Article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting 7% of adults and 13% of children in the United States.^1,2 Atopic dermatitis is characterized by pruritus, dry skin, and pain, all of which can negatively impact quality of life and put patients at higher risk for psychiatric comorbidities such as anxiety and depression.³ The pathogenesis of AD is multifactorial, involving genetics, epidermal barrier dysfunction, and immune dysregulation. Overactivation of helper T cell (T_H2) pathway cytokines, including IL-4, IL-13, and IL-31, is thought to propagate both inflammation and pruritus, which are central to AD. The JAK-STAT signaling pathway plays a pivotal role in the immune system dysregulation and exaggeration of T_H2 cell response, making JAK-STAT inhibitors (or JAK inhibitors) strong theoretical candidates for the treatment of AD.⁴ In humans, the Janus kinases are composed of 4 different members—JAK1, JAK2, JAK3, and tyrosine kinase 2—all of which can be targeted by JAK inhibitors.⁵

JAK inhibitors such as tofacitinib have already been approved by the US Food and Drug Administration (FDA) to treat various inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis; other JAK inhibitors such as baricitinib are only approved for patients with rheumatoid arthritis.^6,7 The success of these small molecule inhibitors in these immune-mediated conditions make them attractive candidates for the treatment of AD. Several JAK inhibitors are in phase 2 and phase 3 clinical trials as oral therapies (moderate to severe AD) or as topical treatments (mild to moderate AD). Currently, ruxolitinib (RUX) is the only topical JAK inhibitor that is FDA approved for the treatment of AD in the United States.⁸ In this editorial, we focus on recent trials of JAK inhibitors tested in patients with AD, including topical RUX, as well as oral abrocitinib, upadacitinib, and baricitinib.

Topical RUX in AD

Ruxolitinib is a topical JAK1/2 small molecule inhibitor approved by the FDA for the treatment of AD in 2021. In a randomized trial by Kim et al⁹ in 2020, all tested regimens of RUX demonstrated significant improvement in eczema area and severity index (EASI) scores vs vehicle; notably, RUX cream 1.5% applied twice daily achieved the greatest mean percentage change in baseline EASI score vs vehicle at 4 weeks (76.1% vs 15.5%; P<.0001). Ruxolitinib cream was well tolerated through week 8 of the trial, and all adverse events (AEs) were mild to moderate in severity and comparable to those in the vehicle group.⁹

Topical JAK inhibitors appear to be effective for mild to moderate AD and have had an acceptable safety profile in clinical trials thus far. Although topical corticosteroids and calcineurin inhibitors can have great clinical benefit in AD, they are recommended for short-term use given side effects such as thinning of the skin, burning, or telangiectasia formation.^10,11 The hope is that topical JAK inhibitors may be an alternative to standard topical treatments for AD, as they can be used for longer periods due to a safer side-effect profile.

Oral JAK Inhibitors in AD

Several oral JAK inhibitors are undergoing investigation for the systemic treatment of moderate to severe AD. Abrocitinib is an oral JAK1 inhibitor that has demonstrated efficacy in several phase 3 trials in patients with moderate to severe AD. In a 2021 trial, patients were randomized in a 2:2:2:1 ratio to receive abrocitinib 200 mg daily, abrocitinib 100 mg daily, subcutaneous dupilumab 300 mg every other week, or placebo, respectively.¹² Patients in both abrocitinib groups showed significant improvement in AD vs placebo, and EASI-75 response was achieved in 70.3%, 58.7%, 58.1%, and 27.1% of patients, respectively (P<.001 for both abrocitinib doses vs placebo). Adverse events occurred more frequently in the abrocitinib 200-mg group vs placebo. Nausea, acne, nasopharyngitis, and headache were the most frequently reported AEs with abrocitinib.¹² Another phase 3 trial by Silverberg et al¹³ (N=391) had similar treatment results, with 38.1% of participants receiving abrocitinib 200 mg and 28.4% of participants receiving abrocitinib 100 mg achieving investigator global assessment scores of 0 (clear) or 1 (almost clear) vs 9.1% of participants receiving placebo (P<.001). Abrocitinib was well tolerated in this trial with few serious AEs (ie, herpangina [0.6%], pneumonia [0.6%]).¹³ In both trials, there were rare instances of laboratory values indicating thrombocytopenia with the 200-mg dose (0.9%¹² and 3.2%¹³) without any clinical manifestations. Although a decrease in platelets was observed, no thrombocytopenia occurred in the abrocitinib 100-mg group in the latter trial.¹³

Baricitinib is another oral inhibitor of JAK1 and JAK2 with potential for the treatment of AD. One randomized trial (N=329) demonstrated its efficacy in combination with a topical corticosteroid (TCS). At 16 weeks, a higher number of participants treated with baricitinib and TCS achieved investigator global assessment scores of 0 (clear) or 1 (almost clear) compared to those who received placebo and TCS (31% with baricitinib 4 mg + TCS, 24% with baricitinib 2 mg + TCS, and 15% with placebo + TCS).¹⁴ Similarly, in BREEZE-AD5,another phase 3 trial (N=440), baricitinib monotherapy demonstrated a higher rate of treatment success vs placebo.¹⁵ Specifically, 13% of patients treated with baricitinib 1 mg and 30% of those treated with baricitinib 2 mg achieved 75% or greater reduction in EASI scores compared to 8% in the placebo group. The most common AEs associated with baricitinib were nasopharyngitis and headache. Adverse events occurred with similar frequency across both experimental and control groups.¹⁵ Reich et al¹⁴ demonstrated a higher overall rate of AEs—most commonly nasopharyngitis, upper respiratory tract infections, and folliculitis—in baricitinib-treated patients; however, serious AEs occurred with similar frequency across all groups, including the control group.

The selective JAK1 inhibitor upadacitinib also is undergoing testing in treating moderate to severe AD. In one trial, 167 patients were randomized to once daily oral upadacitinib 7.5 mg, 15 mg, or 30 mg or placebo.¹⁶ All doses of upadacitinib demonstrated considerably higher percentage improvements from baseline in EASI scores compared to placebo at 16 weeks with a clear dose-response relationship (39%, 62%, and 74% vs 23%, respectively). In this trial, there were no dose-limiting safety events. Serious AEs were infrequent, occurring in 4.8%, 2.4%, and 0% of upadacitinib groups vs 2.5% for placebo. The serious AEs observed with upadacitinib were 1 case of appendicitis, lower jaw pericoronitis in a patient with a history of repeated tooth infections, and an exacerbation of AD.¹⁶

Tofacitinib, another JAK inhibitor, has been shown to increase the risk for blood clots and death in a large trial in the treatment of rheumatoid arthritis. Following this study, the FDA is requiring black box warnings for tofacitinib and also for the 2 JAK inhibitors baricitinib and upadacitinib regarding the risks for heart-related events, cancer, blood clots, and death. Given that these medications share a similar mechanism of action to tofacitinib, they may have similar risks, though they have not yet been fully evaluated in large safety trials.¹⁷

With more recent investigation into novel therapeutics for AD, oral JAK inhibitors may play an important role in the future to treat patients with moderate to severe AD with inadequate response or contraindications to other systemic therapies. In trials thus far, oral JAK inhibitors have exhibited acceptable safety profiles and have demonstrated treatment success in AD. More randomized, controlled, phase 3 studies with larger patient populations are required to confirm their potential as effective treatments and elucidate their long-term safety.

