4.1%]). Most quetiapine drop-outs were attributable to dizziness, headache, and somnolence (n = 4 each), and placebo drop-outs were because of headache (n = 2). Consistent with the profile of quetiapine, adverse events with a rate that was at least 5% higher with quetiapine than with placebo included somnolence (64 of 166 [38.6%] vs 16 of 172 [9.3%]), dry mouth (34 [20.5%] vs 18 [10.5%]), and extrapyramidal symptoms (12 [7.2%] vs 4 [2.3%]). Changes in weight and laboratory test results (eg, glucose, lipid profile) were minimal and not clinically meaningful.

Other clinical data. The efficacy and relatively good tolerability of aripiprazole in older patients with treatment-resistant depression observed in the RCT by Lenze et al²¹ is congruent with the earlier results of 2 small (N = 20 and 24) pilot studies.^18,19 In both studies, the remission rate was 50%, and the most prevalent adverse effects were agitation/restlessness/akathisia or drowsiness/sedation. Similarly, in a post hoc pooled analysis of 409 participants ages 50 to 67 from 3 placebo-controlled randomized trials, the remission rate was significantly higher with aripiprazole than with placebo (32.5% vs 17.1%), and the most common adverse effects were akathisia or restlessness (64 of 210 [30.4%]), somnolence (18 [8.6%]), and insomnia (17 [8.1%]).²⁰

Clinical considerations

When assessing the relative benefits and risks of antipsychotics in older patients, it is important to remember that conclusions and summative opinions are necessarily influenced by the source of the data. Because much of what we know about the use of antipsychotics in geriatric adults is from clinical trials, we know more about their acute efficacy and tolerability than their long-term effectiveness and safety.²⁸ There are similar issues regarding the role of antipsychotics in treating MDD in late life. Based on the results of several RCTs,^8,11 a combination of an antidepressant plus an antipsychotic is the recommended pharmacotherapy for the acute treatment of MDD with psychotic features (Table 2).^{8,11,12,19-21,23-27} However, there are no published data to guide how long the antipsychotic should be continued.²⁹

In older patients with MDD without psychotic features, 1 relatively large placebo-controlled RCT,²¹ 2 smaller open studies,^18,19 and a post hoc analysis of a large placebo-controlled RCT in mixed-age adults²⁰ support the efficacy and relatively good tolerability of aripiprazole augmentation of an antidepressant for treatment-resistant MDD. Similarly, 1 large placebo-controlled RCT supports the efficacy and relatively good tolerability of quetiapine for non–treatment-resistant MDD. However, there are no comparative data assessing the relative merits of using these antipsy­chotics vs other pharmacologic strategies (eg, switching to another antidepressant, lithium augmentation, or combination of 2 antidepressants). Because older patients are more likely to experience adverse effects that may have more serious consequences (Table 3), many prudent clinicians reserve using antipsychotics as a third-line treatment in older patients with MDD without psychotic features and limit the duration of their use to a few months.³⁰

The proportion of older adults in the world population is growing rapidly. In the next 10 to 15 years, the population age >60 will grow 3.5 times more rapidly than the general population.¹ As a result, there is an increased urgency in examining benefits vs risks of antipsychotics in older individuals. In a 2010 U.S. nationally representative observational study, antipsychotic use was observed to rise slowly during early and middle adulthood, peaking at approximately age 55, declining slightly between ages 55 and 65, and then rising again after age 65, with >2% of individuals ages 80 to 84 receiving an anti­psychotic.² This is likely due to the chronology of psychotic, mood, and neurocognitive disorders across the life span. In this large national study, long-term antipsychotic treatment was common, and older patients were more likely to receive their prescriptions from non-psychiatrist physicians than from psychiatrists.² Among patients receiving an antipsychotic, the proportion of those receiving it for >120 days was 54% for individuals ages 70 to 74; 49% for individuals ages 75 to 79; and 46% for individuals ages 80 to 84.

This 3-part review summarizes findings and risk–benefit considerations when prescribing antipsychotics to older individuals. Part 1 focused on those with chronic psychotic disorders, such as schizophrenia or bipolar disorder,³ and part 3 will cover patients with dementia. This review (part 2) aims to:

• briefly summarize the results of randomized controlled trials (RCTs) of second-generation antipsychotics (SGAs) and other major studies and analyses in older patients with major depressive disorder (MDD)
• provide a summative opinion on the relative risks and benefits associated with using antipsychotics in older adults with MDD
• highlight the gaps in the evidence base and areas that need additional research.

Summary of benefits, place in treatment armamentarium

The prevalence of MDD and clinically significant depressive symptoms in community­dwelling older adults is 3% to 4% and 15%, respectively, and as high as 16% and 50%, respectively, in nursing home residents.⁴ Because late-life depression is associated with suffering, disability, and excessive mortality, it needs to be recognized and treated aggressively.⁵ Antidepressants are the mainstay of pharmacotherapy for late-life depression. Guidelines and expert opinion informed by the current evidence recommend using selective serotonin reuptake inhibitors, such as escitalopram or sertraline, as a first-line treatment; serotonin norepinephrine reuptake inhibitors, such as duloxetine or venlafaxine, as a second-line treatment; and other antidepressants, such as bupropion or nortriptyline, as a third-line treatment.^5,6 However, antipsychotics also have a role in treating late-life depression.

Over the past decade, several anti­psychotics have been FDA-approved for treating MDD: aripiprazole and brexpiprazole as adjunctive treatment of MDD in adults; olanzapine-fluoxetine combination for acute and maintenance treatment of treatment-resistant depression in adults and geriatric adults; and quetiapine extended-release (XR) as monotherapy for MDD in adults and as adjunctive treatment of MDD in adults and geriatric adults who have had an inadequate response to antidepressants alone (Table 1). However, “black-box” warnings for all first-generation antipsychotics (FGAs) and SGAs alert clinicians that these medications have been associated with serious adverse events in older adults with dementia, including “deaths […] due to heart-related events (eg, heart failure, sudden death) or infections (mostly pneumonia),” with 15 of 17 placebo-controlled trials showing a higher number of deaths with an antipsychotic compared with placebo.⁷ Although similar controlled data on the mortality risk of antipsychotics in older adults with mood disorders do not exist, most experts limit their use to 2 groups of older patients: those with MDD and psychotic features (“psychotic depression”) and those with treatment-resistant depression.

Clinical trials

Olanzapine plus sertraline as first-line pharmacotherapy for MDD with psychotic features. Meyers et al¹¹ reported on a double-blind randomized comparison of olanzapine plus placebo vs olanzapine plus sertraline in 259 patients with MDD with psychotic features. An unusual feature of this trial is that it included a similar number of younger and older participants (ages 18 to 93): 117 participants were age <60 (mean age [standard deviation (SD)]: 41.3 [10.8]) and 142 were age ≥60 (mean age [SD]: 71.7 [7.8]). The same dose titration schedules based on efficacy and tolerability were used in both younger and older participants. At the end of the study, the mean dose (SD) of sertraline (or placebo) did not differ significantly in younger (174.3 mg/d [34.1]) and older participants (165.7 mg/d [43.4]). However, the mean dose (SD) of olanzapine was significantly higher in younger patients (15.7 mg/d [4.7]) than in older participants (13.4 mg/d [5.1]).

In both age groups, olanzapine plus sertraline was more efficacious than olanzapine plus placebo, and there was no statistical interaction between age, time, and treatment group (ie, the trajectories of improvement were similar in older and younger patients receiving either olanzapine or olanzapine plus sertraline). Similarly, drop-out rates because of poor tolerability did not differ significantly in younger (4.3%) and older participants (5.6%). However, in a multinomial regression, older participants were more likely to discontinue treatment because of poor tolerability.²² Older participants were significantly less likely to experience weight gain (mean [SD]: +3.3 [4.9] vs +6.5 [6.6] kg) or an increase in fasting glucose and more likely to experience a fall, pedal edema, or extrapyramidal symptoms.^11,22-24 Cholesterol and triglyceride increased significantly and similarly in both age groups. The incidence of symptoms of tardive dyskinesia (TD) over the 12-week trial was low (<5%) in both younger and older participants, and clinically diagnosed TD was reported in only 1 (older) participant.²⁵

Venlafaxine plus aripiprazole for treatment-resistant MDD. In the largest double-blind randomized study of augmentation pharmacotherapy for late-life treatment-resistant depression published to date, Lenze et al²¹ compared venlafaxine plus aripiprazole vs venlafaxine plus placebo in 181 patients age >60 (mean age 66, with 49 participants age >70) with MDD who did not remit after 12 weeks of treatment with venlafaxine (up to 300 mg/d). After 12 weeks of augmentation, remission rates were significantly higher with aripiprazole than with placebo: 40 (44%) vs 26 (29%); odds ratio (95% confidence interval [CI]): 2.0 (1.1 to 3.7). The median final aripiprazole dose was 7 mg/d (range 2 to 15 mg/d) in remitters and 10 mg/d (range 2 to 15 mg/d) in nonremitters.

Five of 90 participants (5%) discontinued aripiprazole (1 each: suicide, jitteriness/akathisia, worsening parkinsonism; and 2 withdrew consent); 8 of 90 (9%) discontinued placebo (2 each: lack of efficacy, headache; 1: worsening parkinsonism; and 3 withdrew consent). The completed suicide occurred after 5 weeks of treatment with aripiprazole and was judged to be “neither due to emergent suicidal ideation nor to aripiprazole side-effects, but was concluded by investigators to be a result of the individual’s persisting and long-standing suicidal ideation.”²¹ Including the suicide, there were 4 serious adverse events (5%) in those receiving aripiprazole (1 each: suicide, congestive heart failure, mild stroke, and diverticulitis) and 2 (2%) in those receiving placebo (1 each: myocardial infarction, hospitalized for vomiting due to accidentally taking extra venlafaxine). In 86 participants receiving aripiprazole and 87 receiving placebo, the most frequently reported adverse effects were increased dream activity (aripiprazole: 23 [27%] vs placebo: 12 [14%]), weight gain (17 [20%] vs 8 [9%]), and tremor (5 [6%] vs 0). Akathisia and parkinsonism were observed more frequently with aripiprazole than with placebo (akathisia: 24 [26%] of 91 vs 11 [12%] of 90; parkinsonism: 15 [17%] of 86 vs 2 [2%] of 81). Akathisia was generally mild and resolved with dose adjustment; however, it was associated with a transient increase in suicidality in 3 (3%) participants receiving aripiprazole vs 0 receiving placebo and persisted at the end of the trial in 5 (5%) participants receiving aripiprazole vs 2 (2%) receiving placebo. Participants receiving aripiprazole had a significantly larger increase in weight (mean [SD]: +1.93 [3.00] vs +0.01 [3.15] kg), but there were no differences between aripiprazole and placebo in changes in body fat, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, insulin concentration, or QTc.

Citalopram plus risperidone for treatment-resistant MDD. Alexopoulos et al²⁶ reported an analysis of data from 110 patients age ≥55 years (mean age [SD]: 63.4 [4.8]), among 489 mixed-age patients with MDD. Participants (n = 110) who did not respond to 1 to 3 antidepressants (venlafaxine, sertraline, mirtazapine, fluoxetine, paroxetine, or bupropion in >90%) during their current depressive episode completed 4 to 6 weeks of treatment with citalopram up to 40 mg/d; 93 did not respond and were treated with open-label risperidone (0.25 to 1 mg/d) augmentation for 4 to 6 weeks. Sixty-three (68%) of these 93 patients remitted and were randomized to 24 weeks of double-blind continuation treatment with citalopram plus risperidone vs citalopram plus placebo. Neither the median times to relapse (105 vs 57 days) nor the relapse rates (risperidone: 18 of 32 [56%] vs placebo: 20 of 31 [65%]) differed significantly. During the open-label risperidone augmentation, the most common adverse events were dizziness and dry mouth (n = 9 each, 9.7% of 93). During the continuation phase, headache (n = 3; 9.1% of 32) was observed with risperidone but not with placebo (n = 0). There was no incident parkinsonism or abnormal movements noted, but risperidone was associated with weight gain during both the open-label risperidone augmentation phase (mean [SD]: +0.9 [2.1] kg) and the continuation phase (risperidone: +0.8 [3.5] vs placebo: −0.3 [2.8] kg).

Quetiapine XR monotherapy for MDD. Katila et al²⁷ reported on a placebo-controlled RCT of quetiapine XR (median dose, 158.7 mg/d; range, 50 to 300 mg/d) in 338 patients age ≥66 years (mean age [SD], 71.3 [7.5]) presenting with MDD and a major depressive episode with a duration <1 year and no history of failed antidepressants trials from 2 classes (more than two-thirds of participants had not received treatment). After 9 weeks, the reduction in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale was significantly larger with quetiapine XR than with placebo (mean [SD]: −16.0 [9.3] vs −9.0 [9.9]). There were congruent, significant differences between quetiapine and placebo in terms of response rate (quetiapine XR: 105 of 164 [64%] vs placebo: 52 of 171 [30.4%]) and remission rate (92 of 164 [56.1%] vs placebo: 40 of 171 [23.4%]). The drop-out rates for all causes were similar, but the drop-out rate attributed to adverse events was higher with quetiapine than placebo (16 of 166 [9.6%] vs 7 of 172 [4.1%]). Most quetiapine drop-outs were attributable to dizziness, headache, and somnolence (n = 4 each), and placebo drop-outs were because of headache (n = 2). Consistent with the profile of quetiapine, adverse events with a rate that was at least 5% higher with quetiapine than with placebo included somnolence (64 of 166 [38.6%] vs 16 of 172 [9.3%]), dry mouth (34 [20.5%] vs 18 [10.5%]), and extrapyramidal symptoms (12 [7.2%] vs 4 [2.3%]). Changes in weight and laboratory test results (eg, glucose, lipid profile) were minimal and not clinically meaningful.

Other clinical data. The efficacy and relatively good tolerability of aripiprazole in older patients with treatment-resistant depression observed in the RCT by Lenze et al²¹ is congruent with the earlier results of 2 small (N = 20 and 24) pilot studies.^18,19 In both studies, the remission rate was 50%, and the most prevalent adverse effects were agitation/restlessness/akathisia or drowsiness/sedation. Similarly, in a post hoc pooled analysis of 409 participants ages 50 to 67 from 3 placebo-controlled randomized trials, the remission rate was significantly higher with aripiprazole than with placebo (32.5% vs 17.1%), and the most common adverse effects were akathisia or restlessness (64 of 210 [30.4%]), somnolence (18 [8.6%]), and insomnia (17 [8.1%]).²⁰

Clinical considerations

When assessing the relative benefits and risks of antipsychotics in older patients, it is important to remember that conclusions and summative opinions are necessarily influenced by the source of the data. Because much of what we know about the use of antipsychotics in geriatric adults is from clinical trials, we know more about their acute efficacy and tolerability than their long-term effectiveness and safety.²⁸ There are similar issues regarding the role of antipsychotics in treating MDD in late life. Based on the results of several RCTs,^8,11 a combination of an antidepressant plus an antipsychotic is the recommended pharmacotherapy for the acute treatment of MDD with psychotic features (Table 2).^{8,11,12,19-21,23-27} However, there are no published data to guide how long the antipsychotic should be continued.²⁹

In older patients with MDD without psychotic features, 1 relatively large placebo-controlled RCT,²¹ 2 smaller open studies,^18,19 and a post hoc analysis of a large placebo-controlled RCT in mixed-age adults²⁰ support the efficacy and relatively good tolerability of aripiprazole augmentation of an antidepressant for treatment-resistant MDD. Similarly, 1 large placebo-controlled RCT supports the efficacy and relatively good tolerability of quetiapine for non–treatment-resistant MDD. However, there are no comparative data assessing the relative merits of using these antipsy­chotics vs other pharmacologic strategies (eg, switching to another antidepressant, lithium augmentation, or combination of 2 antidepressants). Because older patients are more likely to experience adverse effects that may have more serious consequences (Table 3), many prudent clinicians reserve using antipsychotics as a third-line treatment in older patients with MDD without psychotic features and limit the duration of their use to a few months.³⁰

There are many rewards for full-time academic psychiatrists such as myself, including didactic teaching, clinical supervision, and 1:1 mentorship of freshly minted medical school graduates, transforming them into accomplished clinical psychiatrists. The technical and personal growth of psychiatric residents over 4 years of post-MD training can be amazing and very gratifying to witness.

But the road to clinical competence often is littered with mistakes. It is the duty of the clinical supervisor to convert every error into a learning opportunity to hone the skills of a future psychiatrist. Over time, fewer mistakes occur, not only because of maturity and seasoning, but also because psychiatric residents learn how to thoughtfully deliberate about their clinical decision-making to select the best treatment option for their patients.

Yet, even with exemplary training, the rigors and constraints of clinical practice inevitably lead to some unforced errors, mostly minor but sometimes consequential. Even experienced practitioners are not immune from making a mistake in the hustle and bustle of daily work (exacerbated by the time-consuming pressures of electronic health record documentation). No one is infallible, but everyone must avoid making the same mistake twice, even if mounting demands lead to “shortcuts” that may not necessarily put the patient at risk but could lead to suboptimal outcomes. But once in a while, a serious complication may ensue.

Here are some common errors of omission or commission that even competent practitioners may make in a busy clinical practice.

