Depression

Rakesh Jain, MD, MPH

Clinical Professor
Department of Psychiatry

Texas Tech Health Sciences Center, School of Medicine

Midland, Texas

Recent Evidence for Treatment Augmentation
With Second-Generation Antipsychotics
in Major Depressive Disorder

Supported by an educational grant from Otsuka and Lundbeck Alliance

 

 

 

 

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Disclosures

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity:

Rakesh Jain, MD, MPH, has disclosed that he has received consulting fees from Acadia, Alfasigma, Alkermes, Allergan, Eisai, Evidera, Impel, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine, Osmotica, Otsuka, Pamlab, Pfizer, Shire, Sunovion, Supernus, Takeda, and Teva; has received fees for non-CME services from Alkermes, Allergan, Ironshore, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine, Otsuka, Pamlab, Pfizer, Shire, Sunovion, Takeda, Teva, and Tris; has received funds for research support from Allergan, Lilly, Lundbeck, Otsuka, Pfizer, Shire, and Takeda; and that his spouse/partner has received consulting fees from Lilly, Otsuka, Pamlab, and Sunovion and fees for non-CME services from Lilly.

 

 

 

Partial Response and Nonresponse to Antidepressant Treatment

Partial Response
(or Response)

●Improvement of symptoms

●≥ 50% decrease in HAM‐D or MADRS

 

Relapse

●Return of symptoms after remission

Recurrence

●Return of symptoms after recovery

McIntyre. Clin Ther. 2006;28:1882. Zimmerman. J Psychiatr Res. 2004;38:577.
Saltiel. Neuropsychiatr Dis Treat. 2015;11:875. Lenox-Smith. J Affect Disord. 2014;169:149.

Remission

●Return to “wellness” or disappearance of symptoms

●Most frequently measured as HAM‐D ≤ 7 or MADRS ≤ 10

Recovery

●Remission for ≥ 2 mos

 

 

Slide credit: clinicaloptions.com

“Normalcy”

Symptoms

Syndrome

Remission

Response

Relapse

Recovery

Recurrence

Relapse/
recurrence

Remission/recovery

Relapse/
recurrence

First episode

Second episode

Third episode

Loading…

 

 

When MDD Treatment Fails

●In 30% to 45% of patients, remission is not achieved
with a single antidepressant, even at adequate dosage
and period[1]

‒Antidepressant efficacy decreases with successive trials[2]

‒More than 2 failed trials: treatment-resistant depression

 

Slide credit: clinicaloptions.com

1. Fava. J Clin Psychiatry. 2000;61 Suppl 1:26. 2. Rush. Am J Psychiatry. 2006;163:1905. 3. Russell. J Clin Psychiatry. 2004;65:341.

30%

70%

 

 

 

Level 4: Consider

●MAOI augmentation
(AVOID CONTRAINDICATED COMBINATIONS)

●FL-methylfolate triple drug combinations*

   SSRI/ SNRI + mirtazapine + bupropion

   SSRI/SNRI + mirtazapine + lithium

   SSRI/SNRI + bupropion + second-    generation antipsychotic

*Little evidence to support/refute this approach

MDD Treatment Augmentation: Florida Best Practice Psychotherapeutic Medication Guidelines

Level 1: Monotherapy

SSRI

SNRI

Vortioxetine

Bupropion

Mirtazapine

 

 

Level 2: Add

●Evidence-based psychotherapy

●Second-generation antipsychotic FDA-approved as adjunctive treatment for MDD

●Intranasal esketamine or intravenous racemic ketamine

●Another antidepressant (do not combine SSRI and SNRI)

Level 3: SSRI/SNRI +  

●Lithium

●T3

●L-methylfolate

●S-adenosylmethionine

●Quetiapine (tolerability concerns)

Slide credit: clinicaloptions.com

 

●McIntyre. J Clin Psychiatry 2017;78:703.