Deucravacitinib in Psoriasis

Deucravacitinib is a first-in-class, oral, selective TYK2 inhibitor currently undergoing testing for the treatment of psoriasis. A randomized phase 2 trial (N=267) found that deucravacitinib was more effective than placebo in treating chronic plaque psoriasis at doses of 3 to 12 mg daily.¹⁸ The percentage of participants with a 75% or greater reduction from baseline in the psoriasis area and severity index score was 7% with placebo, 9% with deucravacitinib 3 mg every other day (P=.49 vs placebo), 39% with 3 mg once daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). The most commonly reported AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection. Adverse events occurred in 51% of participants in the control group and in 55% to 80% of those in the experimental groups. Additionally, there was 1 reported case of melanoma (stage 0) 96 days after the start of treatment in a patient in the 3-mg once-daily group. Serious AEs occurred in only 0% to 2% of participants who received deucravacitinib.¹⁸

Two phase 3 trials—POETYK PSO-1 and POETYK PSO-2 (N=1686)—found deucravacitinib to be notably more effective than both placebo and apremilast in treating psoriasis.¹⁹ Among participants receiving deucravacitinib 6 mg daily, 58.7% and 53.6% in the 2 respective trials achieved psoriasis area and severity index 75 response vs 12.7% and 9.4% receiving placebo and 35.1% and 40.2% receiving apremilast. Overall, the treatment was well tolerated, with a low rate of discontinuation of deucravacitinib due to AEs (2.4% of patients on deucravacitinib compared to 3.8% on placebo and 5.2% on apremilast). The most frequently observed AEs with deucravacitinib were nasopharyngitis and upper respiratory tract infection. The full results of these trials are expected to be published soon.^19,20

Final Thoughts

Overall, JAK inhibitors are a novel class of therapeutics that may have further success in the treatment of other dermatologic conditions that negatively affect patients’ quality of life and productivity. We should look forward to additional successful trials with these promising medications.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting 7% of adults and 13% of children in the United States.^1,2 Atopic dermatitis is characterized by pruritus, dry skin, and pain, all of which can negatively impact quality of life and put patients at higher risk for psychiatric comorbidities such as anxiety and depression.³ The pathogenesis of AD is multifactorial, involving genetics, epidermal barrier dysfunction, and immune dysregulation. Overactivation of helper T cell (T_H2) pathway cytokines, including IL-4, IL-13, and IL-31, is thought to propagate both inflammation and pruritus, which are central to AD. The JAK-STAT signaling pathway plays a pivotal role in the immune system dysregulation and exaggeration of T_H2 cell response, making JAK-STAT inhibitors (or JAK inhibitors) strong theoretical candidates for the treatment of AD.⁴ In humans, the Janus kinases are composed of 4 different members—JAK1, JAK2, JAK3, and tyrosine kinase 2—all of which can be targeted by JAK inhibitors.⁵

JAK inhibitors such as tofacitinib have already been approved by the US Food and Drug Administration (FDA) to treat various inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis; other JAK inhibitors such as baricitinib are only approved for patients with rheumatoid arthritis.^6,7 The success of these small molecule inhibitors in these immune-mediated conditions make them attractive candidates for the treatment of AD. Several JAK inhibitors are in phase 2 and phase 3 clinical trials as oral therapies (moderate to severe AD) or as topical treatments (mild to moderate AD). Currently, ruxolitinib (RUX) is the only topical JAK inhibitor that is FDA approved for the treatment of AD in the United States.⁸ In this editorial, we focus on recent trials of JAK inhibitors tested in patients with AD, including topical RUX, as well as oral abrocitinib, upadacitinib, and baricitinib.

Topical RUX in AD

Ruxolitinib is a topical JAK1/2 small molecule inhibitor approved by the FDA for the treatment of AD in 2021. In a randomized trial by Kim et al⁹ in 2020, all tested regimens of RUX demonstrated significant improvement in eczema area and severity index (EASI) scores vs vehicle; notably, RUX cream 1.5% applied twice daily achieved the greatest mean percentage change in baseline EASI score vs vehicle at 4 weeks (76.1% vs 15.5%; P<.0001). Ruxolitinib cream was well tolerated through week 8 of the trial, and all adverse events (AEs) were mild to moderate in severity and comparable to those in the vehicle group.⁹

Topical JAK inhibitors appear to be effective for mild to moderate AD and have had an acceptable safety profile in clinical trials thus far. Although topical corticosteroids and calcineurin inhibitors can have great clinical benefit in AD, they are recommended for short-term use given side effects such as thinning of the skin, burning, or telangiectasia formation.^10,11 The hope is that topical JAK inhibitors may be an alternative to standard topical treatments for AD, as they can be used for longer periods due to a safer side-effect profile.

Oral JAK Inhibitors in AD

Several oral JAK inhibitors are undergoing investigation for the systemic treatment of moderate to severe AD. Abrocitinib is an oral JAK1 inhibitor that has demonstrated efficacy in several phase 3 trials in patients with moderate to severe AD. In a 2021 trial, patients were randomized in a 2:2:2:1 ratio to receive abrocitinib 200 mg daily, abrocitinib 100 mg daily, subcutaneous dupilumab 300 mg every other week, or placebo, respectively.¹² Patients in both abrocitinib groups showed significant improvement in AD vs placebo, and EASI-75 response was achieved in 70.3%, 58.7%, 58.1%, and 27.1% of patients, respectively (P<.001 for both abrocitinib doses vs placebo). Adverse events occurred more frequently in the abrocitinib 200-mg group vs placebo. Nausea, acne, nasopharyngitis, and headache were the most frequently reported AEs with abrocitinib.¹² Another phase 3 trial by Silverberg et al¹³ (N=391) had similar treatment results, with 38.1% of participants receiving abrocitinib 200 mg and 28.4% of participants receiving abrocitinib 100 mg achieving investigator global assessment scores of 0 (clear) or 1 (almost clear) vs 9.1% of participants receiving placebo (P<.001). Abrocitinib was well tolerated in this trial with few serious AEs (ie, herpangina [0.6%], pneumonia [0.6%]).¹³ In both trials, there were rare instances of laboratory values indicating thrombocytopenia with the 200-mg dose (0.9%¹² and 3.2%¹³) without any clinical manifestations. Although a decrease in platelets was observed, no thrombocytopenia occurred in the abrocitinib 100-mg group in the latter trial.¹³

Baricitinib is another oral inhibitor of JAK1 and JAK2 with potential for the treatment of AD. One randomized trial (N=329) demonstrated its efficacy in combination with a topical corticosteroid (TCS). At 16 weeks, a higher number of participants treated with baricitinib and TCS achieved investigator global assessment scores of 0 (clear) or 1 (almost clear) compared to those who received placebo and TCS (31% with baricitinib 4 mg + TCS, 24% with baricitinib 2 mg + TCS, and 15% with placebo + TCS).¹⁴ Similarly, in BREEZE-AD5,another phase 3 trial (N=440), baricitinib monotherapy demonstrated a higher rate of treatment success vs placebo.¹⁵ Specifically, 13% of patients treated with baricitinib 1 mg and 30% of those treated with baricitinib 2 mg achieved 75% or greater reduction in EASI scores compared to 8% in the placebo group. The most common AEs associated with baricitinib were nasopharyngitis and headache. Adverse events occurred with similar frequency across both experimental and control groups.¹⁵ Reich et al¹⁴ demonstrated a higher overall rate of AEs—most commonly nasopharyngitis, upper respiratory tract infections, and folliculitis—in baricitinib-treated patients; however, serious AEs occurred with similar frequency across all groups, including the control group.