Rushing to a diagnosis. To arrive at a primary psychiatric diagnosis, all potential secondary causes must be ruled out. This includes systematic screening for possible drug-induced psychopathology related not only to drugs of abuse, but also to prescription medications, some of which can have serious iatrogenic effects, including depression, anxiety, mania, psychosis, or cognitive dulling. The other important cause to rule out is the possibility of a general medical condition triggering psychiatric symptoms, which requires targeted questioning about medical history, a review of organ systems, and ordering key laboratory tests.

Skipping a baseline cognitive assessment. Cognitive impairment, especially memory and executive function, is now well recognized as an important component of major psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, anxiety, and attention-deficit/hyperactivity disorder. A standardized cognitive battery can provide a valuable profile of brain functions. Knowing the patient’s cognitive strengths and weaknesses before initiating pharmacotherapy is essential to assess the positive or negative impact of the medications. It also can help with patients’ vocational rehabilitation, matching them with jobs compatible with their cognitive strengths.

Inaccurate differential diagnosis. Is it borderline personality or bipolar disorder? Is it schizophrenia or psychotic bipolar disorder? Is it unipolar or bipolar depression? Is it a conversion reaction or a genuine medical condition? The answers to such questions are critical, because inaccurate diagnosis can lead to a lack of improvement and prolonged suffering for patients or adverse effects that could be avoided.

Using a high dose of a medication immediately for a first-episode psychiatric disorder. One of the least patient-friendly medical decisions is to start a first-episode patient on a high dose of a medication on day 1. Gradual titration can circumvent intolerable adverse effects and help establish the lowest effective dose. Patient acceptance and adherence are far more likely if the patient’s brain is not “abruptly medicated.”

Using combination therapy right away. There are a few psychiatric conditions for which combination therapy is FDA-approved and regarded as “rational polypharmacy.” However, it always makes sense to start with 1 (primary) medication and assess its efficacy, tolerability, and safety before adding an adjunctive agent. Some patients may improve substantially with monotherapy, which is always preferable. Using drug combinations as the initial intervention can be problematic, especially if they are not evidence-based and off-label.

Selecting an obesogenic drug as first-line. Many psychotropics, such as antipsychotics, antidepressants, or mood stabilizers, often come as a class of several agents. Clinicians can select any member of the same class (such as selective serotonin reuptake inhibitors [SSRIs] or atypical antipsychotics) because they are all FDA-approved for efficacy. However, the major difference among what often are called “me too” drugs is the adverse effects profile. For many psychotropic medications, significant weight gain is one of the worst medical adverse effects, because it often leads to metabolic dysregulation (hyperglycemia, dyslipidemia, and hypertension) and increases the risk of cardiovascular disease. Many psychiatric patients become obese and have great difficulty losing weight, especially if they are sedentary and have poor eating habits.

Using benzodiazepines as a first-line treatment for anxiety. Although certainly efficacious, and rapidly so, benzodiazepines must be avoided as a first-line treatment for anxiety. The addiction potential is significant, and patients with anxiety will subsequently not respond adequately to standard anxiolytic pharmacotherapy, such as an SSRI, because the anxiolytic effect of these other medications is gradual and not as rapid or potent. Some primary care providers (PCPs) resort to using strong benzodiazepines (such as alprazolam) as first-line, and then refer the patient to a psychiatrist, who finds it quite challenging to steer the patient to an evidence-based option that is less harmful for long-term management. The residents and I have encountered such situations often, sometimes leading to complex interactions with patients who demand renewal of a high dose of a benzodiazepine that had been prescribed to them by a different clinician.

Low utilization of some efficacious agents. It is surprising how some useful pharmacotherapeutic strategies are not employed as often as they should be. This includes lithium for a manic episode; a long-acting injectable antipsychotic in the early phase of schizophrenia; clozapine for patients who failed to respond to a couple of antipsychotics or have chronic suicidal tendencies; lurasidone or quetiapine for bipolar depression (the only FDA-approved medications for this condition); or monoamine oxidase inhibitors for treatment-resistant depression. These drugs can be useful, although some require ongoing blood-level measurements and monitoring for efficacy and adverse effects.

Not recognizing tardive dyskinesia (TD) earlier. TD is one of the most serious neurologic complications of dopamine-receptor working agents (antipsychotics). FDA-approved treatments finally arrived in 2017, but the recognition of the abnormal oro-bucco-lingual or facial choreiform movements remain low (and the use of the Abnormal Involuntary Movement Scale to screen for TD has faded since second-generation antipsychotics were introduced). It is essential to identify this adverse effect early and treat it promptly to avoid its worsening and potential irreversibility.

Other errors of omission or commission include:

• Not collaborating actively with the patient’s PCP to integrate the medical care to improve the patient’s overall health, not just mental health. Collaborative care improves clinical outcomes for most patients.
• Not using available pharmacogenetics testing to provide the patient with “personalized medicine,” such as establishing if they are poor or rapid metabolizers of certain cytochrome hepatic enzymes or checking whether they are less likely to respond to antidepressant medications.
• “Lowering expectations” for patients with severe psychiatric disorders, giving them the message (verbally or nonverbally) that their condition is “hopeless” and that recovery is beyond their reach. Giving hope and trying hard to find better treatment options are the foundation of good medical practice, especially for the sickest patients.

Psychiatrists always aim to do the right thing for their patients, even when the pressures of clinical practice are intense and palpable. But sometimes, an inadvertent slip may occur in the form of an error of omission or commission. These unforced errors are rarely dangerous, but they have the potential to delay response, increase the disease burden, or complicate the illness course. Compassion may be in generous supply, but it’s not enough: We must strive to make our patient-centered, evidence-based clinical practice an error-free zone.

There are many rewards for full-time academic psychiatrists such as myself, including didactic teaching, clinical supervision, and 1:1 mentorship of freshly minted medical school graduates, transforming them into accomplished clinical psychiatrists. The technical and personal growth of psychiatric residents over 4 years of post-MD training can be amazing and very gratifying to witness.

But the road to clinical competence often is littered with mistakes. It is the duty of the clinical supervisor to convert every error into a learning opportunity to hone the skills of a future psychiatrist. Over time, fewer mistakes occur, not only because of maturity and seasoning, but also because psychiatric residents learn how to thoughtfully deliberate about their clinical decision-making to select the best treatment option for their patients.

Yet, even with exemplary training, the rigors and constraints of clinical practice inevitably lead to some unforced errors, mostly minor but sometimes consequential. Even experienced practitioners are not immune from making a mistake in the hustle and bustle of daily work (exacerbated by the time-consuming pressures of electronic health record documentation). No one is infallible, but everyone must avoid making the same mistake twice, even if mounting demands lead to “shortcuts” that may not necessarily put the patient at risk but could lead to suboptimal outcomes. But once in a while, a serious complication may ensue.

Here are some common errors of omission or commission that even competent practitioners may make in a busy clinical practice.

Rushing to a diagnosis. To arrive at a primary psychiatric diagnosis, all potential secondary causes must be ruled out. This includes systematic screening for possible drug-induced psychopathology related not only to drugs of abuse, but also to prescription medications, some of which can have serious iatrogenic effects, including depression, anxiety, mania, psychosis, or cognitive dulling. The other important cause to rule out is the possibility of a general medical condition triggering psychiatric symptoms, which requires targeted questioning about medical history, a review of organ systems, and ordering key laboratory tests.

Skipping a baseline cognitive assessment. Cognitive impairment, especially memory and executive function, is now well recognized as an important component of major psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, anxiety, and attention-deficit/hyperactivity disorder. A standardized cognitive battery can provide a valuable profile of brain functions. Knowing the patient’s cognitive strengths and weaknesses before initiating pharmacotherapy is essential to assess the positive or negative impact of the medications. It also can help with patients’ vocational rehabilitation, matching them with jobs compatible with their cognitive strengths.

Inaccurate differential diagnosis. Is it borderline personality or bipolar disorder? Is it schizophrenia or psychotic bipolar disorder? Is it unipolar or bipolar depression? Is it a conversion reaction or a genuine medical condition? The answers to such questions are critical, because inaccurate diagnosis can lead to a lack of improvement and prolonged suffering for patients or adverse effects that could be avoided.

Using a high dose of a medication immediately for a first-episode psychiatric disorder. One of the least patient-friendly medical decisions is to start a first-episode patient on a high dose of a medication on day 1. Gradual titration can circumvent intolerable adverse effects and help establish the lowest effective dose. Patient acceptance and adherence are far more likely if the patient’s brain is not “abruptly medicated.”

Using combination therapy right away. There are a few psychiatric conditions for which combination therapy is FDA-approved and regarded as “rational polypharmacy.” However, it always makes sense to start with 1 (primary) medication and assess its efficacy, tolerability, and safety before adding an adjunctive agent. Some patients may improve substantially with monotherapy, which is always preferable. Using drug combinations as the initial intervention can be problematic, especially if they are not evidence-based and off-label.

Selecting an obesogenic drug as first-line. Many psychotropics, such as antipsychotics, antidepressants, or mood stabilizers, often come as a class of several agents. Clinicians can select any member of the same class (such as selective serotonin reuptake inhibitors [SSRIs] or atypical antipsychotics) because they are all FDA-approved for efficacy. However, the major difference among what often are called “me too” drugs is the adverse effects profile. For many psychotropic medications, significant weight gain is one of the worst medical adverse effects, because it often leads to metabolic dysregulation (hyperglycemia, dyslipidemia, and hypertension) and increases the risk of cardiovascular disease. Many psychiatric patients become obese and have great difficulty losing weight, especially if they are sedentary and have poor eating habits.

Using benzodiazepines as a first-line treatment for anxiety. Although certainly efficacious, and rapidly so, benzodiazepines must be avoided as a first-line treatment for anxiety. The addiction potential is significant, and patients with anxiety will subsequently not respond adequately to standard anxiolytic pharmacotherapy, such as an SSRI, because the anxiolytic effect of these other medications is gradual and not as rapid or potent. Some primary care providers (PCPs) resort to using strong benzodiazepines (such as alprazolam) as first-line, and then refer the patient to a psychiatrist, who finds it quite challenging to steer the patient to an evidence-based option that is less harmful for long-term management. The residents and I have encountered such situations often, sometimes leading to complex interactions with patients who demand renewal of a high dose of a benzodiazepine that had been prescribed to them by a different clinician.

Low utilization of some efficacious agents. It is surprising how some useful pharmacotherapeutic strategies are not employed as often as they should be. This includes lithium for a manic episode; a long-acting injectable antipsychotic in the early phase of schizophrenia; clozapine for patients who failed to respond to a couple of antipsychotics or have chronic suicidal tendencies; lurasidone or quetiapine for bipolar depression (the only FDA-approved medications for this condition); or monoamine oxidase inhibitors for treatment-resistant depression. These drugs can be useful, although some require ongoing blood-level measurements and monitoring for efficacy and adverse effects.

Not recognizing tardive dyskinesia (TD) earlier. TD is one of the most serious neurologic complications of dopamine-receptor working agents (antipsychotics). FDA-approved treatments finally arrived in 2017, but the recognition of the abnormal oro-bucco-lingual or facial choreiform movements remain low (and the use of the Abnormal Involuntary Movement Scale to screen for TD has faded since second-generation antipsychotics were introduced). It is essential to identify this adverse effect early and treat it promptly to avoid its worsening and potential irreversibility.

Other errors of omission or commission include:

• Not collaborating actively with the patient’s PCP to integrate the medical care to improve the patient’s overall health, not just mental health. Collaborative care improves clinical outcomes for most patients.
• Not using available pharmacogenetics testing to provide the patient with “personalized medicine,” such as establishing if they are poor or rapid metabolizers of certain cytochrome hepatic enzymes or checking whether they are less likely to respond to antidepressant medications.
• “Lowering expectations” for patients with severe psychiatric disorders, giving them the message (verbally or nonverbally) that their condition is “hopeless” and that recovery is beyond their reach. Giving hope and trying hard to find better treatment options are the foundation of good medical practice, especially for the sickest patients.

Psychiatrists always aim to do the right thing for their patients, even when the pressures of clinical practice are intense and palpable. But sometimes, an inadvertent slip may occur in the form of an error of omission or commission. These unforced errors are rarely dangerous, but they have the potential to delay response, increase the disease burden, or complicate the illness course. Compassion may be in generous supply, but it’s not enough: We must strive to make our patient-centered, evidence-based clinical practice an error-free zone.

There are many rewards for full-time academic psychiatrists such as myself, including didactic teaching, clinical supervision, and 1:1 mentorship of freshly minted medical school graduates, transforming them into accomplished clinical psychiatrists. The technical and personal growth of psychiatric residents over 4 years of post-MD training can be amazing and very gratifying to witness.

But the road to clinical competence often is littered with mistakes. It is the duty of the clinical supervisor to convert every error into a learning opportunity to hone the skills of a future psychiatrist. Over time, fewer mistakes occur, not only because of maturity and seasoning, but also because psychiatric residents learn how to thoughtfully deliberate about their clinical decision-making to select the best treatment option for their patients.

Yet, even with exemplary training, the rigors and constraints of clinical practice inevitably lead to some unforced errors, mostly minor but sometimes consequential. Even experienced practitioners are not immune from making a mistake in the hustle and bustle of daily work (exacerbated by the time-consuming pressures of electronic health record documentation). No one is infallible, but everyone must avoid making the same mistake twice, even if mounting demands lead to “shortcuts” that may not necessarily put the patient at risk but could lead to suboptimal outcomes. But once in a while, a serious complication may ensue.

Here are some common errors of omission or commission that even competent practitioners may make in a busy clinical practice.

Rushing to a diagnosis. To arrive at a primary psychiatric diagnosis, all potential secondary causes must be ruled out. This includes systematic screening for possible drug-induced psychopathology related not only to drugs of abuse, but also to prescription medications, some of which can have serious iatrogenic effects, including depression, anxiety, mania, psychosis, or cognitive dulling. The other important cause to rule out is the possibility of a general medical condition triggering psychiatric symptoms, which requires targeted questioning about medical history, a review of organ systems, and ordering key laboratory tests.

Skipping a baseline cognitive assessment. Cognitive impairment, especially memory and executive function, is now well recognized as an important component of major psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, anxiety, and attention-deficit/hyperactivity disorder. A standardized cognitive battery can provide a valuable profile of brain functions. Knowing the patient’s cognitive strengths and weaknesses before initiating pharmacotherapy is essential to assess the positive or negative impact of the medications. It also can help with patients’ vocational rehabilitation, matching them with jobs compatible with their cognitive strengths.

Inaccurate differential diagnosis. Is it borderline personality or bipolar disorder? Is it schizophrenia or psychotic bipolar disorder? Is it unipolar or bipolar depression? Is it a conversion reaction or a genuine medical condition? The answers to such questions are critical, because inaccurate diagnosis can lead to a lack of improvement and prolonged suffering for patients or adverse effects that could be avoided.

Using a high dose of a medication immediately for a first-episode psychiatric disorder. One of the least patient-friendly medical decisions is to start a first-episode patient on a high dose of a medication on day 1. Gradual titration can circumvent intolerable adverse effects and help establish the lowest effective dose. Patient acceptance and adherence are far more likely if the patient’s brain is not “abruptly medicated.”

Using combination therapy right away. There are a few psychiatric conditions for which combination therapy is FDA-approved and regarded as “rational polypharmacy.” However, it always makes sense to start with 1 (primary) medication and assess its efficacy, tolerability, and safety before adding an adjunctive agent. Some patients may improve substantially with monotherapy, which is always preferable. Using drug combinations as the initial intervention can be problematic, especially if they are not evidence-based and off-label.

Selecting an obesogenic drug as first-line. Many psychotropics, such as antipsychotics, antidepressants, or mood stabilizers, often come as a class of several agents. Clinicians can select any member of the same class (such as selective serotonin reuptake inhibitors [SSRIs] or atypical antipsychotics) because they are all FDA-approved for efficacy. However, the major difference among what often are called “me too” drugs is the adverse effects profile. For many psychotropic medications, significant weight gain is one of the worst medical adverse effects, because it often leads to metabolic dysregulation (hyperglycemia, dyslipidemia, and hypertension) and increases the risk of cardiovascular disease. Many psychiatric patients become obese and have great difficulty losing weight, especially if they are sedentary and have poor eating habits.

Using benzodiazepines as a first-line treatment for anxiety. Although certainly efficacious, and rapidly so, benzodiazepines must be avoided as a first-line treatment for anxiety. The addiction potential is significant, and patients with anxiety will subsequently not respond adequately to standard anxiolytic pharmacotherapy, such as an SSRI, because the anxiolytic effect of these other medications is gradual and not as rapid or potent. Some primary care providers (PCPs) resort to using strong benzodiazepines (such as alprazolam) as first-line, and then refer the patient to a psychiatrist, who finds it quite challenging to steer the patient to an evidence-based option that is less harmful for long-term management. The residents and I have encountered such situations often, sometimes leading to complex interactions with patients who demand renewal of a high dose of a benzodiazepine that had been prescribed to them by a different clinician.

Low utilization of some efficacious agents. It is surprising how some useful pharmacotherapeutic strategies are not employed as often as they should be. This includes lithium for a manic episode; a long-acting injectable antipsychotic in the early phase of schizophrenia; clozapine for patients who failed to respond to a couple of antipsychotics or have chronic suicidal tendencies; lurasidone or quetiapine for bipolar depression (the only FDA-approved medications for this condition); or monoamine oxidase inhibitors for treatment-resistant depression. These drugs can be useful, although some require ongoing blood-level measurements and monitoring for efficacy and adverse effects.