 

 

 

 

MDD Treatment Augmentation:
Second-Generation Antipsychotics

1. Aripiprazole PI. 2. Olanzapine/fluoxetine PI. 3. Quetiapine XR PI. 4. Brexpiprazole PI.

Agent

FDA Approval for MDD Treatment Augmentation

Aripiprazole[1]

2007

Olanzapine/ fluoxetine[2]

2009

Quetiapine XR[3]

2009

Brexpiprazole[4]

2015

Slide credit: clinicaloptions.com

Agent

FDA Approval for MDD Treatment Augmentation

Asenapine

No

Clozapine

No

Cariprazine

No

Iloperidone

No

Lumateperone

No

Lurasidone

No

Paliperidone

No

Risperidone

No

Sulpiride

No

Ziprasidone

No

 

 

 

 

MDD Treatment Augmentation With
Second-Generation Antipsychotics: Considerations

Efficacy

●Best studied strategy, good efficacy[1]

●FDA approved options

●Included in guideline recommendations[2]

 

 

Tolerability (varies by agent)[3]

●Neuroendocrine

‒Prolactin

●Metabolic

‒Weight, lipids, glucose regulation

●Extrapyramidal symptoms

‒Tardive dyskinesia, neuroleptic malignant syndrome, akathisia, parkinsonism, dystonic reactions

 

1. Papakostas. J Clin Psychiatry. 2009;70 Suppl 6:16. 2. McIntyre. J Clin Psychiatry 2017;78:703.

3. Keepers. APA Practice Guideline. 2020. https://www.psychiatry.org/psychiatrists/practice/clinical-practice-guidelines.

Slide credit: clinicaloptions.com

 

 

 

 

CCO Online Interactive Treatment Decision Support Tool for MDD Treatment

●Enter specific patient characteristics and get recommendations from a panel of 5 experts

‒Leslie Citrome, MD, MPH

‒Christoph U. Correll, MD

‒Rakesh Jain, MD, MPH

‒Roger McIntyre, MD, FRCPC

‒Michael E. Thase, MD

 

Slide credit: clinicaloptions.com

Available at clinicaloptions.com/AdvancingMDDTreatment

 

 

 

 

Expert Recommendations for Case: Patient Not in Remission but ≥ 25% Symptom Improvement

Slide credit: clinicaloptions.com

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Khullar 2006

Mattingly 2006

McIntyre 2006

Earley 2007

El-Khalili 2008

MDD Treatment Augmentation With
Second-Generation Antipsychotics: 2009 Meta-Analysis

●Meta-analysis of 16 randomized, placebo-controlled trials of adjunctive second-generation antipsychotics in patients with treatment-resistant major depressive disorder (N = 3480)

Slide credit: clinicaloptions.com

Nelson. Am J Psychiatry. 2009;166:980.

 

 

Test for overall effect

Response Rate

Fixed OR (95% CI)   P Value

1.39 (1.05-1.84)   .02

1.83 (1.18-2.82)   .007

1.60 (1.24-2.08)   .0004

Thase 2006          

Shelton 2001          

Shelton 2005        

Corya 2006            

Thase II 2006          

2.07 (1.58-2.72)   < .00001

1.69 (1.46-1.95)   .00001

Berman 2007              

Marcus 2008          

Berman 2008              

Mahmoud 2007        

Keitner 2009      

Reeves 2008      

Subtotal          

Subtotal          

Subtotal          

Subtotal          

0.5

1

2

5

10

Favors Control

Favors Treatment

Treatment, N

Control, N

181

185

174

540

172

184

169

525

8

24

29

327

289

677

7

13

29

160

143

352

137

62

12

211

131

33

11

175

10

146

230

102

98

586

10

142

56

104

102

414

2014

1466

 

All agents:

●More effective than placebo

‒No differences in ORs among agents

●Had higher rates of discontinuation for adverse events than did placebo

 

Quetiapine

Risperidone

Olanzapine

Aripiprazole

 

 

 

 

Quetiapine XR (250-400 mg)

1.85

(0.19 to 7.14)

1.85

(0.79 to 3.57)

0.99

(0.36 to 4.00)

1.45

(0.42 to 9.09)

1.54

(0.57 to 6.25)

5.68

(1.38 to 90.42)

6.40

(2.94 to 17.83)

-0.03

(-0.49 to 0.38)

Risperidone

0.57

(0.18 to 3.62)

0.30

(0.09 to 2.05)

0.73

(0.22 to 4.78)

0.52

(0.16 to 3.47)