The selective JAK1 inhibitor upadacitinib also is undergoing testing in treating moderate to severe AD. In one trial, 167 patients were randomized to once daily oral upadacitinib 7.5 mg, 15 mg, or 30 mg or placebo.¹⁶ All doses of upadacitinib demonstrated considerably higher percentage improvements from baseline in EASI scores compared to placebo at 16 weeks with a clear dose-response relationship (39%, 62%, and 74% vs 23%, respectively). In this trial, there were no dose-limiting safety events. Serious AEs were infrequent, occurring in 4.8%, 2.4%, and 0% of upadacitinib groups vs 2.5% for placebo. The serious AEs observed with upadacitinib were 1 case of appendicitis, lower jaw pericoronitis in a patient with a history of repeated tooth infections, and an exacerbation of AD.¹⁶

Tofacitinib, another JAK inhibitor, has been shown to increase the risk for blood clots and death in a large trial in the treatment of rheumatoid arthritis. Following this study, the FDA is requiring black box warnings for tofacitinib and also for the 2 JAK inhibitors baricitinib and upadacitinib regarding the risks for heart-related events, cancer, blood clots, and death. Given that these medications share a similar mechanism of action to tofacitinib, they may have similar risks, though they have not yet been fully evaluated in large safety trials.¹⁷

With more recent investigation into novel therapeutics for AD, oral JAK inhibitors may play an important role in the future to treat patients with moderate to severe AD with inadequate response or contraindications to other systemic therapies. In trials thus far, oral JAK inhibitors have exhibited acceptable safety profiles and have demonstrated treatment success in AD. More randomized, controlled, phase 3 studies with larger patient populations are required to confirm their potential as effective treatments and elucidate their long-term safety.

Deucravacitinib in Psoriasis

Deucravacitinib is a first-in-class, oral, selective TYK2 inhibitor currently undergoing testing for the treatment of psoriasis. A randomized phase 2 trial (N=267) found that deucravacitinib was more effective than placebo in treating chronic plaque psoriasis at doses of 3 to 12 mg daily.¹⁸ The percentage of participants with a 75% or greater reduction from baseline in the psoriasis area and severity index score was 7% with placebo, 9% with deucravacitinib 3 mg every other day (P=.49 vs placebo), 39% with 3 mg once daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). The most commonly reported AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection. Adverse events occurred in 51% of participants in the control group and in 55% to 80% of those in the experimental groups. Additionally, there was 1 reported case of melanoma (stage 0) 96 days after the start of treatment in a patient in the 3-mg once-daily group. Serious AEs occurred in only 0% to 2% of participants who received deucravacitinib.¹⁸

Two phase 3 trials—POETYK PSO-1 and POETYK PSO-2 (N=1686)—found deucravacitinib to be notably more effective than both placebo and apremilast in treating psoriasis.¹⁹ Among participants receiving deucravacitinib 6 mg daily, 58.7% and 53.6% in the 2 respective trials achieved psoriasis area and severity index 75 response vs 12.7% and 9.4% receiving placebo and 35.1% and 40.2% receiving apremilast. Overall, the treatment was well tolerated, with a low rate of discontinuation of deucravacitinib due to AEs (2.4% of patients on deucravacitinib compared to 3.8% on placebo and 5.2% on apremilast). The most frequently observed AEs with deucravacitinib were nasopharyngitis and upper respiratory tract infection. The full results of these trials are expected to be published soon.^19,20

Final Thoughts

Overall, JAK inhibitors are a novel class of therapeutics that may have further success in the treatment of other dermatologic conditions that negatively affect patients’ quality of life and productivity. We should look forward to additional successful trials with these promising medications.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting 7% of adults and 13% of children in the United States.^1,2 Atopic dermatitis is characterized by pruritus, dry skin, and pain, all of which can negatively impact quality of life and put patients at higher risk for psychiatric comorbidities such as anxiety and depression.³ The pathogenesis of AD is multifactorial, involving genetics, epidermal barrier dysfunction, and immune dysregulation. Overactivation of helper T cell (T_H2) pathway cytokines, including IL-4, IL-13, and IL-31, is thought to propagate both inflammation and pruritus, which are central to AD. The JAK-STAT signaling pathway plays a pivotal role in the immune system dysregulation and exaggeration of T_H2 cell response, making JAK-STAT inhibitors (or JAK inhibitors) strong theoretical candidates for the treatment of AD.⁴ In humans, the Janus kinases are composed of 4 different members—JAK1, JAK2, JAK3, and tyrosine kinase 2—all of which can be targeted by JAK inhibitors.⁵

JAK inhibitors such as tofacitinib have already been approved by the US Food and Drug Administration (FDA) to treat various inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis; other JAK inhibitors such as baricitinib are only approved for patients with rheumatoid arthritis.^6,7 The success of these small molecule inhibitors in these immune-mediated conditions make them attractive candidates for the treatment of AD. Several JAK inhibitors are in phase 2 and phase 3 clinical trials as oral therapies (moderate to severe AD) or as topical treatments (mild to moderate AD). Currently, ruxolitinib (RUX) is the only topical JAK inhibitor that is FDA approved for the treatment of AD in the United States.⁸ In this editorial, we focus on recent trials of JAK inhibitors tested in patients with AD, including topical RUX, as well as oral abrocitinib, upadacitinib, and baricitinib.

Topical RUX in AD

Ruxolitinib is a topical JAK1/2 small molecule inhibitor approved by the FDA for the treatment of AD in 2021. In a randomized trial by Kim et al⁹ in 2020, all tested regimens of RUX demonstrated significant improvement in eczema area and severity index (EASI) scores vs vehicle; notably, RUX cream 1.5% applied twice daily achieved the greatest mean percentage change in baseline EASI score vs vehicle at 4 weeks (76.1% vs 15.5%; P<.0001). Ruxolitinib cream was well tolerated through week 8 of the trial, and all adverse events (AEs) were mild to moderate in severity and comparable to those in the vehicle group.⁹

Topical JAK inhibitors appear to be effective for mild to moderate AD and have had an acceptable safety profile in clinical trials thus far. Although topical corticosteroids and calcineurin inhibitors can have great clinical benefit in AD, they are recommended for short-term use given side effects such as thinning of the skin, burning, or telangiectasia formation.^10,11 The hope is that topical JAK inhibitors may be an alternative to standard topical treatments for AD, as they can be used for longer periods due to a safer side-effect profile.