Not recognizing tardive dyskinesia (TD) earlier. TD is one of the most serious neurologic complications of dopamine-receptor working agents (antipsychotics). FDA-approved treatments finally arrived in 2017, but the recognition of the abnormal oro-bucco-lingual or facial choreiform movements remain low (and the use of the Abnormal Involuntary Movement Scale to screen for TD has faded since second-generation antipsychotics were introduced). It is essential to identify this adverse effect early and treat it promptly to avoid its worsening and potential irreversibility.

Other errors of omission or commission include:

• Not collaborating actively with the patient’s PCP to integrate the medical care to improve the patient’s overall health, not just mental health. Collaborative care improves clinical outcomes for most patients.
• Not using available pharmacogenetics testing to provide the patient with “personalized medicine,” such as establishing if they are poor or rapid metabolizers of certain cytochrome hepatic enzymes or checking whether they are less likely to respond to antidepressant medications.
• “Lowering expectations” for patients with severe psychiatric disorders, giving them the message (verbally or nonverbally) that their condition is “hopeless” and that recovery is beyond their reach. Giving hope and trying hard to find better treatment options are the foundation of good medical practice, especially for the sickest patients.

Psychiatrists always aim to do the right thing for their patients, even when the pressures of clinical practice are intense and palpable. But sometimes, an inadvertent slip may occur in the form of an error of omission or commission. These unforced errors are rarely dangerous, but they have the potential to delay response, increase the disease burden, or complicate the illness course. Compassion may be in generous supply, but it’s not enough: We must strive to make our patient-centered, evidence-based clinical practice an error-free zone.

“It is a mystery how a ubiquitous treatment used since antiquity was unknown, unnamed, and unidentified until recently. It is even more remarkable because this is the only treatment common to all societies and cultures.”¹

The treatment discussed above is not a specific pill, surgery, plant, or herb. Rather, the authors are referring to placebo. Indeed, the history of medical treatment is largely a chronicle of placebos. When subjected to scientific scrutiny, the overwhelming majority of treatments have turned out to be devoid of intrinsic therapeutic value; they derived their benefits from the placebo effect. Despite these benefits, the term “placebo” comes with unfortunate baggage. Latin for “I shall please,” it is the first word of the Christian vespers for the dead. In the 12th century these vespers were commonly referred to as placebos. By the 1300s, the term had become secular and pejorative, suggesting a flatterer or sycophant. When the word entered medical terminology in the late 18th century, the negative connotation stuck. A placebo was defined as a medicine given to please patients rather than to benefit them. In the modern era, the lack of pharmacologic activity became part of the definition as well.

The word placebo brings with it connotations of deception, fakery, and ineffectiveness. But one of the things about placebos that contribute mightily to the health care community’s aversion toward them is, in fact, their effectiveness. They bring relief across a wide range of medical conditions.² In doing so, placebos impugn the value of our most cherished remedies, hamper the development of new therapeutics, and threaten our livelihoods as health professionals.³

Placebos often are conceptualized as any treatment that lacks intrinsic therapeutic value, such as sugar pills. But looking at what placebo treatment actually entails, both in placebo-controlled treatment trials and in clinical settings, suggests a more comprehensive definition. Placebos encompass all the elements common to any treatment or healing situation. These include a recognized healer, evaluation, diagnosis, prognosis, plausible treatment, and most importantly, the expectation that one will recover. Along these lines, the placebo response can be thought of as the response to the common elements of the treatment or healing situation.³

Research regarding the placebo effect has mushroomed in the past 2 decades. Over this time, we have learned a good deal about both the mechanisms underlying the placebo effect and how the placebo effect can be applied to enhance the benefit of conventional treatment. Brain imaging technology has revealed that when placebo treatment alleviates pain, Parkinson’s disease, and depression, brain changes occur that are similar to those observed with active pharma­cologic treatment.^4,5 Recent studies also show that deliberate, open (nondeceptive) use of placebo can improve the symptoms of several conditions, including depression, pain, and irritable bowel syndrome.⁶ Furthermore, intermittent substitution of placebo pills for pharmacologically active treatment in a conditioning paradigm can be as effective as the “real” treatment.⁷ Also, research over the past decade has verified that certain common features of the treatment situation, particularly the quality of the doctor–patient encounter, contribute to the placebo response and have a demonstrable impact on the outcome of treatment.⁸ Clearly, the placebo effect has gone from being simply a nuisance that interferes with the evaluation of new treatments to a variable worthy of study and application in its own right. Although, for the most part, clinical practice has not kept up with these advances.

Placebos seem to have their greatest impact on the subjective symptoms of disease—pain, distress, and discouragement. It should come as no surprise, then, that placebos are particularly effective in certain psychiatric conditions. In some forms of anxiety and depressive disorders, for example, distress is the illness, and placebos reliably bring relief. Patients with panic disorder, mild to moderate depression, or generalized anxiety disorder get almost as much relief with placebo as they do with conventional treatment (about one-half improve with placebo).^9-11 But <20% of those with obsessive-compulsive disorder improve with placebo, and placebo response rates are also low in patients with schizophrenia or dementia. Mania, attention-deficit/hyperactivity disorder (ADHD), and severe depression fall somewhere in the middle.³

Harnessing the placebo response

There may be a few circumstances in psychiatric practice when it makes sense to intentionally prescribe a placebo as treatment, and we discuss those below. But far more frequently, what we know about the elements that contribute to the placebo effect can be applied to enhance the benefits of any treatment. Patients might be best served if deliberate mobilization of the placebo effect was a standard adjunct to conventional clinical care.

Various components of the treatment situation, collectively referred to as placebo, are a powerful antidote for illness, and some of these healing components exert their influence without special activity on the clinician’s part:

• Simply seeking psychiatric care can bring relief by providing some sense of control over distressing symptoms. The standard trappings of the office or clinic and customary office procedures—from the presentation of one’s insurance card to taking a history—offer reassurance and evoke the expectation that improvement or recovery is around the corner.
• The comfort provided by the psychiatrist’s presence is enhanced when patients feel that they are in the hands of a recognized healer. Psychiatrists inspire confidence when they look like a psychiatrist, or more precisely, like the patient’s idea of what a psychiatrist should look like. In our culture, that means a white coat or business attire.

A thorough evaluation is one of the common treatment elements that does the most to reduce distress and inspire confidence. The quality of an evaluation bears a strong relationship to patients’ satisfaction with the medical encounter, and can influence the amount of disability they suffer.^3,12-15

Although guidelines for conducting effective psychiatric interviews have been around for almost 100 years, psychiatrists vary considerably in the extent to which they elicit complete and accurate information, build rapport, give patients the sense that they are listened to, and provide a thorough assessment. The degree to which patients feel that the clinician is responsive to their concerns depends as much on the style of the interview as on the amount of time devoted to it. Nonverbal behavior can carry the message that the clinician is paying full attention. Something as simple as not answering the phone during an interview (this seems obvious, but a surprising and troubling number of mental health professionals take phone calls during interviews and treatment sessions) conveys an important message about the importance that the clinician places on the patient’s problems.³

The idea that the treatment situation itself provides reassurance and reduces distress, and in doing so, powers a good bit of the placebo effect, is enshrined in such concepts as the importance of good bedside manner. Many feel that the doctor’s thoughtful attention, positive regard, and optimism—so valued by patients—are justified on humanitarian grounds alone; actual evidence that this caring behavior contributes to healing isn’t required. To many, the healing properties of the treatment situation are self-evident. But as the costs of health care snowball and the demands for efficiency and cost-effectiveness rise, the time that psychiatrists can devote to patients has dwindled. Third-party payors demand evidence, beyond intuition and common sense, that diagnostic procedures and treatments have some usefulness, and rightly so.

Is there any evidence that the common components of the treatment situation provide benefit?³ More specifically, does the quality of the doctor–patient relationship and the patient’s feelings about a therapeutic encounter promote healing? Several studies suggest that the doctor–patient relationship has a demonstrable impact on symptom relief.¹⁶ In 1 study, oncologists were randomly assigned to receive a Communication Skills Training (CST) program or not. CST included a 1.5-day face-to-face workshop and 6 hours of monthly videoconferencing that focused on improving communication skills with patients.¹⁷ Lessons included building rapport, engaging in appropriate eye contact, and normalizing difficult experiences. One week after initially consulting with their physician, patients who saw an oncologist in the CST group experienced less anxiety and depression than those who saw an oncologist who did not receive CST. The benefit of CST for patient anxiety mostly persisted at a 3-month follow-up.

A recent meta-analysis pooled the results of 47 studies to examine the relationship between how much trust patients have for their doctors and health outcomes. There was a small to medium association: More trust was associated with greater improvement.¹⁸ It is possible that a good doctor–patient relationship enhances expectancies. However, it is also likely that a positive therapeutic relationship is inherently soothing and reduces distress or dysfunction independent of expectation. Regardless of the precise mechanism, these studies warrant attention. We all understand that it is important on ethical grounds to treat patients with respect and kindness. Research shows that this type of behavior also promotes recovery.

Patient expectations. The idea that expectation of improvement has a major impact on treatment outcome is firmly grounded in research on the placebo effect. Studies have shown that what people expect to experience as an outcome of treatment has a substantial impact on what they actually experience. In a classic study, a doctor told some patients with symptoms of minor illness that they would feel better soon and another group with the same symptoms that he didn’t know what ailed them.¹⁹ Two weeks later, 64% of patients in the “positive expectation” group were improved, compared with only 39% of patients in the “negative” group. In another study, adults were exposed to an allergen that caused a skin reaction.²⁰ Hand lotion (ie, a therapeutically inert substance) was then spread on the skin. Patients were led to believe that the cream would either alleviate or exacerbate the itching. The experimentally-induced wheal-and-flare was measured in both groups a few minutes after the allergen and cream were applied. The wheal-and-flare were worse for participants in the group that expected exacerbation.

Not uncommonly, expectation can have more impact on clinical outcome than a drug’s pharmacologic activity. In a double-blind placebo-controlled study, patients with depression were treated with St. John’s wort, sertraline, or placebo.²¹ They improved to the same extent with all 3 treatments. But when patients were asked to guess the treatment to which they had been assigned, those who thought they had received placebo showed little improvement, irrespective of which intervention they actually received, and those who guessed they had been given St. John’s wort or sertraline showed uniformly large improvement, irrespective of which intervention they actually received (including placebo). The researchers concluded that “Patient beliefs regarding treatment may have a stronger association with clinical outcome than the actual medication received.”

Psychiatrists who wish to use all the therapeutic tools at their disposal must attend to and manage patient expectations. One part of channeling a patient’s expectation is to thoroughly assess the patient’s beliefs regarding the efficacy of various treatments. If a patient’s uncle said that a certain drug is a miracle cure for anxiety, and the patient believes it to be true, then that expectation must be taken into consideration. Many patients prefer alternative treatments to conventional therapies. As long as there is no reason to think an alternative treatment will cause harm, a compromise might be reasonable. For example, if a patient with schizophrenia wants to treat her symptoms with herbal tea, the psychiatrist could say, “In addition to the tea, I recommend that you also take clozapine. The combination is likely to improve your symptoms.”³ More than anything else, the words a psychiatrist uses when recommending treatment shape the patient’s expectations. “You should be feeling a lot less anxious soon after you start taking this” has a different effect than “Try this. It may help.”

Prescribing ‘open-label’ placebo

There may be some limited circumstances where an actual placebo (eg, a sugar pill) might be suitable as a treatment. These include when placebo and conventional treatment provide similar results and a patient is reluctant to take conventional medicine, or when there is no effective conventional treatment. The deceptive prescription of placebo (providing placebo and calling it a drug) has a long history and was considered ethical—and recommended by medical authorities—until the latter half of the 20th century. This practice was deemed unethical in the 1980s, because it was dishonest and violated patient autonomy. Because it was widely believed that placebos given openly would be ineffective, the end of placebo treatment seemed at hand. An intriguing body of evidence, however, suggests that placebos can be effective even when patients know they are taking a placebo. Patients given an “open-label” placebo are told something along the lines of “the pill being prescribed contains no medicine, but some people improve with it, perhaps because the pill stimulates the body’s self-healing.” Open-label placebo has been evaluated for depression,²² low back pain,²³ irritable bowel syndrome,²⁴ neurosis,²⁵ allergic rhinitis,²⁶ and anxiety.²⁷ Most of these studies are small, and some were uncontrolled. Yet they consistently have shown that symptoms improve with a nondeceptive placebo, and improve to a greater extent than with no treatment.

The most recent trial is a promising example of the potential of open-label placebos. In this study, 96 patients with chronic low back pain were randomly assigned to 3 weeks of treatment as usual (TAU) or 3 weeks of TAU plus open-label placebo.²³ Patients who received open-label placebo were educated about the placebo effect and shown a film clip describing promising results of a prior open-label placebo study. They were then given placebo pills to be take once daily, and clearly told the pills contained no active medication. After 3 weeks, patients in the TAU plus placebo group reported less pain and less disability than patients who received TAU without a placebo. Some patients even requested a placebo prescription at the end of the study.

The placebo response provides a rational basis for prescribing innocuous alternative therapies with no intrinsic therapeutic value. Patients who prefer and believe in the effectiveness of alternative remedies—herbal compounds, massage, magnets, homeopathic solutions, etc.—can be recommended these treatments to mobilize a placebo response.

Using a conditioning model. Prescribing a placebo to obtain a conditioned drug response has enormous but untapped clinical potential. Both animal and human research indicates that a wide range of drug responses, from immune suppression to motor stimulation, can be conditioned (a neutral stimulus, such as a pill or injection, associated with drug administration can in itself evoke the drug effect). In many conditioning or dose-extending models, a particular response to real medication (such as pain relief after analgesics) first becomes conditioned due to repeated exposure to the drug given in a particular vehicle. Then, the treatment shifts to some doses comprising of real medicine and some doses comprising of placebo. Because the drug response has been conditioned, it is thought that the response to an identically appearing placebo will mirror the drug response. The active drug often is only replaced by placebo for certain doses under a schedule of partial reinforcement, given the ubiquity of extinction (the conditioned response lessens when the conditioned stimulus is presented alone on repeated trials).

In 1 version of a conditioning study, children with ADHD were randomized to 1 of 3 groups.²⁸ One group (full dose) took the standard dose of medication for 2 months, a second group (reduced dose) took a standard dose during 1 month followed by a half dose during the second month, and children in the third group (reduced dose with placebo) took the standard dose plus a visually distinctive placebo during the first month, followed by a half dose plus the visually distinctive placebo during the second month. Not surprisingly, ADHD symptoms were worse among children in the reduced-dose group. However, there was no difference between those in the reduced-dose with placebo group and those in the full-dose group. It appears as though the symptom reduction associated with a 100% dose was an unconditioned response that could be mimicked with the addition of a placebo pill.

In another study, patients with psoriasis were randomly assigned to receive a full dose of active medication (0.1% triamcinolone cream) twice a day, or a full dose of active medication for 25% to 50% of the doses, with a placebo (moisturizing cream) given for the other 50% to 75% of the doses.²⁹ Relapse rates were not statistically different between groups.

“It is a mystery how a ubiquitous treatment used since antiquity was unknown, unnamed, and unidentified until recently. It is even more remarkable because this is the only treatment common to all societies and cultures.”¹

The treatment discussed above is not a specific pill, surgery, plant, or herb. Rather, the authors are referring to placebo. Indeed, the history of medical treatment is largely a chronicle of placebos. When subjected to scientific scrutiny, the overwhelming majority of treatments have turned out to be devoid of intrinsic therapeutic value; they derived their benefits from the placebo effect. Despite these benefits, the term “placebo” comes with unfortunate baggage. Latin for “I shall please,” it is the first word of the Christian vespers for the dead. In the 12th century these vespers were commonly referred to as placebos. By the 1300s, the term had become secular and pejorative, suggesting a flatterer or sycophant. When the word entered medical terminology in the late 18th century, the negative connotation stuck. A placebo was defined as a medicine given to please patients rather than to benefit them. In the modern era, the lack of pharmacologic activity became part of the definition as well.

The word placebo brings with it connotations of deception, fakery, and ineffectiveness. But one of the things about placebos that contribute mightily to the health care community’s aversion toward them is, in fact, their effectiveness. They bring relief across a wide range of medical conditions.² In doing so, placebos impugn the value of our most cherished remedies, hamper the development of new therapeutics, and threaten our livelihoods as health professionals.³

Placebos often are conceptualized as any treatment that lacks intrinsic therapeutic value, such as sugar pills. But looking at what placebo treatment actually entails, both in placebo-controlled treatment trials and in clinical settings, suggests a more comprehensive definition. Placebos encompass all the elements common to any treatment or healing situation. These include a recognized healer, evaluation, diagnosis, prognosis, plausible treatment, and most importantly, the expectation that one will recover. Along these lines, the placebo response can be thought of as the response to the common elements of the treatment or healing situation.³

Research regarding the placebo effect has mushroomed in the past 2 decades. Over this time, we have learned a good deal about both the mechanisms underlying the placebo effect and how the placebo effect can be applied to enhance the benefit of conventional treatment. Brain imaging technology has revealed that when placebo treatment alleviates pain, Parkinson’s disease, and depression, brain changes occur that are similar to those observed with active pharma­cologic treatment.^4,5 Recent studies also show that deliberate, open (nondeceptive) use of placebo can improve the symptoms of several conditions, including depression, pain, and irritable bowel syndrome.⁶ Furthermore, intermittent substitution of placebo pills for pharmacologically active treatment in a conditioning paradigm can be as effective as the “real” treatment.⁷ Also, research over the past decade has verified that certain common features of the treatment situation, particularly the quality of the doctor–patient encounter, contribute to the placebo response and have a demonstrable impact on the outcome of treatment.⁸ Clearly, the placebo effect has gone from being simply a nuisance that interferes with the evaluation of new treatments to a variable worthy of study and application in its own right. Although, for the most part, clinical practice has not kept up with these advances.