2.10

(0.47 to 43.16)

2.37

(0.87 to 11.14)

-0.06

(-0.34 to 0.19)

-0.04

(-0.45 to 0.41)

Quetiapine XR (150-250 mg)

1.09

(0.12 to 1.42)

0.85

(0.25 to 5.26)

0.90

(0.34 to 3.57)

3.32

(0.81 to 52.63)

3.73

(1.77 to 10.13)

-0.12

(-0.48 to 0.16)

-0.10

(-0.51 to 0.29)

-0.06

(-0.40 to 0.22)

Aripiprazole (Standard)

0.51

(0.12 to 1.42)

0.87

(0.22 to 2.36)

7.59

(0.60 to 37.02)

2.72

(1.34 to 6.82)

-0.16

(-0.59 to 0.17)

-0.14

(-0.60 to 0.29)

-0.10

(-0.51 to 0.24)

-0.04

(-0.34 to 0.24)

Aripiprazole (Low)

1.25

(0.21 to 4.26)

10.26

(0.58 to 53.19)

2.88

(1.00 to 12.96)

-0.16

(-0.51 to 0.13)

-0.14

(-0.54 to 0.27)

-0.10

(-0.43 to 0.20)

-0.04

(-0.30 to 0.25)

0

(-0.32 to 0.36)

Olanzapine/
Fluoxetine (Standard)

8.53

(1.08 to 36.67)

3.52

(1.74 to 8.48)

-0.40

(-0.91 to 0.06)

-0.38

(-0.92 to 0.17)

-0.34

(-0.83 to 0.13)

-0.28

(-0.72 to 0.18)

-0.24

(-0.72 to 0.27)

-0.24

(-0.64 to 0.16)

Olanzapine/
Fluoxetine (Low)

0.43

(0.09 to 4.05)

-0.43

(-0.72 to -0.21)

-0.41

(-0.77 to -0.06)

-0.37

(-0.64 to -0.14)

-0.31

(-0.49 to -0.12)

-0.27

(-0.53 to 0.01)

-0.27

(-0.48 to -0.08)

-0.03

(-0.45 to 0.38)

Placebo

MDD Treatment Augmentation With
Second-Generation Antipsychotics: 2015 Meta-Analysis

●Meta-analysis of 18 randomized, placebo-controlled trials of adjunctive second-generation antipsychotics at standard and low doses in patients with treatment-resistant major depressive disorder (N = 4422)

Zhou. Int J Neuropsychopharmacol. 2015;18:pyv060.

Slide credit: clinicaloptions.com

Efficacy by Depression Symptom Score, standardized mean differences (95% CI)

 

 

Tolerability by OR of adverse event discontinuation (95% CI)

All standard-dose agents:

●More effective than placebo

●Had higher rates of discontinuation for adverse events than did placebo

 

 

 

MDD Treatment Augmentation With Second-Generation Antipsychotics: Efficacy by Degree of Resistance

●Meta-analysis of 11 randomized, controlled trials of adjunctive second-generation antipsychotics in patients with treatment-resistant MDD (N = 3341)

Wang. Int J Neuropsychopharmacol. 2015;18:pyv023.

●Improved efficacy with increasing rates of resistance

Slide credit: clinicaloptions.com

History of Treatment Failures:

Meta-Regression of Response Rate

0

2

2 to 4

Response, log of Risk Ratio

.2

.3

.4

.5

.6

 

 

 

 

MDD Treatment Augmentation: Key Studies of
Second-Generation Antipsychotics

1. Berman. J Clin Psychiatry. 2007;68:843. 2. Tohen. J Clin Psychiatry. 2010;71:451.
3. El-Khalili. Int J Neuropsychopharmacol. 2010;13:917. 4. Thase. J Clin Psychiatry. 2015;76:1224.

 

 

 

N

Mean Change in MADRS After 6 Wks

Agent

Comparator

MDD Population

Treatment

Comparator

Treatment

Comparator

P value

Aripiprazole + antidepressant[1]

Placebo

Incomplete response

184

178

-8.80

-5.80

< .001

Olanzapine/ fluoxetine[2]

Fluoxetine

Treatment resistant

462

342

-12.28

-8.48

< .001

Olanzapine/ fluoxetine[2]

Olanzapine

Treatment resistant

462

342

-12.28

-8.52

< .001

Quetiapine XR + antidepressant[3]

Placebo

Inadequate response

148*

148

-14.70*

-11.70

< .01

Brexpiprazole + antidepressant[4]

Placebo

Inadequate response

175

178

-8.36

-5.15

.0002

Slide credit: clinicaloptions.com

*300 mg/day.