Oral JAK Inhibitors in AD

Several oral JAK inhibitors are undergoing investigation for the systemic treatment of moderate to severe AD. Abrocitinib is an oral JAK1 inhibitor that has demonstrated efficacy in several phase 3 trials in patients with moderate to severe AD. In a 2021 trial, patients were randomized in a 2:2:2:1 ratio to receive abrocitinib 200 mg daily, abrocitinib 100 mg daily, subcutaneous dupilumab 300 mg every other week, or placebo, respectively.¹² Patients in both abrocitinib groups showed significant improvement in AD vs placebo, and EASI-75 response was achieved in 70.3%, 58.7%, 58.1%, and 27.1% of patients, respectively (P<.001 for both abrocitinib doses vs placebo). Adverse events occurred more frequently in the abrocitinib 200-mg group vs placebo. Nausea, acne, nasopharyngitis, and headache were the most frequently reported AEs with abrocitinib.¹² Another phase 3 trial by Silverberg et al¹³ (N=391) had similar treatment results, with 38.1% of participants receiving abrocitinib 200 mg and 28.4% of participants receiving abrocitinib 100 mg achieving investigator global assessment scores of 0 (clear) or 1 (almost clear) vs 9.1% of participants receiving placebo (P<.001). Abrocitinib was well tolerated in this trial with few serious AEs (ie, herpangina [0.6%], pneumonia [0.6%]).¹³ In both trials, there were rare instances of laboratory values indicating thrombocytopenia with the 200-mg dose (0.9%¹² and 3.2%¹³) without any clinical manifestations. Although a decrease in platelets was observed, no thrombocytopenia occurred in the abrocitinib 100-mg group in the latter trial.¹³

Baricitinib is another oral inhibitor of JAK1 and JAK2 with potential for the treatment of AD. One randomized trial (N=329) demonstrated its efficacy in combination with a topical corticosteroid (TCS). At 16 weeks, a higher number of participants treated with baricitinib and TCS achieved investigator global assessment scores of 0 (clear) or 1 (almost clear) compared to those who received placebo and TCS (31% with baricitinib 4 mg + TCS, 24% with baricitinib 2 mg + TCS, and 15% with placebo + TCS).¹⁴ Similarly, in BREEZE-AD5,another phase 3 trial (N=440), baricitinib monotherapy demonstrated a higher rate of treatment success vs placebo.¹⁵ Specifically, 13% of patients treated with baricitinib 1 mg and 30% of those treated with baricitinib 2 mg achieved 75% or greater reduction in EASI scores compared to 8% in the placebo group. The most common AEs associated with baricitinib were nasopharyngitis and headache. Adverse events occurred with similar frequency across both experimental and control groups.¹⁵ Reich et al¹⁴ demonstrated a higher overall rate of AEs—most commonly nasopharyngitis, upper respiratory tract infections, and folliculitis—in baricitinib-treated patients; however, serious AEs occurred with similar frequency across all groups, including the control group.

The selective JAK1 inhibitor upadacitinib also is undergoing testing in treating moderate to severe AD. In one trial, 167 patients were randomized to once daily oral upadacitinib 7.5 mg, 15 mg, or 30 mg or placebo.¹⁶ All doses of upadacitinib demonstrated considerably higher percentage improvements from baseline in EASI scores compared to placebo at 16 weeks with a clear dose-response relationship (39%, 62%, and 74% vs 23%, respectively). In this trial, there were no dose-limiting safety events. Serious AEs were infrequent, occurring in 4.8%, 2.4%, and 0% of upadacitinib groups vs 2.5% for placebo. The serious AEs observed with upadacitinib were 1 case of appendicitis, lower jaw pericoronitis in a patient with a history of repeated tooth infections, and an exacerbation of AD.¹⁶

Tofacitinib, another JAK inhibitor, has been shown to increase the risk for blood clots and death in a large trial in the treatment of rheumatoid arthritis. Following this study, the FDA is requiring black box warnings for tofacitinib and also for the 2 JAK inhibitors baricitinib and upadacitinib regarding the risks for heart-related events, cancer, blood clots, and death. Given that these medications share a similar mechanism of action to tofacitinib, they may have similar risks, though they have not yet been fully evaluated in large safety trials.¹⁷

With more recent investigation into novel therapeutics for AD, oral JAK inhibitors may play an important role in the future to treat patients with moderate to severe AD with inadequate response or contraindications to other systemic therapies. In trials thus far, oral JAK inhibitors have exhibited acceptable safety profiles and have demonstrated treatment success in AD. More randomized, controlled, phase 3 studies with larger patient populations are required to confirm their potential as effective treatments and elucidate their long-term safety.

Deucravacitinib in Psoriasis

Deucravacitinib is a first-in-class, oral, selective TYK2 inhibitor currently undergoing testing for the treatment of psoriasis. A randomized phase 2 trial (N=267) found that deucravacitinib was more effective than placebo in treating chronic plaque psoriasis at doses of 3 to 12 mg daily.¹⁸ The percentage of participants with a 75% or greater reduction from baseline in the psoriasis area and severity index score was 7% with placebo, 9% with deucravacitinib 3 mg every other day (P=.49 vs placebo), 39% with 3 mg once daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). The most commonly reported AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection. Adverse events occurred in 51% of participants in the control group and in 55% to 80% of those in the experimental groups. Additionally, there was 1 reported case of melanoma (stage 0) 96 days after the start of treatment in a patient in the 3-mg once-daily group. Serious AEs occurred in only 0% to 2% of participants who received deucravacitinib.¹⁸

Two phase 3 trials—POETYK PSO-1 and POETYK PSO-2 (N=1686)—found deucravacitinib to be notably more effective than both placebo and apremilast in treating psoriasis.¹⁹ Among participants receiving deucravacitinib 6 mg daily, 58.7% and 53.6% in the 2 respective trials achieved psoriasis area and severity index 75 response vs 12.7% and 9.4% receiving placebo and 35.1% and 40.2% receiving apremilast. Overall, the treatment was well tolerated, with a low rate of discontinuation of deucravacitinib due to AEs (2.4% of patients on deucravacitinib compared to 3.8% on placebo and 5.2% on apremilast). The most frequently observed AEs with deucravacitinib were nasopharyngitis and upper respiratory tract infection. The full results of these trials are expected to be published soon.^19,20

Final Thoughts

Overall, JAK inhibitors are a novel class of therapeutics that may have further success in the treatment of other dermatologic conditions that negatively affect patients’ quality of life and productivity. We should look forward to additional successful trials with these promising medications.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Multicolored (pink, brown, and white) indurated plaques in a butterfly distribution on the face of a 30-year-old woman with a darker skin tone.

B Pink, elevated, indurated plaques with hypopigmentation in a butterfly distribution on the face of a 19-year-old woman with a lighter skin tone.

Cutaneous lupus erythematosus may occur with or without systemic lupus erythematosus. Discoid lupus erythematosus (DLE), a form of chronic cutaneous lupus, is most commonly found on the scalp, face, and ears.¹

Epidemiology

Discoid lupus erythematosus is most common in adult women (age range, 20–40 years).² It occurs more frequently in women of African descent.^3,4

Key clinical features in people with darker skin tones:

Clinical features of DLE lesions include erythema, induration, follicular plugging, dyspigmentation, and scarring alopecia.¹ In patients of African descent, lesions may be annular and hypopigmented to depigmented centrally with a border of hyperpigmentation. Active lesions may be painful and/or pruritic.²

Discoid lupus erythematosus lesions occur in photodistributed areas, although not exclusively. Photoprotective clothing and sunscreen are an important part of the treatment plan.¹ Although sunscreen is recommended for patients with DLE, those with darker skin tones may find some sunscreens cosmetically unappealing due to a mismatch with their normal skin color.⁵ Tinted sunscreens may be beneficial additions.