Placebos seem to have their greatest impact on the subjective symptoms of disease—pain, distress, and discouragement. It should come as no surprise, then, that placebos are particularly effective in certain psychiatric conditions. In some forms of anxiety and depressive disorders, for example, distress is the illness, and placebos reliably bring relief. Patients with panic disorder, mild to moderate depression, or generalized anxiety disorder get almost as much relief with placebo as they do with conventional treatment (about one-half improve with placebo).^9-11 But <20% of those with obsessive-compulsive disorder improve with placebo, and placebo response rates are also low in patients with schizophrenia or dementia. Mania, attention-deficit/hyperactivity disorder (ADHD), and severe depression fall somewhere in the middle.³

Harnessing the placebo response

There may be a few circumstances in psychiatric practice when it makes sense to intentionally prescribe a placebo as treatment, and we discuss those below. But far more frequently, what we know about the elements that contribute to the placebo effect can be applied to enhance the benefits of any treatment. Patients might be best served if deliberate mobilization of the placebo effect was a standard adjunct to conventional clinical care.

Various components of the treatment situation, collectively referred to as placebo, are a powerful antidote for illness, and some of these healing components exert their influence without special activity on the clinician’s part:

• Simply seeking psychiatric care can bring relief by providing some sense of control over distressing symptoms. The standard trappings of the office or clinic and customary office procedures—from the presentation of one’s insurance card to taking a history—offer reassurance and evoke the expectation that improvement or recovery is around the corner.
• The comfort provided by the psychiatrist’s presence is enhanced when patients feel that they are in the hands of a recognized healer. Psychiatrists inspire confidence when they look like a psychiatrist, or more precisely, like the patient’s idea of what a psychiatrist should look like. In our culture, that means a white coat or business attire.

A thorough evaluation is one of the common treatment elements that does the most to reduce distress and inspire confidence. The quality of an evaluation bears a strong relationship to patients’ satisfaction with the medical encounter, and can influence the amount of disability they suffer.^3,12-15

Although guidelines for conducting effective psychiatric interviews have been around for almost 100 years, psychiatrists vary considerably in the extent to which they elicit complete and accurate information, build rapport, give patients the sense that they are listened to, and provide a thorough assessment. The degree to which patients feel that the clinician is responsive to their concerns depends as much on the style of the interview as on the amount of time devoted to it. Nonverbal behavior can carry the message that the clinician is paying full attention. Something as simple as not answering the phone during an interview (this seems obvious, but a surprising and troubling number of mental health professionals take phone calls during interviews and treatment sessions) conveys an important message about the importance that the clinician places on the patient’s problems.³

The idea that the treatment situation itself provides reassurance and reduces distress, and in doing so, powers a good bit of the placebo effect, is enshrined in such concepts as the importance of good bedside manner. Many feel that the doctor’s thoughtful attention, positive regard, and optimism—so valued by patients—are justified on humanitarian grounds alone; actual evidence that this caring behavior contributes to healing isn’t required. To many, the healing properties of the treatment situation are self-evident. But as the costs of health care snowball and the demands for efficiency and cost-effectiveness rise, the time that psychiatrists can devote to patients has dwindled. Third-party payors demand evidence, beyond intuition and common sense, that diagnostic procedures and treatments have some usefulness, and rightly so.

Is there any evidence that the common components of the treatment situation provide benefit?³ More specifically, does the quality of the doctor–patient relationship and the patient’s feelings about a therapeutic encounter promote healing? Several studies suggest that the doctor–patient relationship has a demonstrable impact on symptom relief.¹⁶ In 1 study, oncologists were randomly assigned to receive a Communication Skills Training (CST) program or not. CST included a 1.5-day face-to-face workshop and 6 hours of monthly videoconferencing that focused on improving communication skills with patients.¹⁷ Lessons included building rapport, engaging in appropriate eye contact, and normalizing difficult experiences. One week after initially consulting with their physician, patients who saw an oncologist in the CST group experienced less anxiety and depression than those who saw an oncologist who did not receive CST. The benefit of CST for patient anxiety mostly persisted at a 3-month follow-up.

A recent meta-analysis pooled the results of 47 studies to examine the relationship between how much trust patients have for their doctors and health outcomes. There was a small to medium association: More trust was associated with greater improvement.¹⁸ It is possible that a good doctor–patient relationship enhances expectancies. However, it is also likely that a positive therapeutic relationship is inherently soothing and reduces distress or dysfunction independent of expectation. Regardless of the precise mechanism, these studies warrant attention. We all understand that it is important on ethical grounds to treat patients with respect and kindness. Research shows that this type of behavior also promotes recovery.

Patient expectations. The idea that expectation of improvement has a major impact on treatment outcome is firmly grounded in research on the placebo effect. Studies have shown that what people expect to experience as an outcome of treatment has a substantial impact on what they actually experience. In a classic study, a doctor told some patients with symptoms of minor illness that they would feel better soon and another group with the same symptoms that he didn’t know what ailed them.¹⁹ Two weeks later, 64% of patients in the “positive expectation” group were improved, compared with only 39% of patients in the “negative” group. In another study, adults were exposed to an allergen that caused a skin reaction.²⁰ Hand lotion (ie, a therapeutically inert substance) was then spread on the skin. Patients were led to believe that the cream would either alleviate or exacerbate the itching. The experimentally-induced wheal-and-flare was measured in both groups a few minutes after the allergen and cream were applied. The wheal-and-flare were worse for participants in the group that expected exacerbation.

Not uncommonly, expectation can have more impact on clinical outcome than a drug’s pharmacologic activity. In a double-blind placebo-controlled study, patients with depression were treated with St. John’s wort, sertraline, or placebo.²¹ They improved to the same extent with all 3 treatments. But when patients were asked to guess the treatment to which they had been assigned, those who thought they had received placebo showed little improvement, irrespective of which intervention they actually received, and those who guessed they had been given St. John’s wort or sertraline showed uniformly large improvement, irrespective of which intervention they actually received (including placebo). The researchers concluded that “Patient beliefs regarding treatment may have a stronger association with clinical outcome than the actual medication received.”

Psychiatrists who wish to use all the therapeutic tools at their disposal must attend to and manage patient expectations. One part of channeling a patient’s expectation is to thoroughly assess the patient’s beliefs regarding the efficacy of various treatments. If a patient’s uncle said that a certain drug is a miracle cure for anxiety, and the patient believes it to be true, then that expectation must be taken into consideration. Many patients prefer alternative treatments to conventional therapies. As long as there is no reason to think an alternative treatment will cause harm, a compromise might be reasonable. For example, if a patient with schizophrenia wants to treat her symptoms with herbal tea, the psychiatrist could say, “In addition to the tea, I recommend that you also take clozapine. The combination is likely to improve your symptoms.”³ More than anything else, the words a psychiatrist uses when recommending treatment shape the patient’s expectations. “You should be feeling a lot less anxious soon after you start taking this” has a different effect than “Try this. It may help.”

Prescribing ‘open-label’ placebo

There may be some limited circumstances where an actual placebo (eg, a sugar pill) might be suitable as a treatment. These include when placebo and conventional treatment provide similar results and a patient is reluctant to take conventional medicine, or when there is no effective conventional treatment. The deceptive prescription of placebo (providing placebo and calling it a drug) has a long history and was considered ethical—and recommended by medical authorities—until the latter half of the 20th century. This practice was deemed unethical in the 1980s, because it was dishonest and violated patient autonomy. Because it was widely believed that placebos given openly would be ineffective, the end of placebo treatment seemed at hand. An intriguing body of evidence, however, suggests that placebos can be effective even when patients know they are taking a placebo. Patients given an “open-label” placebo are told something along the lines of “the pill being prescribed contains no medicine, but some people improve with it, perhaps because the pill stimulates the body’s self-healing.” Open-label placebo has been evaluated for depression,²² low back pain,²³ irritable bowel syndrome,²⁴ neurosis,²⁵ allergic rhinitis,²⁶ and anxiety.²⁷ Most of these studies are small, and some were uncontrolled. Yet they consistently have shown that symptoms improve with a nondeceptive placebo, and improve to a greater extent than with no treatment.

The most recent trial is a promising example of the potential of open-label placebos. In this study, 96 patients with chronic low back pain were randomly assigned to 3 weeks of treatment as usual (TAU) or 3 weeks of TAU plus open-label placebo.²³ Patients who received open-label placebo were educated about the placebo effect and shown a film clip describing promising results of a prior open-label placebo study. They were then given placebo pills to be take once daily, and clearly told the pills contained no active medication. After 3 weeks, patients in the TAU plus placebo group reported less pain and less disability than patients who received TAU without a placebo. Some patients even requested a placebo prescription at the end of the study.

The placebo response provides a rational basis for prescribing innocuous alternative therapies with no intrinsic therapeutic value. Patients who prefer and believe in the effectiveness of alternative remedies—herbal compounds, massage, magnets, homeopathic solutions, etc.—can be recommended these treatments to mobilize a placebo response.

Using a conditioning model. Prescribing a placebo to obtain a conditioned drug response has enormous but untapped clinical potential. Both animal and human research indicates that a wide range of drug responses, from immune suppression to motor stimulation, can be conditioned (a neutral stimulus, such as a pill or injection, associated with drug administration can in itself evoke the drug effect). In many conditioning or dose-extending models, a particular response to real medication (such as pain relief after analgesics) first becomes conditioned due to repeated exposure to the drug given in a particular vehicle. Then, the treatment shifts to some doses comprising of real medicine and some doses comprising of placebo. Because the drug response has been conditioned, it is thought that the response to an identically appearing placebo will mirror the drug response. The active drug often is only replaced by placebo for certain doses under a schedule of partial reinforcement, given the ubiquity of extinction (the conditioned response lessens when the conditioned stimulus is presented alone on repeated trials).

In 1 version of a conditioning study, children with ADHD were randomized to 1 of 3 groups.²⁸ One group (full dose) took the standard dose of medication for 2 months, a second group (reduced dose) took a standard dose during 1 month followed by a half dose during the second month, and children in the third group (reduced dose with placebo) took the standard dose plus a visually distinctive placebo during the first month, followed by a half dose plus the visually distinctive placebo during the second month. Not surprisingly, ADHD symptoms were worse among children in the reduced-dose group. However, there was no difference between those in the reduced-dose with placebo group and those in the full-dose group. It appears as though the symptom reduction associated with a 100% dose was an unconditioned response that could be mimicked with the addition of a placebo pill.

In another study, patients with psoriasis were randomly assigned to receive a full dose of active medication (0.1% triamcinolone cream) twice a day, or a full dose of active medication for 25% to 50% of the doses, with a placebo (moisturizing cream) given for the other 50% to 75% of the doses.²⁹ Relapse rates were not statistically different between groups.

“It is a mystery how a ubiquitous treatment used since antiquity was unknown, unnamed, and unidentified until recently. It is even more remarkable because this is the only treatment common to all societies and cultures.”¹

The treatment discussed above is not a specific pill, surgery, plant, or herb. Rather, the authors are referring to placebo. Indeed, the history of medical treatment is largely a chronicle of placebos. When subjected to scientific scrutiny, the overwhelming majority of treatments have turned out to be devoid of intrinsic therapeutic value; they derived their benefits from the placebo effect. Despite these benefits, the term “placebo” comes with unfortunate baggage. Latin for “I shall please,” it is the first word of the Christian vespers for the dead. In the 12th century these vespers were commonly referred to as placebos. By the 1300s, the term had become secular and pejorative, suggesting a flatterer or sycophant. When the word entered medical terminology in the late 18th century, the negative connotation stuck. A placebo was defined as a medicine given to please patients rather than to benefit them. In the modern era, the lack of pharmacologic activity became part of the definition as well.

The word placebo brings with it connotations of deception, fakery, and ineffectiveness. But one of the things about placebos that contribute mightily to the health care community’s aversion toward them is, in fact, their effectiveness. They bring relief across a wide range of medical conditions.² In doing so, placebos impugn the value of our most cherished remedies, hamper the development of new therapeutics, and threaten our livelihoods as health professionals.³

Placebos often are conceptualized as any treatment that lacks intrinsic therapeutic value, such as sugar pills. But looking at what placebo treatment actually entails, both in placebo-controlled treatment trials and in clinical settings, suggests a more comprehensive definition. Placebos encompass all the elements common to any treatment or healing situation. These include a recognized healer, evaluation, diagnosis, prognosis, plausible treatment, and most importantly, the expectation that one will recover. Along these lines, the placebo response can be thought of as the response to the common elements of the treatment or healing situation.³

Research regarding the placebo effect has mushroomed in the past 2 decades. Over this time, we have learned a good deal about both the mechanisms underlying the placebo effect and how the placebo effect can be applied to enhance the benefit of conventional treatment. Brain imaging technology has revealed that when placebo treatment alleviates pain, Parkinson’s disease, and depression, brain changes occur that are similar to those observed with active pharma­cologic treatment.^4,5 Recent studies also show that deliberate, open (nondeceptive) use of placebo can improve the symptoms of several conditions, including depression, pain, and irritable bowel syndrome.⁶ Furthermore, intermittent substitution of placebo pills for pharmacologically active treatment in a conditioning paradigm can be as effective as the “real” treatment.⁷ Also, research over the past decade has verified that certain common features of the treatment situation, particularly the quality of the doctor–patient encounter, contribute to the placebo response and have a demonstrable impact on the outcome of treatment.⁸ Clearly, the placebo effect has gone from being simply a nuisance that interferes with the evaluation of new treatments to a variable worthy of study and application in its own right. Although, for the most part, clinical practice has not kept up with these advances.

Placebos seem to have their greatest impact on the subjective symptoms of disease—pain, distress, and discouragement. It should come as no surprise, then, that placebos are particularly effective in certain psychiatric conditions. In some forms of anxiety and depressive disorders, for example, distress is the illness, and placebos reliably bring relief. Patients with panic disorder, mild to moderate depression, or generalized anxiety disorder get almost as much relief with placebo as they do with conventional treatment (about one-half improve with placebo).^9-11 But <20% of those with obsessive-compulsive disorder improve with placebo, and placebo response rates are also low in patients with schizophrenia or dementia. Mania, attention-deficit/hyperactivity disorder (ADHD), and severe depression fall somewhere in the middle.³

Harnessing the placebo response

There may be a few circumstances in psychiatric practice when it makes sense to intentionally prescribe a placebo as treatment, and we discuss those below. But far more frequently, what we know about the elements that contribute to the placebo effect can be applied to enhance the benefits of any treatment. Patients might be best served if deliberate mobilization of the placebo effect was a standard adjunct to conventional clinical care.

Various components of the treatment situation, collectively referred to as placebo, are a powerful antidote for illness, and some of these healing components exert their influence without special activity on the clinician’s part:

• Simply seeking psychiatric care can bring relief by providing some sense of control over distressing symptoms. The standard trappings of the office or clinic and customary office procedures—from the presentation of one’s insurance card to taking a history—offer reassurance and evoke the expectation that improvement or recovery is around the corner.
• The comfort provided by the psychiatrist’s presence is enhanced when patients feel that they are in the hands of a recognized healer. Psychiatrists inspire confidence when they look like a psychiatrist, or more precisely, like the patient’s idea of what a psychiatrist should look like. In our culture, that means a white coat or business attire.

A thorough evaluation is one of the common treatment elements that does the most to reduce distress and inspire confidence. The quality of an evaluation bears a strong relationship to patients’ satisfaction with the medical encounter, and can influence the amount of disability they suffer.^3,12-15

Although guidelines for conducting effective psychiatric interviews have been around for almost 100 years, psychiatrists vary considerably in the extent to which they elicit complete and accurate information, build rapport, give patients the sense that they are listened to, and provide a thorough assessment. The degree to which patients feel that the clinician is responsive to their concerns depends as much on the style of the interview as on the amount of time devoted to it. Nonverbal behavior can carry the message that the clinician is paying full attention. Something as simple as not answering the phone during an interview (this seems obvious, but a surprising and troubling number of mental health professionals take phone calls during interviews and treatment sessions) conveys an important message about the importance that the clinician places on the patient’s problems.³

The idea that the treatment situation itself provides reassurance and reduces distress, and in doing so, powers a good bit of the placebo effect, is enshrined in such concepts as the importance of good bedside manner. Many feel that the doctor’s thoughtful attention, positive regard, and optimism—so valued by patients—are justified on humanitarian grounds alone; actual evidence that this caring behavior contributes to healing isn’t required. To many, the healing properties of the treatment situation are self-evident. But as the costs of health care snowball and the demands for efficiency and cost-effectiveness rise, the time that psychiatrists can devote to patients has dwindled. Third-party payors demand evidence, beyond intuition and common sense, that diagnostic procedures and treatments have some usefulness, and rightly so.