All are superior to placebo, but none has been shown to be superior to others

 

 

 

MDD Treatment Augmentation With Aripiprazole

●Multicenter, randomized, double-blind, placebo-controlled phase III study in patients with MDD and incomplete response to antidepressant therapy (N = 362)

*

*

*

*

*

Wk

Berman. J Clin Psychiatry. 2007;68:843.

Slide credit: clinicaloptions.com

Placebo +
SSRI
(n = 172)

Aripiprazole +
SSRI
(n = 181)

 

0

-2

-4

-6

-8

-10

-12

-14

-16

Baseline

1

2

3

4

5

6

 

 

 

 

 

 

 

Mean Change
in MADRS Total Score

*P < .001

 

 

 

MDD Treatment Augmentation With Aripiprazole: Safety

Berman. J Clin Psychiatry. 2007;68:843.

Slide credit: clinicaloptions.com

Adverse Events, n (%)

Aripiprazole +

Antidepressant (n = 182)

Placebo +

Antidepressant  (n = 176)

Any

149 (81.9)

110 (62.5)

Akathisia

42 (23.1)

8 (4.5)

Restlessness

26 (14.3)

6 (3.4)

Upper respiratory tract infection

15 (8.2)

7 (4.0)

Insomnia

14 (7.7)

4 (2.3)

Blurred vision

12 (6.6)

3 (1.7)

Fatigue

11 (6.0)

6 (3.4)

Headache

11 (6.0)

19 (10.8)

Diarrhea

6 (3.3)

10 (5.7)

Dry mouth

6 (3.3)

11 (6.3)

Nausea

5 (2.7)

9 (5.1)

 

 

 

Olanzapine/Fluoxetine in Treatment-Resistant MDD

Tohen. J Clin Psychiatry. 2010;71:451.

Slide credit: clinicaloptions.com

●Pooled analysis of 5 outpatient studies of olanzapine/fluoxetine in patients with treatment-resistant MDD (N = 1146)

*P < .001 vs fluoxetine

†P ≤ .011 vs olanzapine

*

 

*

*

*

*

*

Fluoxetine
(n = 203)

Olanzapine
(n = 197)

Olanzapine/fluoxetine
combination
(n = 198)

Wk

0

-2

-4

-6

-8

-10

-12

-14

-16

Baseline

1

2

3

4

5

6

 

 

 

 

 

 

 

7

8

*

*

*

Mean Change
in MADRS Total Score

 

 

 

 

 

 

Olanzapine/Fluoxetine in Treatment Resistant MDD: Safety

Tohen. J Clin Psychiatry. 2010;71:451.

Slide credit: clinicaloptions.com

Adverse Events, %

Olanzapine/ Fluoxetine

(n = 462)

Fluoxetine

(n = 342)

Olanzapine

(n = 342)

P Values

Overall

Olanzapine/ Fluoxetine

vs Fluoxetine

Olanzapine/ Fluoxetine

vs Olanzapine

Increase weight

35.0

6.8

39.7

< .001

< .001

.353

Increased appetite

32.0

5.8

30.7

< .001

< .001

.829

Dry mouth

28.5

8.7

31.7

< .001

< .001

.514

Somnolence

17.5

5.3

12.1

< .001

< .001

.158

Fatigue

14.0

7.8

14.1

.070

.055

1.00

Headache

12.5

19.4

13.1

.103

.060

.882

Peripheral edema

12.0

1.0

7.5

< .001

< .001

.177

Hypersomnia

10.5

2.4

11.1

< .001

< .001

.873

Tremor

10.5

8.7

8.0

.686

.615

.490

 

 

 

MDD Treatment Augmentation With Quetiapine XR

●Multicenter, randomized, double-blind, placebo-controlled phase III study of in patients with MDD and incomplete response to antidepressant therapy (N = 446)

El-Khalali. Int J Neuropsychopharmacology. 2010;13:917.