Worth noting

Approximately 5% to 25% of patients with cutaneous lupus go on to develop systemic lupus erythematosus.⁶

Health disparity highlight

Discoid lesions may cause cutaneous scars that are quite disfiguring and may negatively impact quality of life. Some patients may have a few scattered lesions, whereas others have extensive disease covering most of the scalp. Discoid lupus erythematosus lesions of the scalp have classic clinical features including hair loss, erythema, hypopigmentation, and hyperpigmentation. The clinician’s comfort with performing a scalp examination with cultural humility is an important acquired skill and is especially important when the examination is performed on patients with more tightly coiled hair.⁷ For example, physicians may adopt the “compliment, discuss, and suggest” method when counseling patients.⁸

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Multicolored (pink, brown, and white) indurated plaques in a butterfly distribution on the face of a 30-year-old woman with a darker skin tone.

B Pink, elevated, indurated plaques with hypopigmentation in a butterfly distribution on the face of a 19-year-old woman with a lighter skin tone.

Cutaneous lupus erythematosus may occur with or without systemic lupus erythematosus. Discoid lupus erythematosus (DLE), a form of chronic cutaneous lupus, is most commonly found on the scalp, face, and ears.¹

Epidemiology

Discoid lupus erythematosus is most common in adult women (age range, 20–40 years).² It occurs more frequently in women of African descent.^3,4

Key clinical features in people with darker skin tones:

Clinical features of DLE lesions include erythema, induration, follicular plugging, dyspigmentation, and scarring alopecia.¹ In patients of African descent, lesions may be annular and hypopigmented to depigmented centrally with a border of hyperpigmentation. Active lesions may be painful and/or pruritic.²

Discoid lupus erythematosus lesions occur in photodistributed areas, although not exclusively. Photoprotective clothing and sunscreen are an important part of the treatment plan.¹ Although sunscreen is recommended for patients with DLE, those with darker skin tones may find some sunscreens cosmetically unappealing due to a mismatch with their normal skin color.⁵ Tinted sunscreens may be beneficial additions.

Worth noting

Approximately 5% to 25% of patients with cutaneous lupus go on to develop systemic lupus erythematosus.⁶

Health disparity highlight

Discoid lesions may cause cutaneous scars that are quite disfiguring and may negatively impact quality of life. Some patients may have a few scattered lesions, whereas others have extensive disease covering most of the scalp. Discoid lupus erythematosus lesions of the scalp have classic clinical features including hair loss, erythema, hypopigmentation, and hyperpigmentation. The clinician’s comfort with performing a scalp examination with cultural humility is an important acquired skill and is especially important when the examination is performed on patients with more tightly coiled hair.⁷ For example, physicians may adopt the “compliment, discuss, and suggest” method when counseling patients.⁸

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Multicolored (pink, brown, and white) indurated plaques in a butterfly distribution on the face of a 30-year-old woman with a darker skin tone.

B Pink, elevated, indurated plaques with hypopigmentation in a butterfly distribution on the face of a 19-year-old woman with a lighter skin tone.

Cutaneous lupus erythematosus may occur with or without systemic lupus erythematosus. Discoid lupus erythematosus (DLE), a form of chronic cutaneous lupus, is most commonly found on the scalp, face, and ears.¹

Epidemiology

Discoid lupus erythematosus is most common in adult women (age range, 20–40 years).² It occurs more frequently in women of African descent.^3,4

Key clinical features in people with darker skin tones:

Clinical features of DLE lesions include erythema, induration, follicular plugging, dyspigmentation, and scarring alopecia.¹ In patients of African descent, lesions may be annular and hypopigmented to depigmented centrally with a border of hyperpigmentation. Active lesions may be painful and/or pruritic.²

Discoid lupus erythematosus lesions occur in photodistributed areas, although not exclusively. Photoprotective clothing and sunscreen are an important part of the treatment plan.¹ Although sunscreen is recommended for patients with DLE, those with darker skin tones may find some sunscreens cosmetically unappealing due to a mismatch with their normal skin color.⁵ Tinted sunscreens may be beneficial additions.

Worth noting

Approximately 5% to 25% of patients with cutaneous lupus go on to develop systemic lupus erythematosus.⁶

Health disparity highlight

Discoid lesions may cause cutaneous scars that are quite disfiguring and may negatively impact quality of life. Some patients may have a few scattered lesions, whereas others have extensive disease covering most of the scalp. Discoid lupus erythematosus lesions of the scalp have classic clinical features including hair loss, erythema, hypopigmentation, and hyperpigmentation. The clinician’s comfort with performing a scalp examination with cultural humility is an important acquired skill and is especially important when the examination is performed on patients with more tightly coiled hair.⁷ For example, physicians may adopt the “compliment, discuss, and suggest” method when counseling patients.⁸

Well-demarcated, map-like tongue markings are consistent with migratory glossitis, also called geographic tongue, and can be recognized by its distinct clinical appearance. If performed, a biopsy would show psoriasiform mucositis.

Migratory glossitis is an uncommon condition found mostly in adults and occasionally in children. The prevalence may be as high as 2.5% globally and it may occur in conjunction with psoriasis, sharing some histologic features.¹ (On close inspection, this patient was noted to have plaques on his elbows that were consistent with psoriasis.) While an immunogenic cause is suspected, the exact etiology is unknown.

Patients may develop these clinical findings quickly and just as quickly they may resolve. Discomfort and taste disturbances rarely occur. Hot, spicy, or acidic foods may be a contributing trigger. Tobacco-use appears to be protective. The presence of ulceration should prompt evaluation for a different diagnosis, such as erosive lichen planus, leukoplakia, candidiasis, or Behçet syndrome.

With minimal symptoms, treatment is rarely needed. Patients with any discomfort can be treated with topical lidocaine 2% swish and spit mouthwash, topical tacrolimus, or topical steroids.

The patient in this case was reassured that the diagnosis was not concerning and he was observed without active treatment. His psoriasis was treated with topical clobetasol ointment 0.05%. He has continued to have intermittent flares that he has yet to associate with any specific dietary causes.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Well-demarcated, map-like tongue markings are consistent with migratory glossitis, also called geographic tongue, and can be recognized by its distinct clinical appearance. If performed, a biopsy would show psoriasiform mucositis.

Migratory glossitis is an uncommon condition found mostly in adults and occasionally in children. The prevalence may be as high as 2.5% globally and it may occur in conjunction with psoriasis, sharing some histologic features.¹ (On close inspection, this patient was noted to have plaques on his elbows that were consistent with psoriasis.) While an immunogenic cause is suspected, the exact etiology is unknown.