Is there any evidence that the common components of the treatment situation provide benefit?³ More specifically, does the quality of the doctor–patient relationship and the patient’s feelings about a therapeutic encounter promote healing? Several studies suggest that the doctor–patient relationship has a demonstrable impact on symptom relief.¹⁶ In 1 study, oncologists were randomly assigned to receive a Communication Skills Training (CST) program or not. CST included a 1.5-day face-to-face workshop and 6 hours of monthly videoconferencing that focused on improving communication skills with patients.¹⁷ Lessons included building rapport, engaging in appropriate eye contact, and normalizing difficult experiences. One week after initially consulting with their physician, patients who saw an oncologist in the CST group experienced less anxiety and depression than those who saw an oncologist who did not receive CST. The benefit of CST for patient anxiety mostly persisted at a 3-month follow-up.

A recent meta-analysis pooled the results of 47 studies to examine the relationship between how much trust patients have for their doctors and health outcomes. There was a small to medium association: More trust was associated with greater improvement.¹⁸ It is possible that a good doctor–patient relationship enhances expectancies. However, it is also likely that a positive therapeutic relationship is inherently soothing and reduces distress or dysfunction independent of expectation. Regardless of the precise mechanism, these studies warrant attention. We all understand that it is important on ethical grounds to treat patients with respect and kindness. Research shows that this type of behavior also promotes recovery.

Patient expectations. The idea that expectation of improvement has a major impact on treatment outcome is firmly grounded in research on the placebo effect. Studies have shown that what people expect to experience as an outcome of treatment has a substantial impact on what they actually experience. In a classic study, a doctor told some patients with symptoms of minor illness that they would feel better soon and another group with the same symptoms that he didn’t know what ailed them.¹⁹ Two weeks later, 64% of patients in the “positive expectation” group were improved, compared with only 39% of patients in the “negative” group. In another study, adults were exposed to an allergen that caused a skin reaction.²⁰ Hand lotion (ie, a therapeutically inert substance) was then spread on the skin. Patients were led to believe that the cream would either alleviate or exacerbate the itching. The experimentally-induced wheal-and-flare was measured in both groups a few minutes after the allergen and cream were applied. The wheal-and-flare were worse for participants in the group that expected exacerbation.

Not uncommonly, expectation can have more impact on clinical outcome than a drug’s pharmacologic activity. In a double-blind placebo-controlled study, patients with depression were treated with St. John’s wort, sertraline, or placebo.²¹ They improved to the same extent with all 3 treatments. But when patients were asked to guess the treatment to which they had been assigned, those who thought they had received placebo showed little improvement, irrespective of which intervention they actually received, and those who guessed they had been given St. John’s wort or sertraline showed uniformly large improvement, irrespective of which intervention they actually received (including placebo). The researchers concluded that “Patient beliefs regarding treatment may have a stronger association with clinical outcome than the actual medication received.”

Psychiatrists who wish to use all the therapeutic tools at their disposal must attend to and manage patient expectations. One part of channeling a patient’s expectation is to thoroughly assess the patient’s beliefs regarding the efficacy of various treatments. If a patient’s uncle said that a certain drug is a miracle cure for anxiety, and the patient believes it to be true, then that expectation must be taken into consideration. Many patients prefer alternative treatments to conventional therapies. As long as there is no reason to think an alternative treatment will cause harm, a compromise might be reasonable. For example, if a patient with schizophrenia wants to treat her symptoms with herbal tea, the psychiatrist could say, “In addition to the tea, I recommend that you also take clozapine. The combination is likely to improve your symptoms.”³ More than anything else, the words a psychiatrist uses when recommending treatment shape the patient’s expectations. “You should be feeling a lot less anxious soon after you start taking this” has a different effect than “Try this. It may help.”

Prescribing ‘open-label’ placebo

There may be some limited circumstances where an actual placebo (eg, a sugar pill) might be suitable as a treatment. These include when placebo and conventional treatment provide similar results and a patient is reluctant to take conventional medicine, or when there is no effective conventional treatment. The deceptive prescription of placebo (providing placebo and calling it a drug) has a long history and was considered ethical—and recommended by medical authorities—until the latter half of the 20th century. This practice was deemed unethical in the 1980s, because it was dishonest and violated patient autonomy. Because it was widely believed that placebos given openly would be ineffective, the end of placebo treatment seemed at hand. An intriguing body of evidence, however, suggests that placebos can be effective even when patients know they are taking a placebo. Patients given an “open-label” placebo are told something along the lines of “the pill being prescribed contains no medicine, but some people improve with it, perhaps because the pill stimulates the body’s self-healing.” Open-label placebo has been evaluated for depression,²² low back pain,²³ irritable bowel syndrome,²⁴ neurosis,²⁵ allergic rhinitis,²⁶ and anxiety.²⁷ Most of these studies are small, and some were uncontrolled. Yet they consistently have shown that symptoms improve with a nondeceptive placebo, and improve to a greater extent than with no treatment.

The most recent trial is a promising example of the potential of open-label placebos. In this study, 96 patients with chronic low back pain were randomly assigned to 3 weeks of treatment as usual (TAU) or 3 weeks of TAU plus open-label placebo.²³ Patients who received open-label placebo were educated about the placebo effect and shown a film clip describing promising results of a prior open-label placebo study. They were then given placebo pills to be take once daily, and clearly told the pills contained no active medication. After 3 weeks, patients in the TAU plus placebo group reported less pain and less disability than patients who received TAU without a placebo. Some patients even requested a placebo prescription at the end of the study.

The placebo response provides a rational basis for prescribing innocuous alternative therapies with no intrinsic therapeutic value. Patients who prefer and believe in the effectiveness of alternative remedies—herbal compounds, massage, magnets, homeopathic solutions, etc.—can be recommended these treatments to mobilize a placebo response.

Using a conditioning model. Prescribing a placebo to obtain a conditioned drug response has enormous but untapped clinical potential. Both animal and human research indicates that a wide range of drug responses, from immune suppression to motor stimulation, can be conditioned (a neutral stimulus, such as a pill or injection, associated with drug administration can in itself evoke the drug effect). In many conditioning or dose-extending models, a particular response to real medication (such as pain relief after analgesics) first becomes conditioned due to repeated exposure to the drug given in a particular vehicle. Then, the treatment shifts to some doses comprising of real medicine and some doses comprising of placebo. Because the drug response has been conditioned, it is thought that the response to an identically appearing placebo will mirror the drug response. The active drug often is only replaced by placebo for certain doses under a schedule of partial reinforcement, given the ubiquity of extinction (the conditioned response lessens when the conditioned stimulus is presented alone on repeated trials).

In 1 version of a conditioning study, children with ADHD were randomized to 1 of 3 groups.²⁸ One group (full dose) took the standard dose of medication for 2 months, a second group (reduced dose) took a standard dose during 1 month followed by a half dose during the second month, and children in the third group (reduced dose with placebo) took the standard dose plus a visually distinctive placebo during the first month, followed by a half dose plus the visually distinctive placebo during the second month. Not surprisingly, ADHD symptoms were worse among children in the reduced-dose group. However, there was no difference between those in the reduced-dose with placebo group and those in the full-dose group. It appears as though the symptom reduction associated with a 100% dose was an unconditioned response that could be mimicked with the addition of a placebo pill.

In another study, patients with psoriasis were randomly assigned to receive a full dose of active medication (0.1% triamcinolone cream) twice a day, or a full dose of active medication for 25% to 50% of the doses, with a placebo (moisturizing cream) given for the other 50% to 75% of the doses.²⁹ Relapse rates were not statistically different between groups.

Mr. C, age 30, with schizoaffective disorder, bipolar type, Cannabis abuse, and nicotine dependence, has been enrolled in a Program of Assertive Community Treatment (PACT) for approximately 5 years. He presents to the PACT clinic for follow-up with his psychiatrist. Mr. C reports dizziness, lightheadedness, blurred vision, and nausea worsening over the last few days, and he appears drowsy and hypoactive. He does not report any chest pain, abdominal pain, swelling, cold extremities, shortness of breath, vomiting, diarrhea, or blood loss. Mr. C admits he has eaten only once daily for several weeks because of delusional ideation that he is responsible for others suffering from anorexia nervosa.

His medical history includes gastroesophageal reflux disease. Mr. C’s medication regimen for the past year included total daily oral doses of benztropine, 2 mg, divalproex extended-release, 1,000 mg, fluphenazine, 15 mg, and gabapentin, 300 mg. He also receives IM fluphenazine decanoate, 50 mg every 2 weeks; lithium, 600 mg/d, was added to his regimen 5 months ago. Vital signs include temperature 97°F, weight 162 lb, height 69 inches, blood pressure 105/64 mm Hg, heart rate (HR) 46 beats per minute (bpm), and respirations 18 breaths per minute.

Because of Mr. C’s complaints, appearance, and low HR, the psychiatrist calls emergency medical services (EMS). Although the paramedics recommend emergency transport to the hospital, Mr. C refuses. The psychiatrist instructs Mr. C to stop taking lithium because of suspected lithium-induced bradycardia and a concern that he may be more susceptible to lithium toxicity with prolonged anorexia nervosa. When nursing staff evaluate Mr. C the next day, his vitals are HR 60 bpm, respirations 20 breaths per minute, and blood pressure 124/81 mm Hg; his dizziness, blurred vision, lightheadedness, and nausea are resolved.

Bradycardia is defined as a HR <60 bpm; however, symptoms may not occur until the HR is <50 bpm. Symptoms include fatigue, dizziness, lightheadedness, chest pain, shortness of breath, and syncope. The incidence of bradycardia during lithium treatment is unknown; it is considered a rare but serious adverse effect. A literature review reveals several case reports of bradycardia with lithium treatment,^2-4 including symptomatic bradycardia after a single dose of lithium.⁵ Other possible causes of bradycardia include anorexia nervosa, hypothermia, hypothyroidism, hypoxia, infection, stroke, acute myocardial infarction, sedative or opiate use, increased vagal tone with exercise conditioning, and other medications including fluphenazine.⁶

Mr. C’s symptoms may have been assumed to be secondary to several possible causes, including bradycardia, dehydration from poor oral intake, lithium toxicity, or an undiagnosed medical condition. The combination of nausea, dizziness, anorexia nervosa, blurred vision, and lightheadedness in a patient receiving lithium would certainly trigger a clinician’s concern for lithium toxicity, but he (she) may not be aware of the risk of bradycardia as an adverse effect of lithium. Because Mr. C refused hospital transportation by EMS, discontinuing lithium appears to have been the safest option. Laboratory studies from the day after Mr. C presented to the clinic appeared to lessen the probability that lithium toxicity, hypothyroidism, valproate toxicity, type 2 diabetes mellitus, or infection had caused Mr. C’s symptoms.

Although psychiatrists may be vigilant about monitoring for signs and symptoms of toxicity with lithium use by utilizing regular laboratory studies, they may not be as vigilant with monitoring vital signs at every patient visit (Table). This case demonstrates the importance of regular vital sign measurements to be able to detect this rare but serious adverse effect.

Mr. C, age 30, with schizoaffective disorder, bipolar type, Cannabis abuse, and nicotine dependence, has been enrolled in a Program of Assertive Community Treatment (PACT) for approximately 5 years. He presents to the PACT clinic for follow-up with his psychiatrist. Mr. C reports dizziness, lightheadedness, blurred vision, and nausea worsening over the last few days, and he appears drowsy and hypoactive. He does not report any chest pain, abdominal pain, swelling, cold extremities, shortness of breath, vomiting, diarrhea, or blood loss. Mr. C admits he has eaten only once daily for several weeks because of delusional ideation that he is responsible for others suffering from anorexia nervosa.

His medical history includes gastroesophageal reflux disease. Mr. C’s medication regimen for the past year included total daily oral doses of benztropine, 2 mg, divalproex extended-release, 1,000 mg, fluphenazine, 15 mg, and gabapentin, 300 mg. He also receives IM fluphenazine decanoate, 50 mg every 2 weeks; lithium, 600 mg/d, was added to his regimen 5 months ago. Vital signs include temperature 97°F, weight 162 lb, height 69 inches, blood pressure 105/64 mm Hg, heart rate (HR) 46 beats per minute (bpm), and respirations 18 breaths per minute.

Because of Mr. C’s complaints, appearance, and low HR, the psychiatrist calls emergency medical services (EMS). Although the paramedics recommend emergency transport to the hospital, Mr. C refuses. The psychiatrist instructs Mr. C to stop taking lithium because of suspected lithium-induced bradycardia and a concern that he may be more susceptible to lithium toxicity with prolonged anorexia nervosa. When nursing staff evaluate Mr. C the next day, his vitals are HR 60 bpm, respirations 20 breaths per minute, and blood pressure 124/81 mm Hg; his dizziness, blurred vision, lightheadedness, and nausea are resolved.

Bradycardia is defined as a HR <60 bpm; however, symptoms may not occur until the HR is <50 bpm. Symptoms include fatigue, dizziness, lightheadedness, chest pain, shortness of breath, and syncope. The incidence of bradycardia during lithium treatment is unknown; it is considered a rare but serious adverse effect. A literature review reveals several case reports of bradycardia with lithium treatment,^2-4 including symptomatic bradycardia after a single dose of lithium.⁵ Other possible causes of bradycardia include anorexia nervosa, hypothermia, hypothyroidism, hypoxia, infection, stroke, acute myocardial infarction, sedative or opiate use, increased vagal tone with exercise conditioning, and other medications including fluphenazine.⁶

Mr. C’s symptoms may have been assumed to be secondary to several possible causes, including bradycardia, dehydration from poor oral intake, lithium toxicity, or an undiagnosed medical condition. The combination of nausea, dizziness, anorexia nervosa, blurred vision, and lightheadedness in a patient receiving lithium would certainly trigger a clinician’s concern for lithium toxicity, but he (she) may not be aware of the risk of bradycardia as an adverse effect of lithium. Because Mr. C refused hospital transportation by EMS, discontinuing lithium appears to have been the safest option. Laboratory studies from the day after Mr. C presented to the clinic appeared to lessen the probability that lithium toxicity, hypothyroidism, valproate toxicity, type 2 diabetes mellitus, or infection had caused Mr. C’s symptoms.

Although psychiatrists may be vigilant about monitoring for signs and symptoms of toxicity with lithium use by utilizing regular laboratory studies, they may not be as vigilant with monitoring vital signs at every patient visit (Table). This case demonstrates the importance of regular vital sign measurements to be able to detect this rare but serious adverse effect.

Mr. C, age 30, with schizoaffective disorder, bipolar type, Cannabis abuse, and nicotine dependence, has been enrolled in a Program of Assertive Community Treatment (PACT) for approximately 5 years. He presents to the PACT clinic for follow-up with his psychiatrist. Mr. C reports dizziness, lightheadedness, blurred vision, and nausea worsening over the last few days, and he appears drowsy and hypoactive. He does not report any chest pain, abdominal pain, swelling, cold extremities, shortness of breath, vomiting, diarrhea, or blood loss. Mr. C admits he has eaten only once daily for several weeks because of delusional ideation that he is responsible for others suffering from anorexia nervosa.

His medical history includes gastroesophageal reflux disease. Mr. C’s medication regimen for the past year included total daily oral doses of benztropine, 2 mg, divalproex extended-release, 1,000 mg, fluphenazine, 15 mg, and gabapentin, 300 mg. He also receives IM fluphenazine decanoate, 50 mg every 2 weeks; lithium, 600 mg/d, was added to his regimen 5 months ago. Vital signs include temperature 97°F, weight 162 lb, height 69 inches, blood pressure 105/64 mm Hg, heart rate (HR) 46 beats per minute (bpm), and respirations 18 breaths per minute.

Because of Mr. C’s complaints, appearance, and low HR, the psychiatrist calls emergency medical services (EMS). Although the paramedics recommend emergency transport to the hospital, Mr. C refuses. The psychiatrist instructs Mr. C to stop taking lithium because of suspected lithium-induced bradycardia and a concern that he may be more susceptible to lithium toxicity with prolonged anorexia nervosa. When nursing staff evaluate Mr. C the next day, his vitals are HR 60 bpm, respirations 20 breaths per minute, and blood pressure 124/81 mm Hg; his dizziness, blurred vision, lightheadedness, and nausea are resolved.

Bradycardia is defined as a HR <60 bpm; however, symptoms may not occur until the HR is <50 bpm. Symptoms include fatigue, dizziness, lightheadedness, chest pain, shortness of breath, and syncope. The incidence of bradycardia during lithium treatment is unknown; it is considered a rare but serious adverse effect. A literature review reveals several case reports of bradycardia with lithium treatment,^2-4 including symptomatic bradycardia after a single dose of lithium.⁵ Other possible causes of bradycardia include anorexia nervosa, hypothermia, hypothyroidism, hypoxia, infection, stroke, acute myocardial infarction, sedative or opiate use, increased vagal tone with exercise conditioning, and other medications including fluphenazine.⁶

Mr. C’s symptoms may have been assumed to be secondary to several possible causes, including bradycardia, dehydration from poor oral intake, lithium toxicity, or an undiagnosed medical condition. The combination of nausea, dizziness, anorexia nervosa, blurred vision, and lightheadedness in a patient receiving lithium would certainly trigger a clinician’s concern for lithium toxicity, but he (she) may not be aware of the risk of bradycardia as an adverse effect of lithium. Because Mr. C refused hospital transportation by EMS, discontinuing lithium appears to have been the safest option. Laboratory studies from the day after Mr. C presented to the clinic appeared to lessen the probability that lithium toxicity, hypothyroidism, valproate toxicity, type 2 diabetes mellitus, or infection had caused Mr. C’s symptoms.