Slide credit: clinicaloptions.com

 

*

Wk

0

-2

-4

-6

-8

-10

-12

-14

-16

Baseline

1

2

3

4

5

6

 

 

 

 

Placebo + antidepressant
(n = 143)

Quetiapine XR
150 mg/day + antidepressant
(n = 143)

Quetiapine XR
300 mg/day + antidepressant
(n = 146)

 

Mean Change
in MADRS Total Score

*P < .05

†P < .01

‡P < .001

(all vs placebo)

 

 

 

MDD Treatment Augmentation With Quetiapine XR: Safety

El-Khalali. Int J Neuropsychopharmacology. 2010;13:917.

Slide credit: clinicaloptions.com

Adverse Events, n (%)

Quetiapine XR 150 mg +

Antidepressant (n = 148)

Quetiapine XR 300 mg +

Antidepressant (n = 149)

Placebo +

Antidepressant (n = 148)

Dry mouth

52 (35.1)

66 (44.3)

13 (8.8)

Somnolence

43 (29.1)

43 (28.9)

6 (4.1)

Sedation

25 (16.9)

33 (22.1)

6 (4.1)

Dizziness

17 (11.5)

21 (14.1)

8 (5.4)

Constipation

11 (7.4)

16 (10.7)

5 (3.4)

Nausea

13 (8.8)

15 (10.1)

12 (8.1)

Headache/fatigue

16 (10.8)/23 (15.5)

11 (7.4)/10 (6.7)

20 (13.5)/7 (4.7)

Diarrhea

10 (6.8)

10 (6.7)

10 (6.8)

Increased appetite

8 (5.4)

10 (6.7)

8 (5.4)

Increased weight

3 (2.0)

9 (6.0)

1 (0.7)

Irritability

9 (6.1)

5 (3.4)

9 (6.1)

Insomnia

16 (10.8)

12 (8.1)

10 (6.8)

 

 

 

*

 

 

 

MDD Treatment Augmentation With Brexpiprazole

●Randomized, placebo-controlled phase III study of adjunctive brexpiprazole in patients with MDD and incomplete response to antidepressant therapy (N = 353)

Thase. J Clin Psychiatry. 2015;76:1224.

Slide credit: clinicaloptions.com

Mean (SE) Change
in MADRS Total Score

Wk

0

-2

-4

-6

-8

-10

-12

-14

-16

Baseline

1

2

3

4

5

6

 

 

 

 

Placebo +
antidepressant
(n = 178)

Brexpiprazole + antidepressant
(n = 175)

 

*P < .05

†P < .01

‡P < .001

(all vs placebo)

 

 

 

MDD Treatment Augmentation With Brexpiprazole: Safety

Thase. J Clin Psychiatry. 2015;76:1224.

Slide credit: clinicaloptions.com

Treatment-Related Adverse Events, n (%)

Brexpiprazole +

Antidepressant

(n = 188)

Placebo +

Antidepressant

(n = 191)

≥ 1 treatment-related adverse event

111 (59.0)

89 (46.6)

Serious adverse events

2 (1.1)

2 (1.0)

Discontinuation due to treatment-related adverse event

6 (3.2)

0

Treatment-related adverse event occurring in ≥ 5% of brexpiprazole group

●Weight gain

●Akathisia

 

15 (8.0)

14 (7.4)

 

6 (3.1)

2 (1.0)

 

 

 

 

 

 

 

*Odds ratios based on multivariable logistic regression with adherence as dependent variable.

Antipsychotics: Impact of AEs on Adherence

●Survey of N = 876 community-dwelling people with schizophrenia

DiBonaventura. BMC Psychiatry. 2012;12:20.