Patients may develop these clinical findings quickly and just as quickly they may resolve. Discomfort and taste disturbances rarely occur. Hot, spicy, or acidic foods may be a contributing trigger. Tobacco-use appears to be protective. The presence of ulceration should prompt evaluation for a different diagnosis, such as erosive lichen planus, leukoplakia, candidiasis, or Behçet syndrome.

With minimal symptoms, treatment is rarely needed. Patients with any discomfort can be treated with topical lidocaine 2% swish and spit mouthwash, topical tacrolimus, or topical steroids.

The patient in this case was reassured that the diagnosis was not concerning and he was observed without active treatment. His psoriasis was treated with topical clobetasol ointment 0.05%. He has continued to have intermittent flares that he has yet to associate with any specific dietary causes.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Well-demarcated, map-like tongue markings are consistent with migratory glossitis, also called geographic tongue, and can be recognized by its distinct clinical appearance. If performed, a biopsy would show psoriasiform mucositis.

Migratory glossitis is an uncommon condition found mostly in adults and occasionally in children. The prevalence may be as high as 2.5% globally and it may occur in conjunction with psoriasis, sharing some histologic features.¹ (On close inspection, this patient was noted to have plaques on his elbows that were consistent with psoriasis.) While an immunogenic cause is suspected, the exact etiology is unknown.

Patients may develop these clinical findings quickly and just as quickly they may resolve. Discomfort and taste disturbances rarely occur. Hot, spicy, or acidic foods may be a contributing trigger. Tobacco-use appears to be protective. The presence of ulceration should prompt evaluation for a different diagnosis, such as erosive lichen planus, leukoplakia, candidiasis, or Behçet syndrome.

With minimal symptoms, treatment is rarely needed. Patients with any discomfort can be treated with topical lidocaine 2% swish and spit mouthwash, topical tacrolimus, or topical steroids.

The patient in this case was reassured that the diagnosis was not concerning and he was observed without active treatment. His psoriasis was treated with topical clobetasol ointment 0.05%. He has continued to have intermittent flares that he has yet to associate with any specific dietary causes.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

In January 2022, the US Preventive Services Task Force updated its 2018 statement on screening for atrial fibrillation (AF) in older adults (≥ 50 years).^1,2 The supporting evidence review sought to include data on newer screening methods, such as automated blood pressure cuffs, pulse oximeters, and consumer-facing devices (eg, smartphone apps). However, ultimately, the recommendation did not change; it remains an “I” statement, meaning the evidence is insufficient to assess the balance of benefits and harms of screening for AF in asymptomatic adults with no signs or symptoms.^1,2

Atrial fibrillation and stroke. AF is common, and the prevalence increases with age: from < 0.2% in those younger than 55 years to about 10% for those ages 85 and older.^1,2 AF is a strong risk factor for stroke, and when detected, stroke prevention measures—either restoration of normal rhythm or use of anticoagulants—can be implemented as appropriate.

The available evidence for the effectiveness of stroke prevention comes from patients with AF that was detected because of symptoms or pulse palpation during routine care. It is not known if screening asymptomatic adults using electrocardiography, or newer electronic devices that detect irregular heartbeats, achieves these same benefits—and there is the potential for harm from the use of anticoagulants.

How does this compare to other recommendations? The American Heart Association and the American Stroke Association recommend active screening for AF, by pulse assessment, in those ages 65 years and older.³ This does not differ as much as it appears to from the USPSTF statement. The difference is in terminology: The USPSTF considers pulse assessment part of routine care; the other organizations call it “screening.”

What you should—and shouldn’t—do. The USPSTF states that “Clinicians should use their clinical judgement regarding whether to screen and how to screen for AF.” Any patient with signs or symptoms of AF or who is discovered to have an irregular pulse should be assessed for AF. Those found to have AF should be assessed for their risk of stroke and treated accordingly. However, attempting to find “silent” AF in those who do not have an irregular pulse on exam, by way of any screening devices, has no proven benefit.

In January 2022, the US Preventive Services Task Force updated its 2018 statement on screening for atrial fibrillation (AF) in older adults (≥ 50 years).^1,2 The supporting evidence review sought to include data on newer screening methods, such as automated blood pressure cuffs, pulse oximeters, and consumer-facing devices (eg, smartphone apps). However, ultimately, the recommendation did not change; it remains an “I” statement, meaning the evidence is insufficient to assess the balance of benefits and harms of screening for AF in asymptomatic adults with no signs or symptoms.^1,2

Atrial fibrillation and stroke. AF is common, and the prevalence increases with age: from < 0.2% in those younger than 55 years to about 10% for those ages 85 and older.^1,2 AF is a strong risk factor for stroke, and when detected, stroke prevention measures—either restoration of normal rhythm or use of anticoagulants—can be implemented as appropriate.

The available evidence for the effectiveness of stroke prevention comes from patients with AF that was detected because of symptoms or pulse palpation during routine care. It is not known if screening asymptomatic adults using electrocardiography, or newer electronic devices that detect irregular heartbeats, achieves these same benefits—and there is the potential for harm from the use of anticoagulants.

How does this compare to other recommendations? The American Heart Association and the American Stroke Association recommend active screening for AF, by pulse assessment, in those ages 65 years and older.³ This does not differ as much as it appears to from the USPSTF statement. The difference is in terminology: The USPSTF considers pulse assessment part of routine care; the other organizations call it “screening.”

What you should—and shouldn’t—do. The USPSTF states that “Clinicians should use their clinical judgement regarding whether to screen and how to screen for AF.” Any patient with signs or symptoms of AF or who is discovered to have an irregular pulse should be assessed for AF. Those found to have AF should be assessed for their risk of stroke and treated accordingly. However, attempting to find “silent” AF in those who do not have an irregular pulse on exam, by way of any screening devices, has no proven benefit.

In January 2022, the US Preventive Services Task Force updated its 2018 statement on screening for atrial fibrillation (AF) in older adults (≥ 50 years).^1,2 The supporting evidence review sought to include data on newer screening methods, such as automated blood pressure cuffs, pulse oximeters, and consumer-facing devices (eg, smartphone apps). However, ultimately, the recommendation did not change; it remains an “I” statement, meaning the evidence is insufficient to assess the balance of benefits and harms of screening for AF in asymptomatic adults with no signs or symptoms.^1,2

Atrial fibrillation and stroke. AF is common, and the prevalence increases with age: from < 0.2% in those younger than 55 years to about 10% for those ages 85 and older.^1,2 AF is a strong risk factor for stroke, and when detected, stroke prevention measures—either restoration of normal rhythm or use of anticoagulants—can be implemented as appropriate.

The available evidence for the effectiveness of stroke prevention comes from patients with AF that was detected because of symptoms or pulse palpation during routine care. It is not known if screening asymptomatic adults using electrocardiography, or newer electronic devices that detect irregular heartbeats, achieves these same benefits—and there is the potential for harm from the use of anticoagulants.

How does this compare to other recommendations? The American Heart Association and the American Stroke Association recommend active screening for AF, by pulse assessment, in those ages 65 years and older.³ This does not differ as much as it appears to from the USPSTF statement. The difference is in terminology: The USPSTF considers pulse assessment part of routine care; the other organizations call it “screening.”