Although psychiatrists may be vigilant about monitoring for signs and symptoms of toxicity with lithium use by utilizing regular laboratory studies, they may not be as vigilant with monitoring vital signs at every patient visit (Table). This case demonstrates the importance of regular vital sign measurements to be able to detect this rare but serious adverse effect.

CASE Grieving, delusional

Mr. M, age 51, is brought to the emergency department (ED) because of new-onset delusions and decreased self-care over the last 2 weeks following the sudden death of his wife. He has become expansive and grandiose, with pressured speech, increased energy, and markedly reduced sleep. Mr. M is preoccupied with the idea that he is “the first to survive a human reboot process” and says that his and his wife’s bodies and brains had been “split apart.” Mr. M has limited his food and fluid intake and lost 15 lb within the past 2 to 3 weeks.

Mr. M has no history of any affective, psychotic, or other major mental disorders or treatment. He reports that he has regularly used Cannabis over the last 10 years, and a few years ago, he started occasionally using nitrous oxide (N₂O). He says that in the week following his wife’s death, he used N₂O almost daily and in copious amounts. In an attempt to “self-anesthetize” himself after his wife’s funeral, he isolated himself in his bedroom and used escalating amounts of Cannabis and N₂O, while continually working on a book about their life together.

At first, Mr. M shows little emotion and describes his situation as “interesting and fascinating.” He mentions that he thinks he might have been “psychotic” the week after his wife’s death, but he shows no sustained insight and immediately relapses into psychotic thinking. Over several hours in the ED, he is tearful and sad about his wife’s death. Mr. M recalls a similar experience of grief after his mother died when he was a teenager, but at that time he did not abuse substances or have psychotic symptoms. He is fully alert, fully oriented, and has no significant deficits of attention or memory.

[polldaddy:9859135]

The authors’ observations

Grief was a precipitating event, but by itself grief cannot explain psychosis. Psychotic depression is a possibility, but Mr. M’s psychotic features are incongruent with his mood. Mania would be a diagnosis of exclusion. Mr. M had no prior history of major affective illness. Mr. M was abusing Cannabis, which might independently contribute to psychosis¹; however, he had been using it recreationally for 10 years without psychiatric problems. N₂O, however, can cause symptoms consistent with Mr. M’s presentation.

[polldaddy:9859140]

EVALUATION Laboratory tests

Mr. M’s physical examination is notable only for an elevated blood pressure of 196/120 mm Hg. Neurologic examination is normal. Toxicology is positive for cannabinoids and negative for amphetamines, cocaine, opiates, and phencyclidine. Chemistries are normal except for a potassium of 3.4 mEq/L (reference range, 3.7 to 5.2 mEq/L) and a blood urine nitrogen of 25 mg/dL (reference range, 6 to 20 mg/dL), which are consistent with reduced food and fluid intake. Mr. M shows no signs of anemia. Hematocrit is 42% and mean corpuscular volume is 90 fL. Syphilis screen is negative; a head CT scan is unremarkable.

The authors’ observations

N₂O, also known as “laughing gas,” is routinely used by dentists and pediatric anesthesiologists, and has other medical uses. Some studies have examined an adjunctive use of N₂O for pain control in the ED and during colonoscopies.^3,4

In the 2013 U.S. National Survey on Drug Use and Health, 16% of respondents reported lifetime illicit use of N₂O.^5,6 It is readily available in tanks used in medicine and industry and in small dispensers called “whippits” that can be legally purchased. Acute effects of N₂O include euphoric mood, numbness, feeling of warmth, dizziness, and auditory hallucinations.⁷ The anesthetic effects of N₂O are linked to endogenous release of opiates, and recent research links its anxiolytic activity to the facilitation of GABAergic inhibitory and N-methyl-d-aspartic acid (NMDA)-mediated transmission.⁸ Abuse of N₂O has been the presumptive cause of death in 29 cases.⁹

TREATMENT Supplementation

Mr. M is diagnosed with substance-induced psychotic disorder. His symptoms were precipitated by an acute increase in N₂O use, which has been shown to cause vitamin B₁₂ deficiency, which we consider was likely a primary contributor to his presentation. Other potential contributing factors are premorbid hyperthymic temperament, a possible propensity to psychotic thinking under stress, the sudden death of his wife, acute grief, the potentiating role of Cannabis, dehydration, and general malnutrition. The death of a loved one is associated with an increased risk of developing substance use disorders.²⁷

During a 15-day psychiatric hospitalization, Mr. M is given olanzapine, increased to 15 mg/d and oral vitamin B₁₂, 1,000 mcg/d for 4 days, then IM cyanocobalamin for 7 days. Mr. M’s symptoms steadily improve, with normalization of sleep and near-total resolution of delusions. On hospital Day 14, his vitamin B₁₂ levels are within normal limits (844 pg/mL). At discharge, Mr. M shows residual mild grandiosity, with limited insight into his illness and what caused it, but frank delusional ideation has clearly receded. He still shows some signs of grief. Mr. M is advised to stop using Cannabis and N₂O and about the potential consequences of continued use.

The authors’ observations

For patients with vitamin B₁₂ deficiency, guidelines from the National Health Service in the United Kingdom and the British Society for Haematology recommend treatment with IM hydroxocobalamin, 1,000 IU, 3 times weekly, for 2 weeks.^21,28 For patients with neurologic symptoms, the British National Foundation recommends treatment with IM hydroxocobalamin, 1,000 IU, on alternative days until there is no further improvement.²¹

This case is a reminder for clinicians to screen for inhalant use, specifically N₂O, which can precipitate vitamin B₁₂ deficiency with psychiatric symptoms as the only presenting concern. Clinicians should consider measuring vitamin B₁₂ levels in psychiatric patients at risk of deficiency of this nutrient, including older adults, vegetarians, and those with alimentary disorders.^29,30 Dietary sources of vitamin B₁₂ include meat, milk, egg, fish, and shellfish.³¹ The body can store a total of 2 to 5 mg of vitamin B₁₂; thus, it takes 2 to 5 years to develop vitamin B₁₂ deficiency from malabsorption and can take as long as 20 years to develop vitamin B₁₂ deficiency from vegetarianism.³² However, by chemically inactivating vitamin B₁₂, N₂O causes a rapid functional deficiency, as was seen in our patient.

OUTCOME Improved insight

At a 1-week follow-up appointment with a psychiatrist, Mr. M has no evident psychotic symptoms. He reports that he has not used Cannabis or N₂O, and he discontinues olanzapine following this visit. Two weeks later, Mr. M shows no psychotic or affective symptoms other than grief, which is appropriately expressed. His insight has improved. He commits to not using Cannabis, N₂O, or any other illicit substances. Mr. M is referred back to his long-standing primary care provider with the understanding that if any psychiatric symptoms recur he will see a psychiatrist again.

CASE Grieving, delusional

Mr. M, age 51, is brought to the emergency department (ED) because of new-onset delusions and decreased self-care over the last 2 weeks following the sudden death of his wife. He has become expansive and grandiose, with pressured speech, increased energy, and markedly reduced sleep. Mr. M is preoccupied with the idea that he is “the first to survive a human reboot process” and says that his and his wife’s bodies and brains had been “split apart.” Mr. M has limited his food and fluid intake and lost 15 lb within the past 2 to 3 weeks.

Mr. M has no history of any affective, psychotic, or other major mental disorders or treatment. He reports that he has regularly used Cannabis over the last 10 years, and a few years ago, he started occasionally using nitrous oxide (N₂O). He says that in the week following his wife’s death, he used N₂O almost daily and in copious amounts. In an attempt to “self-anesthetize” himself after his wife’s funeral, he isolated himself in his bedroom and used escalating amounts of Cannabis and N₂O, while continually working on a book about their life together.

At first, Mr. M shows little emotion and describes his situation as “interesting and fascinating.” He mentions that he thinks he might have been “psychotic” the week after his wife’s death, but he shows no sustained insight and immediately relapses into psychotic thinking. Over several hours in the ED, he is tearful and sad about his wife’s death. Mr. M recalls a similar experience of grief after his mother died when he was a teenager, but at that time he did not abuse substances or have psychotic symptoms. He is fully alert, fully oriented, and has no significant deficits of attention or memory.

[polldaddy:9859135]

The authors’ observations

Grief was a precipitating event, but by itself grief cannot explain psychosis. Psychotic depression is a possibility, but Mr. M’s psychotic features are incongruent with his mood. Mania would be a diagnosis of exclusion. Mr. M had no prior history of major affective illness. Mr. M was abusing Cannabis, which might independently contribute to psychosis¹; however, he had been using it recreationally for 10 years without psychiatric problems. N₂O, however, can cause symptoms consistent with Mr. M’s presentation.

[polldaddy:9859140]

EVALUATION Laboratory tests

Mr. M’s physical examination is notable only for an elevated blood pressure of 196/120 mm Hg. Neurologic examination is normal. Toxicology is positive for cannabinoids and negative for amphetamines, cocaine, opiates, and phencyclidine. Chemistries are normal except for a potassium of 3.4 mEq/L (reference range, 3.7 to 5.2 mEq/L) and a blood urine nitrogen of 25 mg/dL (reference range, 6 to 20 mg/dL), which are consistent with reduced food and fluid intake. Mr. M shows no signs of anemia. Hematocrit is 42% and mean corpuscular volume is 90 fL. Syphilis screen is negative; a head CT scan is unremarkable.

The authors’ observations

N₂O, also known as “laughing gas,” is routinely used by dentists and pediatric anesthesiologists, and has other medical uses. Some studies have examined an adjunctive use of N₂O for pain control in the ED and during colonoscopies.^3,4

In the 2013 U.S. National Survey on Drug Use and Health, 16% of respondents reported lifetime illicit use of N₂O.^5,6 It is readily available in tanks used in medicine and industry and in small dispensers called “whippits” that can be legally purchased. Acute effects of N₂O include euphoric mood, numbness, feeling of warmth, dizziness, and auditory hallucinations.⁷ The anesthetic effects of N₂O are linked to endogenous release of opiates, and recent research links its anxiolytic activity to the facilitation of GABAergic inhibitory and N-methyl-d-aspartic acid (NMDA)-mediated transmission.⁸ Abuse of N₂O has been the presumptive cause of death in 29 cases.⁹

TREATMENT Supplementation

Mr. M is diagnosed with substance-induced psychotic disorder. His symptoms were precipitated by an acute increase in N₂O use, which has been shown to cause vitamin B₁₂ deficiency, which we consider was likely a primary contributor to his presentation. Other potential contributing factors are premorbid hyperthymic temperament, a possible propensity to psychotic thinking under stress, the sudden death of his wife, acute grief, the potentiating role of Cannabis, dehydration, and general malnutrition. The death of a loved one is associated with an increased risk of developing substance use disorders.²⁷

During a 15-day psychiatric hospitalization, Mr. M is given olanzapine, increased to 15 mg/d and oral vitamin B₁₂, 1,000 mcg/d for 4 days, then IM cyanocobalamin for 7 days. Mr. M’s symptoms steadily improve, with normalization of sleep and near-total resolution of delusions. On hospital Day 14, his vitamin B₁₂ levels are within normal limits (844 pg/mL). At discharge, Mr. M shows residual mild grandiosity, with limited insight into his illness and what caused it, but frank delusional ideation has clearly receded. He still shows some signs of grief. Mr. M is advised to stop using Cannabis and N₂O and about the potential consequences of continued use.

The authors’ observations

For patients with vitamin B₁₂ deficiency, guidelines from the National Health Service in the United Kingdom and the British Society for Haematology recommend treatment with IM hydroxocobalamin, 1,000 IU, 3 times weekly, for 2 weeks.^21,28 For patients with neurologic symptoms, the British National Foundation recommends treatment with IM hydroxocobalamin, 1,000 IU, on alternative days until there is no further improvement.²¹

This case is a reminder for clinicians to screen for inhalant use, specifically N₂O, which can precipitate vitamin B₁₂ deficiency with psychiatric symptoms as the only presenting concern. Clinicians should consider measuring vitamin B₁₂ levels in psychiatric patients at risk of deficiency of this nutrient, including older adults, vegetarians, and those with alimentary disorders.^29,30 Dietary sources of vitamin B₁₂ include meat, milk, egg, fish, and shellfish.³¹ The body can store a total of 2 to 5 mg of vitamin B₁₂; thus, it takes 2 to 5 years to develop vitamin B₁₂ deficiency from malabsorption and can take as long as 20 years to develop vitamin B₁₂ deficiency from vegetarianism.³² However, by chemically inactivating vitamin B₁₂, N₂O causes a rapid functional deficiency, as was seen in our patient.

OUTCOME Improved insight

At a 1-week follow-up appointment with a psychiatrist, Mr. M has no evident psychotic symptoms. He reports that he has not used Cannabis or N₂O, and he discontinues olanzapine following this visit. Two weeks later, Mr. M shows no psychotic or affective symptoms other than grief, which is appropriately expressed. His insight has improved. He commits to not using Cannabis, N₂O, or any other illicit substances. Mr. M is referred back to his long-standing primary care provider with the understanding that if any psychiatric symptoms recur he will see a psychiatrist again.

CASE Grieving, delusional

Mr. M, age 51, is brought to the emergency department (ED) because of new-onset delusions and decreased self-care over the last 2 weeks following the sudden death of his wife. He has become expansive and grandiose, with pressured speech, increased energy, and markedly reduced sleep. Mr. M is preoccupied with the idea that he is “the first to survive a human reboot process” and says that his and his wife’s bodies and brains had been “split apart.” Mr. M has limited his food and fluid intake and lost 15 lb within the past 2 to 3 weeks.

Mr. M has no history of any affective, psychotic, or other major mental disorders or treatment. He reports that he has regularly used Cannabis over the last 10 years, and a few years ago, he started occasionally using nitrous oxide (N₂O). He says that in the week following his wife’s death, he used N₂O almost daily and in copious amounts. In an attempt to “self-anesthetize” himself after his wife’s funeral, he isolated himself in his bedroom and used escalating amounts of Cannabis and N₂O, while continually working on a book about their life together.

At first, Mr. M shows little emotion and describes his situation as “interesting and fascinating.” He mentions that he thinks he might have been “psychotic” the week after his wife’s death, but he shows no sustained insight and immediately relapses into psychotic thinking. Over several hours in the ED, he is tearful and sad about his wife’s death. Mr. M recalls a similar experience of grief after his mother died when he was a teenager, but at that time he did not abuse substances or have psychotic symptoms. He is fully alert, fully oriented, and has no significant deficits of attention or memory.

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The authors’ observations

Grief was a precipitating event, but by itself grief cannot explain psychosis. Psychotic depression is a possibility, but Mr. M’s psychotic features are incongruent with his mood. Mania would be a diagnosis of exclusion. Mr. M had no prior history of major affective illness. Mr. M was abusing Cannabis, which might independently contribute to psychosis¹; however, he had been using it recreationally for 10 years without psychiatric problems. N₂O, however, can cause symptoms consistent with Mr. M’s presentation.

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EVALUATION Laboratory tests

Mr. M’s physical examination is notable only for an elevated blood pressure of 196/120 mm Hg. Neurologic examination is normal. Toxicology is positive for cannabinoids and negative for amphetamines, cocaine, opiates, and phencyclidine. Chemistries are normal except for a potassium of 3.4 mEq/L (reference range, 3.7 to 5.2 mEq/L) and a blood urine nitrogen of 25 mg/dL (reference range, 6 to 20 mg/dL), which are consistent with reduced food and fluid intake. Mr. M shows no signs of anemia. Hematocrit is 42% and mean corpuscular volume is 90 fL. Syphilis screen is negative; a head CT scan is unremarkable.

The authors’ observations

N₂O, also known as “laughing gas,” is routinely used by dentists and pediatric anesthesiologists, and has other medical uses. Some studies have examined an adjunctive use of N₂O for pain control in the ED and during colonoscopies.^3,4

In the 2013 U.S. National Survey on Drug Use and Health, 16% of respondents reported lifetime illicit use of N₂O.^5,6 It is readily available in tanks used in medicine and industry and in small dispensers called “whippits” that can be legally purchased. Acute effects of N₂O include euphoric mood, numbness, feeling of warmth, dizziness, and auditory hallucinations.⁷ The anesthetic effects of N₂O are linked to endogenous release of opiates, and recent research links its anxiolytic activity to the facilitation of GABAergic inhibitory and N-methyl-d-aspartic acid (NMDA)-mediated transmission.⁸ Abuse of N₂O has been the presumptive cause of death in 29 cases.⁹

TREATMENT Supplementation

Mr. M is diagnosed with substance-induced psychotic disorder. His symptoms were precipitated by an acute increase in N₂O use, which has been shown to cause vitamin B₁₂ deficiency, which we consider was likely a primary contributor to his presentation. Other potential contributing factors are premorbid hyperthymic temperament, a possible propensity to psychotic thinking under stress, the sudden death of his wife, acute grief, the potentiating role of Cannabis, dehydration, and general malnutrition. The death of a loved one is associated with an increased risk of developing substance use disorders.²⁷

During a 15-day psychiatric hospitalization, Mr. M is given olanzapine, increased to 15 mg/d and oral vitamin B₁₂, 1,000 mcg/d for 4 days, then IM cyanocobalamin for 7 days. Mr. M’s symptoms steadily improve, with normalization of sleep and near-total resolution of delusions. On hospital Day 14, his vitamin B₁₂ levels are within normal limits (844 pg/mL). At discharge, Mr. M shows residual mild grandiosity, with limited insight into his illness and what caused it, but frank delusional ideation has clearly receded. He still shows some signs of grief. Mr. M is advised to stop using Cannabis and N₂O and about the potential consequences of continued use.

The authors’ observations

For patients with vitamin B₁₂ deficiency, guidelines from the National Health Service in the United Kingdom and the British Society for Haematology recommend treatment with IM hydroxocobalamin, 1,000 IU, 3 times weekly, for 2 weeks.^21,28 For patients with neurologic symptoms, the British National Foundation recommends treatment with IM hydroxocobalamin, 1,000 IU, on alternative days until there is no further improvement.²¹

This case is a reminder for clinicians to screen for inhalant use, specifically N₂O, which can precipitate vitamin B₁₂ deficiency with psychiatric symptoms as the only presenting concern. Clinicians should consider measuring vitamin B₁₂ levels in psychiatric patients at risk of deficiency of this nutrient, including older adults, vegetarians, and those with alimentary disorders.^29,30 Dietary sources of vitamin B₁₂ include meat, milk, egg, fish, and shellfish.³¹ The body can store a total of 2 to 5 mg of vitamin B₁₂; thus, it takes 2 to 5 years to develop vitamin B₁₂ deficiency from malabsorption and can take as long as 20 years to develop vitamin B₁₂ deficiency from vegetarianism.³² However, by chemically inactivating vitamin B₁₂, N₂O causes a rapid functional deficiency, as was seen in our patient.

OUTCOME Improved insight

At a 1-week follow-up appointment with a psychiatrist, Mr. M has no evident psychotic symptoms. He reports that he has not used Cannabis or N₂O, and he discontinues olanzapine following this visit. Two weeks later, Mr. M shows no psychotic or affective symptoms other than grief, which is appropriately expressed. His insight has improved. He commits to not using Cannabis, N₂O, or any other illicit substances. Mr. M is referred back to his long-standing primary care provider with the understanding that if any psychiatric symptoms recur he will see a psychiatrist again.

As physicians, we are cognizant of the importance of patient-centered care, active listening, empathy, and patience—the so-called “hidden curriculum of medicine.”¹ However, our attempts to centralize these concepts may be overshadowed by the deeply rooted drive to treat and fix. At times, we are simply treating uncertainty, whether it be diagnostic uncertainty or the uncertainty arising from clinical responses and outcomes that are far from binary. Definitive actions, such as adding medications or altering dosages, may appear to both patients and physicians to be a step closer to a “cure.” However, watchful waiting, re-evaluation, and accepting uncertainty are the true skills of effective care.

Be savvy about psychopharmacology

Psychotropics can take weeks to months to reach their full potential, and have varying responses and adverse effects. Beware of changing regimens prematurely, and keep in mind basic, yet crucial, pharma­cokinetic concepts (eg, 4 to 5 half-lives to reach steady state, variations in metabolism). Receptor binding and dosing heuristics are notably common in psychiatry. Although such concepts are important to grasp, there is no one-size-fits-all rule. The brain simply does not possess the heart’s machine-like, linear functioning. Therefore, targeting individual parts (ie, receptors) will not equate to fixing the whole organ systematically or predictably.

Is the patient truly treatment-resistant?

Even the best treatment regimen has no clinical benefit if the patient cannot afford the prescription or does not take the medication. If cost is an impediment, switch from brand name drugs to generic formulations or to older medications in the same class. Before declaring the patient “treatment-resistant” and making medication changes, assess for compliance. This may require assistance from collateral informants. Ask family members to count the number of pills remaining in the bottle, and call the pharmacy to find out the last refill dates. If the patient exhibits a partial response to what should be a therapeutic dose, consider obtaining drug plasma levels to rule out rapid metabolism before deeming the medication trial a failure.²

Medications as liabilities

Overreliance on medications can result in the medications becoming liabilities. The polypharmacy problem is not unique to psychiatry.³ However, psychiatric patients may be more likely to inadvertently use medications in a maladaptive manner and disrupt the fundamental goals of long-term care. Avoid making medication adjustments in response to a patient’s life stressors and normative situational reactions. Doing so is a disservice to patients, because we are robbing them of chances to develop necessary coping skills and defenses. This can be overtly damaging in certain patient populations, such as those with borderline personality disorder, who may use medication adjustments as a crutch during crises.⁴

Treat the patient, not yourself

We physicians mean well in prescribing evidence-based treatments; however, if the symptoms or adverse effects are not bother­some or cause functional impairment, we risk losing sight of the patient’s goals in treatment and imposing our own instead. Displacing the treatment focus can alienate the patient, harm the therapeutic alliance, and result in “pill fatigue.” For example, we may be tempted to treat antipsychotic-induced tardive dyskinesia, even if the patient is not concerned about abnormal movements. Although we see this adverse effect as a secondary problem that necessitates treatment, from the patient’s perspective, taking additional medication may be a far greater burden. The patient’s perception of direct beneficial effects from medications is crucial not only for patient-oriented care but also for adherence.⁵

Change does not happen overnight

Picking a treatment option out of a lineup of choices, à la UWorld questions, does not always translate into patients agreeing with the suggested treatment, let alone the idea of receiving treatment at all. Motivational interviewing is our chance to shine in such situations and the reason why we are physicians, rather than answer-picking bots. Patients cannot change if they are not ready. However, we should be ready to roll with resistance while looking for signs of readiness to change. We must accept that it may take a week, a month, a year, or even longer for patients to align with our plan of action. The only futile decision is deeming our efforts as futile while discounting the benefits of incremental care.

As physicians, we are cognizant of the importance of patient-centered care, active listening, empathy, and patience—the so-called “hidden curriculum of medicine.”¹ However, our attempts to centralize these concepts may be overshadowed by the deeply rooted drive to treat and fix. At times, we are simply treating uncertainty, whether it be diagnostic uncertainty or the uncertainty arising from clinical responses and outcomes that are far from binary. Definitive actions, such as adding medications or altering dosages, may appear to both patients and physicians to be a step closer to a “cure.” However, watchful waiting, re-evaluation, and accepting uncertainty are the true skills of effective care.

Be savvy about psychopharmacology

Psychotropics can take weeks to months to reach their full potential, and have varying responses and adverse effects. Beware of changing regimens prematurely, and keep in mind basic, yet crucial, pharma­cokinetic concepts (eg, 4 to 5 half-lives to reach steady state, variations in metabolism). Receptor binding and dosing heuristics are notably common in psychiatry. Although such concepts are important to grasp, there is no one-size-fits-all rule. The brain simply does not possess the heart’s machine-like, linear functioning. Therefore, targeting individual parts (ie, receptors) will not equate to fixing the whole organ systematically or predictably.

Is the patient truly treatment-resistant?

Even the best treatment regimen has no clinical benefit if the patient cannot afford the prescription or does not take the medication. If cost is an impediment, switch from brand name drugs to generic formulations or to older medications in the same class. Before declaring the patient “treatment-resistant” and making medication changes, assess for compliance. This may require assistance from collateral informants. Ask family members to count the number of pills remaining in the bottle, and call the pharmacy to find out the last refill dates. If the patient exhibits a partial response to what should be a therapeutic dose, consider obtaining drug plasma levels to rule out rapid metabolism before deeming the medication trial a failure.²

Medications as liabilities

Overreliance on medications can result in the medications becoming liabilities. The polypharmacy problem is not unique to psychiatry.³ However, psychiatric patients may be more likely to inadvertently use medications in a maladaptive manner and disrupt the fundamental goals of long-term care. Avoid making medication adjustments in response to a patient’s life stressors and normative situational reactions. Doing so is a disservice to patients, because we are robbing them of chances to develop necessary coping skills and defenses. This can be overtly damaging in certain patient populations, such as those with borderline personality disorder, who may use medication adjustments as a crutch during crises.⁴

Treat the patient, not yourself

We physicians mean well in prescribing evidence-based treatments; however, if the symptoms or adverse effects are not bother­some or cause functional impairment, we risk losing sight of the patient’s goals in treatment and imposing our own instead. Displacing the treatment focus can alienate the patient, harm the therapeutic alliance, and result in “pill fatigue.” For example, we may be tempted to treat antipsychotic-induced tardive dyskinesia, even if the patient is not concerned about abnormal movements. Although we see this adverse effect as a secondary problem that necessitates treatment, from the patient’s perspective, taking additional medication may be a far greater burden. The patient’s perception of direct beneficial effects from medications is crucial not only for patient-oriented care but also for adherence.⁵

Change does not happen overnight

Picking a treatment option out of a lineup of choices, à la UWorld questions, does not always translate into patients agreeing with the suggested treatment, let alone the idea of receiving treatment at all. Motivational interviewing is our chance to shine in such situations and the reason why we are physicians, rather than answer-picking bots. Patients cannot change if they are not ready. However, we should be ready to roll with resistance while looking for signs of readiness to change. We must accept that it may take a week, a month, a year, or even longer for patients to align with our plan of action. The only futile decision is deeming our efforts as futile while discounting the benefits of incremental care.

As physicians, we are cognizant of the importance of patient-centered care, active listening, empathy, and patience—the so-called “hidden curriculum of medicine.”¹ However, our attempts to centralize these concepts may be overshadowed by the deeply rooted drive to treat and fix. At times, we are simply treating uncertainty, whether it be diagnostic uncertainty or the uncertainty arising from clinical responses and outcomes that are far from binary. Definitive actions, such as adding medications or altering dosages, may appear to both patients and physicians to be a step closer to a “cure.” However, watchful waiting, re-evaluation, and accepting uncertainty are the true skills of effective care.

Be savvy about psychopharmacology

Psychotropics can take weeks to months to reach their full potential, and have varying responses and adverse effects. Beware of changing regimens prematurely, and keep in mind basic, yet crucial, pharma­cokinetic concepts (eg, 4 to 5 half-lives to reach steady state, variations in metabolism). Receptor binding and dosing heuristics are notably common in psychiatry. Although such concepts are important to grasp, there is no one-size-fits-all rule. The brain simply does not possess the heart’s machine-like, linear functioning. Therefore, targeting individual parts (ie, receptors) will not equate to fixing the whole organ systematically or predictably.

Is the patient truly treatment-resistant?

Even the best treatment regimen has no clinical benefit if the patient cannot afford the prescription or does not take the medication. If cost is an impediment, switch from brand name drugs to generic formulations or to older medications in the same class. Before declaring the patient “treatment-resistant” and making medication changes, assess for compliance. This may require assistance from collateral informants. Ask family members to count the number of pills remaining in the bottle, and call the pharmacy to find out the last refill dates. If the patient exhibits a partial response to what should be a therapeutic dose, consider obtaining drug plasma levels to rule out rapid metabolism before deeming the medication trial a failure.²

Medications as liabilities

Overreliance on medications can result in the medications becoming liabilities. The polypharmacy problem is not unique to psychiatry.³ However, psychiatric patients may be more likely to inadvertently use medications in a maladaptive manner and disrupt the fundamental goals of long-term care. Avoid making medication adjustments in response to a patient’s life stressors and normative situational reactions. Doing so is a disservice to patients, because we are robbing them of chances to develop necessary coping skills and defenses. This can be overtly damaging in certain patient populations, such as those with borderline personality disorder, who may use medication adjustments as a crutch during crises.⁴

Treat the patient, not yourself

We physicians mean well in prescribing evidence-based treatments; however, if the symptoms or adverse effects are not bother­some or cause functional impairment, we risk losing sight of the patient’s goals in treatment and imposing our own instead. Displacing the treatment focus can alienate the patient, harm the therapeutic alliance, and result in “pill fatigue.” For example, we may be tempted to treat antipsychotic-induced tardive dyskinesia, even if the patient is not concerned about abnormal movements. Although we see this adverse effect as a secondary problem that necessitates treatment, from the patient’s perspective, taking additional medication may be a far greater burden. The patient’s perception of direct beneficial effects from medications is crucial not only for patient-oriented care but also for adherence.⁵

Change does not happen overnight

Picking a treatment option out of a lineup of choices, à la UWorld questions, does not always translate into patients agreeing with the suggested treatment, let alone the idea of receiving treatment at all. Motivational interviewing is our chance to shine in such situations and the reason why we are physicians, rather than answer-picking bots. Patients cannot change if they are not ready. However, we should be ready to roll with resistance while looking for signs of readiness to change. We must accept that it may take a week, a month, a year, or even longer for patients to align with our plan of action. The only futile decision is deeming our efforts as futile while discounting the benefits of incremental care.

Although the biological aspects of psychiatry are crucial, psychotherapy is an integral part of psychiatry. Unfortunately, the emphasis on psychotherapy training in psychiatry residency programs has declined compared with a decade or more ago. In an era of dwindling psychotherapy training and resources, the quality and type of psychotherapy training has become more variable. In addition to helping maintain the therapeutic alliance, nuanced psychotherapy by a trained professional can be transformational by helping patients to:

• process complex life events and emotions
• feel understood
• overcome psychological barriers to recovery
• enhance self-esteem.

For the therapist, effective psychotherapy usually involves warmth and empathy, active listening, an authentic and genuine positive regard for the patient and his (her) experiences. The therapist should also pay attention to her (his) own emotions and internal responses, as well as the patient’s, while having the perseverance to address and help the patient work through challenging aspects.

When providing psychotherapy for adult patients, consider these basic, but salient points that are often overlooked.

Refrain from making life decisions for patients, except in exceptional circumstances, such as in situations of abuse and other crises.¹ Telling an adult patient what to do about life decisions that he finds challenging fits more under life coaching than psychotherapy. Through therapy, patients should be helped in processing the pros and cons of certain decisions and in navigating the decision-making process to arrive at a decision that makes the most sense to them. Also, it’s not uncommon for thera­peutic relationships to rupture when therapists give advice such as suggesting that a patient divorce his spouse, date a certain individual, or have children.

There are many reasons why giving advice in psychotherapy is not recommended. Giving advice can be an impediment to the therapeutic process.² What is good advice for one patient may not be good for another. Therapists who give advice often do so from their own lens and perspective. This perspective may not only be different from the patient’s priorities and life circumstances, but the therapist also may have inadequate information about the patient’s situation,^1,2 which could lead to providing advice that could even harm the patient. In addition, providing advice might prevent a patient from gaining adequate agency or self-directedness while promoting an unhealthy dependence on the therapist and reinforcing the patient’s self-doubt or lack of confidence. In these cases, the patient may later resent the therapist for the advice.

Address the ‘here and now.’¹ Pay attention to immediate issues or themes that emerge, and address them with the patient gently and thoughtfully, as appropriate. Ignoring these may create risks of missing vital, underlying material that could reveal more of the patient’s inner world, as these themes can sometimes reflect other themes of the patient’s life outside of treatment.

Acknowledging and empathizing, when appropriate, are key initial steps that help decrease resistance and facilitate the therapeutic process.

Explore the affect. Paying attention to the patient’s emotional state is critical.³ This holds true for all types of psychotherapy. For example, if a patient suddenly becomes tearful when telling his story or describing recent events, this is usually a sign that the subject matter affects or holds value to the patient in a significant or meaningful way and should be further explored.

‘Meet the patient where they are.’ This doesn’t mean you should yield to the patient or give in to his demands. It implies that you should assess the patient’s readiness for a particular intervention and devise interventions from that standpoint, exploring the patient’s ambivalence, noticing resistance, and continuing to acknowledge and empathize with where the patient is in life or treatment. When utilized judiciously, this technique can help the therapist align with the patient, and help the patient move forward through resistance and ambivalence.

Be nonjudgmental and empathetic. Patients place trust in their therapists when they disclose thoughts or emotions that are sensitive, meaningful, or close to the heart. A nonjudgmental response helps the patient accept his experiences and emotions. Being empathetic requires putting oneself in another’s shoes; it does not mean agreeing with the patient. Of course, if you learn that your patient abused a child or an older adult, you are required to report it to the appropriate state agency. In addition, follow the duty to warn and protect in case of any other safety issues, as appropriate.

Do not assume. Open-ended questions and exploration are key. For example, a patient told her resident therapist that her father recently passed away. The therapist expressed to the patient how hard this must be for her. However, the patient said she was relieved by her father’s death, because he had been abusive to her for years. Because of the therapist’s comment, the patient doubted her own reaction and felt guilty for not being more upset about her father’s death.

Avoid over-identifying with your patient. If you find yourself over-identifying with a patient because you have a common background or life events, seek supervision. Over-identification not only can pose barriers to objectively identifying patterns and trends in the patient’s behavior or presentation but also can increase the risk of crossing boundaries or even minimizing the patient’s experience. Exercise caution if you find yourself wanting to be liked by your patient; this is a common mistake among beginning therapists.⁴

Seek supervision. If you are feeling angry, frustrated, indifferent, or overly attached toward a patient, recognize this countertransference and seek consultation or supervision from an experienced colleague or supervisor. These emotions can be valuable tools that shed light not only on the patient’s life and the session itself, but also help you identify any other factors, such as your own feelings or experiences, that might be contributing to these reactions.