What you should—and shouldn’t—do. The USPSTF states that “Clinicians should use their clinical judgement regarding whether to screen and how to screen for AF.” Any patient with signs or symptoms of AF or who is discovered to have an irregular pulse should be assessed for AF. Those found to have AF should be assessed for their risk of stroke and treated accordingly. However, attempting to find “silent” AF in those who do not have an irregular pulse on exam, by way of any screening devices, has no proven benefit.

This supplement reviews key aspects of Mycoplasma genitalium and further testing and treatment options for the STI. To read more about this click the link below. 

Click Here to Read More

This supplement reviews key aspects of Mycoplasma genitalium and further testing and treatment options for the STI. To read more about this click the link below. 

Click Here to Read More

This supplement reviews key aspects of Mycoplasma genitalium and further testing and treatment options for the STI. To read more about this click the link below. 

Click Here to Read More

Antiretroviral therapy (ART) regimens provide long-lasting suppression of HIV replication and have helped people with HIV live healthier lives for decades.  

Today's ART regimens are associated with fewer serious and intolerable adverse effects than those used in the past, but weight gain remains a concern in clinical practice. 

In this ReCAP, Dr David Wohl, from the University of North Carolina at Chapel Hill, reports on the relationship between ART and weight gain, as well as the implications of excessive weight gain in HIV management. 

He shares data from multiple studies, including the ADVANCE trial, which offer insight on how different HIV therapies affect patient weight. 

Dr Wohl also discusses the steps clinicians should take if weight gain does occur in people who are on HIV therapy.  

--

Professor of Medicine; Medical Director, UNC COVID-19 Vaccine Clinic, COVID-19 Monoclonal Antibody Infusion Clinic, University of North Carolina at Chapel Hill 

David Wohl, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; ViiV; Janssen; Merck 

Serve(d) as a speaker or a member of a speakers bureau for: Gilead 

Received research grant from: Gilead; Merck; ViiV 

Antiretroviral therapy (ART) regimens provide long-lasting suppression of HIV replication and have helped people with HIV live healthier lives for decades.  

Today's ART regimens are associated with fewer serious and intolerable adverse effects than those used in the past, but weight gain remains a concern in clinical practice. 

In this ReCAP, Dr David Wohl, from the University of North Carolina at Chapel Hill, reports on the relationship between ART and weight gain, as well as the implications of excessive weight gain in HIV management. 

He shares data from multiple studies, including the ADVANCE trial, which offer insight on how different HIV therapies affect patient weight. 

Dr Wohl also discusses the steps clinicians should take if weight gain does occur in people who are on HIV therapy.  

--

Professor of Medicine; Medical Director, UNC COVID-19 Vaccine Clinic, COVID-19 Monoclonal Antibody Infusion Clinic, University of North Carolina at Chapel Hill 

David Wohl, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; ViiV; Janssen; Merck 

Serve(d) as a speaker or a member of a speakers bureau for: Gilead 

Received research grant from: Gilead; Merck; ViiV 

Antiretroviral therapy (ART) regimens provide long-lasting suppression of HIV replication and have helped people with HIV live healthier lives for decades.  

Today's ART regimens are associated with fewer serious and intolerable adverse effects than those used in the past, but weight gain remains a concern in clinical practice. 

In this ReCAP, Dr David Wohl, from the University of North Carolina at Chapel Hill, reports on the relationship between ART and weight gain, as well as the implications of excessive weight gain in HIV management. 

He shares data from multiple studies, including the ADVANCE trial, which offer insight on how different HIV therapies affect patient weight. 

Dr Wohl also discusses the steps clinicians should take if weight gain does occur in people who are on HIV therapy.  

--

Professor of Medicine; Medical Director, UNC COVID-19 Vaccine Clinic, COVID-19 Monoclonal Antibody Infusion Clinic, University of North Carolina at Chapel Hill 

David Wohl, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; ViiV; Janssen; Merck 

Serve(d) as a speaker or a member of a speakers bureau for: Gilead 

Received research grant from: Gilead; Merck; ViiV 

How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.

Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.

This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.

Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,¹ we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.

Psychosis-proneness underlies functional psychoses

Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.^2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”⁴ It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,⁵ each corresponding to a specific anxiety or depressive subtype.

The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.^6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).^5-7

An evolutionary perspective

One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.⁵

More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.⁵ In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counter­intuitive approach may improve our ability to help patients.⁸

Continue to: Five affective comorbidities evolved from primeval altruistic instincts...

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.

Obsessive-compulsive disorder⁵

Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.

Panic anxiety⁵

Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.

Social anxiety⁵

Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.

Atypical depression and bipolar I mania⁵

Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.⁹

Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.⁵

Continue to: Five comorbidity psychoses from 5 primeval instincts.....

The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.^1,10

One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.¹⁰ At least 85% met criteria for ≥1 of the 5 subtypes.¹⁰ Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.¹

Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.^11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.^11,12

Our proposed 5 comorbidity subtypes are¹:

Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.

Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.

Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.¹³ These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.¹⁴ That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.

Box 1

Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).¹⁶ Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.¹⁷ Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.¹⁸

Continue to: Bipolar 1 mania with delusions...

Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.

Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.

Recognizing affective trees in a psychotic forest

Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.^11-13

Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.^11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.

Diagnostic approaches

Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).

Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.¹

Structured interview tools can assist diagnosis. The PaSI (Box 1,¹⁵) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.

Continue to: Treatment by comorbidity subtype...

Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.

The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.^1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.

Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.

Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (consider long-acting injectable formulation for increased compliance). Aripiprazole also may enhance the benefit of fluoxetine for comorbid OCD. Carefully titrate, as tolerated, to optimal dose of fluoxetine (40 to 80 mg/d; the long half-life of fluoxetine and its metabolite norfluoxetine also improves compliance), while watching for activation and other adverse effects.^21,22 Limited clinical experience suggests that lower-dose clonazepam every 12 hours may reduce the adverse effects of fluoxetine.

Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.²³ Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).¹⁴ Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.

Persecutory delusional disorder. Anti­psychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.

Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.

Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).²⁴

Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.²⁵ Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.²⁵ However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.

Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.

To illustrate this new approach to psychosis diagnosis and treatment, our book¹ includes detailed case studies on each of the 5 psychosis subtypes. The brief fictional case we present in Box 2 describes a patient who had both premorbid social anxiety and panic anxiety, and then developed a mixed psychosis that reflected both of those contributing anxiety disorders.

Box 2

Larger studies are needed

Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.

Bottom Line

New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.

How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.

Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.

This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.

Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,¹ we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.

Psychosis-proneness underlies functional psychoses

Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.^2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”⁴ It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,⁵ each corresponding to a specific anxiety or depressive subtype.

The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.^6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).^5-7

An evolutionary perspective

One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.⁵

More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.⁵ In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counter­intuitive approach may improve our ability to help patients.⁸

Continue to: Five affective comorbidities evolved from primeval altruistic instincts...

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.

Obsessive-compulsive disorder⁵

Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.

Panic anxiety⁵

Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.

Social anxiety⁵

Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.

Atypical depression and bipolar I mania⁵

Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.⁹

Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.⁵

Continue to: Five comorbidity psychoses from 5 primeval instincts.....

The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.^1,10

One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.¹⁰ At least 85% met criteria for ≥1 of the 5 subtypes.¹⁰ Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.¹

Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.^11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.^11,12

Our proposed 5 comorbidity subtypes are¹:

Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.

Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.

Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.¹³ These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.¹⁴ That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.

Box 1

Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).¹⁶ Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.¹⁷ Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.¹⁸

Continue to: Bipolar 1 mania with delusions...

Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.

Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.

Recognizing affective trees in a psychotic forest

Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.^11-13

Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.^11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.

Diagnostic approaches

Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).

Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.¹

Structured interview tools can assist diagnosis. The PaSI (Box 1,¹⁵) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.

Continue to: Treatment by comorbidity subtype...

Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.

The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.^1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.

Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.

Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (consider long-acting injectable formulation for increased compliance). Aripiprazole also may enhance the benefit of fluoxetine for comorbid OCD. Carefully titrate, as tolerated, to optimal dose of fluoxetine (40 to 80 mg/d; the long half-life of fluoxetine and its metabolite norfluoxetine also improves compliance), while watching for activation and other adverse effects.^21,22 Limited clinical experience suggests that lower-dose clonazepam every 12 hours may reduce the adverse effects of fluoxetine.

Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.²³ Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).¹⁴ Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.

Persecutory delusional disorder. Anti­psychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.

Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.

Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).²⁴

Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.²⁵ Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.²⁵ However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.

Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.

To illustrate this new approach to psychosis diagnosis and treatment, our book¹ includes detailed case studies on each of the 5 psychosis subtypes. The brief fictional case we present in Box 2 describes a patient who had both premorbid social anxiety and panic anxiety, and then developed a mixed psychosis that reflected both of those contributing anxiety disorders.

Box 2

Larger studies are needed

Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.

Bottom Line

New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.

How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.

Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.

This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.

Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,¹ we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.

Psychosis-proneness underlies functional psychoses

Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.^2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”⁴ It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,⁵ each corresponding to a specific anxiety or depressive subtype.

The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.^6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).^5-7

An evolutionary perspective

One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.⁵

More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.⁵ In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counter­intuitive approach may improve our ability to help patients.⁸

Continue to: Five affective comorbidities evolved from primeval altruistic instincts...

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.

Obsessive-compulsive disorder⁵

Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.

Panic anxiety⁵

Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.

Social anxiety⁵

Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.

Atypical depression and bipolar I mania⁵

Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.⁹

Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.⁵

Continue to: Five comorbidity psychoses from 5 primeval instincts.....

The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.^1,10

One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.¹⁰ At least 85% met criteria for ≥1 of the 5 subtypes.¹⁰ Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.¹

Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.^11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.^11,12

Our proposed 5 comorbidity subtypes are¹:

Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.

Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.

Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.¹³ These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.¹⁴ That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.

Box 1

Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).¹⁶ Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.¹⁷ Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.¹⁸

Continue to: Bipolar 1 mania with delusions...

Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.

Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.

Recognizing affective trees in a psychotic forest

Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.^11-13

Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.^11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.

Diagnostic approaches

Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).

Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.¹

Structured interview tools can assist diagnosis. The PaSI (Box 1,¹⁵) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.

Continue to: Treatment by comorbidity subtype...

Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.

The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.^1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.

Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.

Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (consider long-acting injectable formulation for increased compliance). Aripiprazole also may enhance the benefit of fluoxetine for comorbid OCD. Carefully titrate, as tolerated, to optimal dose of fluoxetine (40 to 80 mg/d; the long half-life of fluoxetine and its metabolite norfluoxetine also improves compliance), while watching for activation and other adverse effects.^21,22 Limited clinical experience suggests that lower-dose clonazepam every 12 hours may reduce the adverse effects of fluoxetine.

Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.²³ Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).¹⁴ Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.

Persecutory delusional disorder. Anti­psychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.

Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.

Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).²⁴

Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.²⁵ Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.²⁵ However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.

Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.

To illustrate this new approach to psychosis diagnosis and treatment, our book¹ includes detailed case studies on each of the 5 psychosis subtypes. The brief fictional case we present in Box 2 describes a patient who had both premorbid social anxiety and panic anxiety, and then developed a mixed psychosis that reflected both of those contributing anxiety disorders.

Box 2

Larger studies are needed

Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.

Bottom Line

New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.

Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.

Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.

T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.¹ This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.

Metformin exerts its hypoglycemic effects by:

• decreasing glucose production from the liver
• increasing insulin receptors’ sensitivity in various body tissues
• increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.

In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.² In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.

The adverse effects of metformin are dose-related and mostly gastro­intestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.

The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.

Metabolic benefits

• Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.³
• Decreasing weight, body mass index, and waist circumference with the use of clozapine.⁴
• Decreasing triglycerides and total cholesterol.⁵
• Mitigating clozapine-induced obesity, especially if used prophylactically.⁶
• Lowering antipsychotic-induced weight gain.⁷

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

• Lowering elevated serum prolactin levels to avert sexual dysfunction.^8-10
• Increasing the production of neurons by inducing neurogenesis.^11,12
• Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.¹³
• Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.¹⁴
• Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.¹⁵
• Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.¹⁶
• Exerting multiple anti-aging effects (Table¹⁷). Metformin reduces several hallmarks of aging and may increase longevity.¹⁷
• Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes¹⁸ due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
• Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.¹⁹

Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.²⁰ So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”

Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.

Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.

T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.¹ This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.

Metformin exerts its hypoglycemic effects by:

• decreasing glucose production from the liver
• increasing insulin receptors’ sensitivity in various body tissues
• increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.

In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.² In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.

The adverse effects of metformin are dose-related and mostly gastro­intestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.

The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.

Metabolic benefits

• Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.³
• Decreasing weight, body mass index, and waist circumference with the use of clozapine.⁴
• Decreasing triglycerides and total cholesterol.⁵
• Mitigating clozapine-induced obesity, especially if used prophylactically.⁶
• Lowering antipsychotic-induced weight gain.⁷

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

• Lowering elevated serum prolactin levels to avert sexual dysfunction.^8-10
• Increasing the production of neurons by inducing neurogenesis.^11,12
• Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.¹³
• Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.¹⁴
• Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.¹⁵
• Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.¹⁶
• Exerting multiple anti-aging effects (Table¹⁷). Metformin reduces several hallmarks of aging and may increase longevity.¹⁷
• Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes¹⁸ due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
• Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.¹⁹

Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.²⁰ So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”

Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.

Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.

T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.¹ This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.

Metformin exerts its hypoglycemic effects by:

• decreasing glucose production from the liver
• increasing insulin receptors’ sensitivity in various body tissues
• increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.

In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.² In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.

The adverse effects of metformin are dose-related and mostly gastro­intestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.

The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.

Metabolic benefits

• Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.³
• Decreasing weight, body mass index, and waist circumference with the use of clozapine.⁴
• Decreasing triglycerides and total cholesterol.⁵
• Mitigating clozapine-induced obesity, especially if used prophylactically.⁶
• Lowering antipsychotic-induced weight gain.⁷

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

• Lowering elevated serum prolactin levels to avert sexual dysfunction.^8-10
• Increasing the production of neurons by inducing neurogenesis.^11,12
• Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.¹³
• Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.¹⁴
• Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.¹⁵
• Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.¹⁶
• Exerting multiple anti-aging effects (Table¹⁷). Metformin reduces several hallmarks of aging and may increase longevity.¹⁷
• Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes¹⁸ due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
• Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.¹⁹

Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.²⁰ So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”