Although the biological aspects of psychiatry are crucial, psychotherapy is an integral part of psychiatry. Unfortunately, the emphasis on psychotherapy training in psychiatry residency programs has declined compared with a decade or more ago. In an era of dwindling psychotherapy training and resources, the quality and type of psychotherapy training has become more variable. In addition to helping maintain the therapeutic alliance, nuanced psychotherapy by a trained professional can be transformational by helping patients to:

• process complex life events and emotions
• feel understood
• overcome psychological barriers to recovery
• enhance self-esteem.

For the therapist, effective psychotherapy usually involves warmth and empathy, active listening, an authentic and genuine positive regard for the patient and his (her) experiences. The therapist should also pay attention to her (his) own emotions and internal responses, as well as the patient’s, while having the perseverance to address and help the patient work through challenging aspects.

When providing psychotherapy for adult patients, consider these basic, but salient points that are often overlooked.

Refrain from making life decisions for patients, except in exceptional circumstances, such as in situations of abuse and other crises.¹ Telling an adult patient what to do about life decisions that he finds challenging fits more under life coaching than psychotherapy. Through therapy, patients should be helped in processing the pros and cons of certain decisions and in navigating the decision-making process to arrive at a decision that makes the most sense to them. Also, it’s not uncommon for thera­peutic relationships to rupture when therapists give advice such as suggesting that a patient divorce his spouse, date a certain individual, or have children.

There are many reasons why giving advice in psychotherapy is not recommended. Giving advice can be an impediment to the therapeutic process.² What is good advice for one patient may not be good for another. Therapists who give advice often do so from their own lens and perspective. This perspective may not only be different from the patient’s priorities and life circumstances, but the therapist also may have inadequate information about the patient’s situation,^1,2 which could lead to providing advice that could even harm the patient. In addition, providing advice might prevent a patient from gaining adequate agency or self-directedness while promoting an unhealthy dependence on the therapist and reinforcing the patient’s self-doubt or lack of confidence. In these cases, the patient may later resent the therapist for the advice.

Address the ‘here and now.’¹ Pay attention to immediate issues or themes that emerge, and address them with the patient gently and thoughtfully, as appropriate. Ignoring these may create risks of missing vital, underlying material that could reveal more of the patient’s inner world, as these themes can sometimes reflect other themes of the patient’s life outside of treatment.

Acknowledging and empathizing, when appropriate, are key initial steps that help decrease resistance and facilitate the therapeutic process.

Explore the affect. Paying attention to the patient’s emotional state is critical.³ This holds true for all types of psychotherapy. For example, if a patient suddenly becomes tearful when telling his story or describing recent events, this is usually a sign that the subject matter affects or holds value to the patient in a significant or meaningful way and should be further explored.

‘Meet the patient where they are.’ This doesn’t mean you should yield to the patient or give in to his demands. It implies that you should assess the patient’s readiness for a particular intervention and devise interventions from that standpoint, exploring the patient’s ambivalence, noticing resistance, and continuing to acknowledge and empathize with where the patient is in life or treatment. When utilized judiciously, this technique can help the therapist align with the patient, and help the patient move forward through resistance and ambivalence.

Be nonjudgmental and empathetic. Patients place trust in their therapists when they disclose thoughts or emotions that are sensitive, meaningful, or close to the heart. A nonjudgmental response helps the patient accept his experiences and emotions. Being empathetic requires putting oneself in another’s shoes; it does not mean agreeing with the patient. Of course, if you learn that your patient abused a child or an older adult, you are required to report it to the appropriate state agency. In addition, follow the duty to warn and protect in case of any other safety issues, as appropriate.

Do not assume. Open-ended questions and exploration are key. For example, a patient told her resident therapist that her father recently passed away. The therapist expressed to the patient how hard this must be for her. However, the patient said she was relieved by her father’s death, because he had been abusive to her for years. Because of the therapist’s comment, the patient doubted her own reaction and felt guilty for not being more upset about her father’s death.

Avoid over-identifying with your patient. If you find yourself over-identifying with a patient because you have a common background or life events, seek supervision. Over-identification not only can pose barriers to objectively identifying patterns and trends in the patient’s behavior or presentation but also can increase the risk of crossing boundaries or even minimizing the patient’s experience. Exercise caution if you find yourself wanting to be liked by your patient; this is a common mistake among beginning therapists.⁴

Seek supervision. If you are feeling angry, frustrated, indifferent, or overly attached toward a patient, recognize this countertransference and seek consultation or supervision from an experienced colleague or supervisor. These emotions can be valuable tools that shed light not only on the patient’s life and the session itself, but also help you identify any other factors, such as your own feelings or experiences, that might be contributing to these reactions.

Although the biological aspects of psychiatry are crucial, psychotherapy is an integral part of psychiatry. Unfortunately, the emphasis on psychotherapy training in psychiatry residency programs has declined compared with a decade or more ago. In an era of dwindling psychotherapy training and resources, the quality and type of psychotherapy training has become more variable. In addition to helping maintain the therapeutic alliance, nuanced psychotherapy by a trained professional can be transformational by helping patients to:

• process complex life events and emotions
• feel understood
• overcome psychological barriers to recovery
• enhance self-esteem.

For the therapist, effective psychotherapy usually involves warmth and empathy, active listening, an authentic and genuine positive regard for the patient and his (her) experiences. The therapist should also pay attention to her (his) own emotions and internal responses, as well as the patient’s, while having the perseverance to address and help the patient work through challenging aspects.

When providing psychotherapy for adult patients, consider these basic, but salient points that are often overlooked.

Refrain from making life decisions for patients, except in exceptional circumstances, such as in situations of abuse and other crises.¹ Telling an adult patient what to do about life decisions that he finds challenging fits more under life coaching than psychotherapy. Through therapy, patients should be helped in processing the pros and cons of certain decisions and in navigating the decision-making process to arrive at a decision that makes the most sense to them. Also, it’s not uncommon for thera­peutic relationships to rupture when therapists give advice such as suggesting that a patient divorce his spouse, date a certain individual, or have children.

There are many reasons why giving advice in psychotherapy is not recommended. Giving advice can be an impediment to the therapeutic process.² What is good advice for one patient may not be good for another. Therapists who give advice often do so from their own lens and perspective. This perspective may not only be different from the patient’s priorities and life circumstances, but the therapist also may have inadequate information about the patient’s situation,^1,2 which could lead to providing advice that could even harm the patient. In addition, providing advice might prevent a patient from gaining adequate agency or self-directedness while promoting an unhealthy dependence on the therapist and reinforcing the patient’s self-doubt or lack of confidence. In these cases, the patient may later resent the therapist for the advice.

Address the ‘here and now.’¹ Pay attention to immediate issues or themes that emerge, and address them with the patient gently and thoughtfully, as appropriate. Ignoring these may create risks of missing vital, underlying material that could reveal more of the patient’s inner world, as these themes can sometimes reflect other themes of the patient’s life outside of treatment.

Acknowledging and empathizing, when appropriate, are key initial steps that help decrease resistance and facilitate the therapeutic process.

Explore the affect. Paying attention to the patient’s emotional state is critical.³ This holds true for all types of psychotherapy. For example, if a patient suddenly becomes tearful when telling his story or describing recent events, this is usually a sign that the subject matter affects or holds value to the patient in a significant or meaningful way and should be further explored.

‘Meet the patient where they are.’ This doesn’t mean you should yield to the patient or give in to his demands. It implies that you should assess the patient’s readiness for a particular intervention and devise interventions from that standpoint, exploring the patient’s ambivalence, noticing resistance, and continuing to acknowledge and empathize with where the patient is in life or treatment. When utilized judiciously, this technique can help the therapist align with the patient, and help the patient move forward through resistance and ambivalence.

Be nonjudgmental and empathetic. Patients place trust in their therapists when they disclose thoughts or emotions that are sensitive, meaningful, or close to the heart. A nonjudgmental response helps the patient accept his experiences and emotions. Being empathetic requires putting oneself in another’s shoes; it does not mean agreeing with the patient. Of course, if you learn that your patient abused a child or an older adult, you are required to report it to the appropriate state agency. In addition, follow the duty to warn and protect in case of any other safety issues, as appropriate.

Do not assume. Open-ended questions and exploration are key. For example, a patient told her resident therapist that her father recently passed away. The therapist expressed to the patient how hard this must be for her. However, the patient said she was relieved by her father’s death, because he had been abusive to her for years. Because of the therapist’s comment, the patient doubted her own reaction and felt guilty for not being more upset about her father’s death.

Avoid over-identifying with your patient. If you find yourself over-identifying with a patient because you have a common background or life events, seek supervision. Over-identification not only can pose barriers to objectively identifying patterns and trends in the patient’s behavior or presentation but also can increase the risk of crossing boundaries or even minimizing the patient’s experience. Exercise caution if you find yourself wanting to be liked by your patient; this is a common mistake among beginning therapists.⁴

Seek supervision. If you are feeling angry, frustrated, indifferent, or overly attached toward a patient, recognize this countertransference and seek consultation or supervision from an experienced colleague or supervisor. These emotions can be valuable tools that shed light not only on the patient’s life and the session itself, but also help you identify any other factors, such as your own feelings or experiences, that might be contributing to these reactions.

Despite a lack of evidence, polypharmacy often is used to treat autism spectrum disorder (ASD),¹ while educational techniques are underutilized. Compared with the general population, children with ASD may be more prone to the adverse effects of the medications used to treat symptoms, such as antipsychotics and antidepressants.² Therefore, when addressing problem behaviors, such as tantrums, aggressiveness, or self-injury, in a patient with ASD, before prescribing a medication, consider the ABCs of these behaviors.³

Antecedents. What happened before the behavior occurred? Where and when did the behavior occur? Was the individual unable to get a desired tangible item, such as a preferred food, toy, or another object? Was the individual told complete a task that he (she) did not want to do? Did the individual see someone else getting attention?

Behaviors. What behavior(s) occurred after each antecedent?

Consequences. What happened after the behavior occurred? Did the caregiver give the individual the item he wanted? Was the individual able to get out of doing work that he did not want to do or become the center of attention?

Having parents document the ABCs is useful not only for finding out why a behavior occurred, but also for objectively determining if and how a medication is affecting the frequency of a behavior. Charts that parents can use to document ABC data are available online (eg, http://www.positively­autism.com/downloads/datasheet_abc.pdf). Once this data is collected, it can be used to implement appropriate interventions, which I describe as DEFG.

Differential reinforcement of other behaviors is a procedure that provides positive reinforcement for not engaging in a problem behavior or for staying on task. For example, use a token board to reward positive behaviors, with physical tokens or written marks. However, some patients require immediate reinforcement. I suggest that parents or caregivers carry small pieces of preferred food to give to the patient to reinforce positive behavior.

Exercise. A review of 18 studies reported that physical exercise, such as jogging, weight training, and bike riding, can help reduce problem behaviors in individuals with ASD.⁴ Among 64 participants with ASD, there was a decrease in aggression, stereotypy, off-task behavior, and elopement, and improvements in on-task and motor behavior such as playing catch.

Function. Refer to the ABCs to determine why a specific problem behavior is occurring. Each behavior can have 1 or multiple functions; therefore, develop a plan specific to the reason the patient engages in the behavior. For example, if the individual engages in a behavior to avoid a task, the parent or caregiver can give individual tokens that the individual can later exchange for a break, instead of engaging in the problem behavior to avoid the task. If a behavior appears to be done for attention, instruct the caregivers to provide frequent periods of attention when the individual engages in positive behaviors.

Go to the appropriate placement. By law, persons age ≤21 have the right to an education and to make meaningful progress. If a patient with ASD exhibits behaviors that interfere with learning, he is entitled to a placement that can provide intensive applied behavior analysis. If you feel that the child needs a different school, write an evaluation for the parent or guardian to submit to the school district and clearly outline the patient’s needs and requirements.

Despite a lack of evidence, polypharmacy often is used to treat autism spectrum disorder (ASD),¹ while educational techniques are underutilized. Compared with the general population, children with ASD may be more prone to the adverse effects of the medications used to treat symptoms, such as antipsychotics and antidepressants.² Therefore, when addressing problem behaviors, such as tantrums, aggressiveness, or self-injury, in a patient with ASD, before prescribing a medication, consider the ABCs of these behaviors.³

Antecedents. What happened before the behavior occurred? Where and when did the behavior occur? Was the individual unable to get a desired tangible item, such as a preferred food, toy, or another object? Was the individual told complete a task that he (she) did not want to do? Did the individual see someone else getting attention?

Behaviors. What behavior(s) occurred after each antecedent?

Consequences. What happened after the behavior occurred? Did the caregiver give the individual the item he wanted? Was the individual able to get out of doing work that he did not want to do or become the center of attention?

Having parents document the ABCs is useful not only for finding out why a behavior occurred, but also for objectively determining if and how a medication is affecting the frequency of a behavior. Charts that parents can use to document ABC data are available online (eg, http://www.positively­autism.com/downloads/datasheet_abc.pdf). Once this data is collected, it can be used to implement appropriate interventions, which I describe as DEFG.

Differential reinforcement of other behaviors is a procedure that provides positive reinforcement for not engaging in a problem behavior or for staying on task. For example, use a token board to reward positive behaviors, with physical tokens or written marks. However, some patients require immediate reinforcement. I suggest that parents or caregivers carry small pieces of preferred food to give to the patient to reinforce positive behavior.

Exercise. A review of 18 studies reported that physical exercise, such as jogging, weight training, and bike riding, can help reduce problem behaviors in individuals with ASD.⁴ Among 64 participants with ASD, there was a decrease in aggression, stereotypy, off-task behavior, and elopement, and improvements in on-task and motor behavior such as playing catch.

Function. Refer to the ABCs to determine why a specific problem behavior is occurring. Each behavior can have 1 or multiple functions; therefore, develop a plan specific to the reason the patient engages in the behavior. For example, if the individual engages in a behavior to avoid a task, the parent or caregiver can give individual tokens that the individual can later exchange for a break, instead of engaging in the problem behavior to avoid the task. If a behavior appears to be done for attention, instruct the caregivers to provide frequent periods of attention when the individual engages in positive behaviors.

Go to the appropriate placement. By law, persons age ≤21 have the right to an education and to make meaningful progress. If a patient with ASD exhibits behaviors that interfere with learning, he is entitled to a placement that can provide intensive applied behavior analysis. If you feel that the child needs a different school, write an evaluation for the parent or guardian to submit to the school district and clearly outline the patient’s needs and requirements.

Despite a lack of evidence, polypharmacy often is used to treat autism spectrum disorder (ASD),¹ while educational techniques are underutilized. Compared with the general population, children with ASD may be more prone to the adverse effects of the medications used to treat symptoms, such as antipsychotics and antidepressants.² Therefore, when addressing problem behaviors, such as tantrums, aggressiveness, or self-injury, in a patient with ASD, before prescribing a medication, consider the ABCs of these behaviors.³

Antecedents. What happened before the behavior occurred? Where and when did the behavior occur? Was the individual unable to get a desired tangible item, such as a preferred food, toy, or another object? Was the individual told complete a task that he (she) did not want to do? Did the individual see someone else getting attention?

Behaviors. What behavior(s) occurred after each antecedent?

Consequences. What happened after the behavior occurred? Did the caregiver give the individual the item he wanted? Was the individual able to get out of doing work that he did not want to do or become the center of attention?

Having parents document the ABCs is useful not only for finding out why a behavior occurred, but also for objectively determining if and how a medication is affecting the frequency of a behavior. Charts that parents can use to document ABC data are available online (eg, http://www.positively­autism.com/downloads/datasheet_abc.pdf). Once this data is collected, it can be used to implement appropriate interventions, which I describe as DEFG.

Differential reinforcement of other behaviors is a procedure that provides positive reinforcement for not engaging in a problem behavior or for staying on task. For example, use a token board to reward positive behaviors, with physical tokens or written marks. However, some patients require immediate reinforcement. I suggest that parents or caregivers carry small pieces of preferred food to give to the patient to reinforce positive behavior.

Exercise. A review of 18 studies reported that physical exercise, such as jogging, weight training, and bike riding, can help reduce problem behaviors in individuals with ASD.⁴ Among 64 participants with ASD, there was a decrease in aggression, stereotypy, off-task behavior, and elopement, and improvements in on-task and motor behavior such as playing catch.

Function. Refer to the ABCs to determine why a specific problem behavior is occurring. Each behavior can have 1 or multiple functions; therefore, develop a plan specific to the reason the patient engages in the behavior. For example, if the individual engages in a behavior to avoid a task, the parent or caregiver can give individual tokens that the individual can later exchange for a break, instead of engaging in the problem behavior to avoid the task. If a behavior appears to be done for attention, instruct the caregivers to provide frequent periods of attention when the individual engages in positive behaviors.

Go to the appropriate placement. By law, persons age ≤21 have the right to an education and to make meaningful progress. If a patient with ASD exhibits behaviors that interfere with learning, he is entitled to a placement that can provide intensive applied behavior analysis. If you feel that the child needs a different school, write an evaluation for the parent or guardian to submit to the school district and clearly outline the patient’s needs and requirements.