Slide credit: clinicaloptions.com

Likelihood of Complete Adherence

Agitation

Tremors

Restlessness/feeling jittery

Insomnia

Increased blood glucose levels

Weight gain

Painful menstrual periods

Gynecomastia and galactorrhea

Decreased interest in sex

Sexual dysfunction

Sedation

Difficulty thinking/concentrating

Sleepiness

Dizziness

Nausea/vomiting

Constipation

0

1.0

0.5

1.5

2.0

2.5

3.0

3.5

Adjusted Odds Ratios

Reduced Adherence

EPS/agitation

OR: 0.57

Metabolic

OR: 0.64

Prolactin/endocrine

OR: 0.69

Sedation/cognition

OR: 0.70

Gastrointestinal

OR: 0.79

Adverse Event Clusters*

Reduced Adherence

 

 

 

Second-Generation Antipsychotics: Weight Gain Among Adults in Short-term Randomized Controlled Studies

Slide credit: clinicaloptions.com

 

Weight Gain ≥ 7% of Baseline

Medication[1]

Schizophrenia

Bipolar Mania

MDD

Bipolar Depression

Iloperidone

10

Asenapine

35

19

Lurasidone

67

58[2]

Brexpiprazole

17

52

Cariprazine (≤ 6 mg/day)

34

No difference

Aripiprazole

21

No difference

22

Olanzapine/fluoxetine

6

6

3

6[2,3]

Paliperidone

35

Quetiapine IR

6

8

16[2]

Quetiapine XR

22

20

29

16[2]

Risperidone (≤ 8 mg/day)

18

18

Ziprasidone

16

58

1. Citrome. Int J Clin Pract. 2015;69:1211. 2. Citrome. CNS Spectr. 2014;19(suppl 1):4. 3. Citrome. Expert Opin Pharmacother. 2011;12:2751.

 

 

 

 

Second-Generation Antipsychotics: Metabolic AEs

●Systematic review and network analysis of 100 randomized, controlled trials
of 18 antipsychotics in schizophrenia (N = 25,952)

 

 

 

 

 

Subset of Agents FDA Approved in MDD Augmentation

P-Score Ranking of AEs From 0 to 1*

Weight Increase

Glucose
Increase

LDL-C
Increase

Total C
Increase

HDL-C Decrease

TG
Increase

Aripiprazole

.26

.55

.48

.50

.26

.33

Brexpiprazole

.45

.40

.66

.52

.18

.23

Quetiapine XR

.65

.47

.91

.82

.59

.71

Olanzapine/fluoxetine

.92

.67

.96

.91

.76

.83

Pillinger. Lancet Psychiatry. 2020;7:64.

Slide credit: clinicaloptions.com

*P-score ≥ .50 shown in red.

 

 

Antipsychotic-Associated Weight Gain:
Pharmacologic Interventions

●Meta-analysis of 32 randomized, controlled trials of 15 different medications (N = 1482)

Weighted Mean Difference in Bodyweight Change, kg (95% CI)

Favors Placebo

Favors Intervention

4

2

0

-2

6

-4

-6

Metformin + Sibutramine

 

 

 

 

 

 

 

 

 

 

 

 

 

Famotidine

Dextroamphetamine

Fluoxetine

Rosiglitazone

Orlistat

Nizatidine

Amantadine

Reboxetine

Topiramate

Sibutramine

D-Fenfluramine

Metformin

Maayan. Neuropsychopharmacology. 2010;35:1520.

Slide credit: clinicaloptions.com

Significant difference vs placebo

 

 

 

AEs: Medical Risk Prevention Strategies

At Treatment Initiation

(Primary Prevention)

●Healthy lifestyle counseling/intervention

●Start with lower-risk antipsychotic

Slide credit: clinicaloptions.com

Correll. CNS Spectr. 2007;12:12.

If AE is Present

(Secondary Prevention)

●Healthy lifestyle counseling/intervention

●Consider changing to lower-risk antipsychotic

●Consider weight loss intervention

If AE Progresses/Serious

(Tertiary Prevention)

●Healthy lifestyle counseling/intervention

●Consider changing to lower-risk antipsychotic

●Add targeted treatment for pathological values

●Consider referral to specialist

 

 

 

Algorithm to Manage Treatment-Emergent Akathisia

Salem. Current Neuropharmacol. 2017;15:789.

Slide credit: clinicaloptions.com

Reduce dose

Change

antipsychotic

Switch to low
potency first-generation

antipsychotic

Switch to second-generation

antipsychotic with

lower akathisia potential
(eg, quetiapine)

Add antiakathisia

agent

First line

Second line

Switch to clozapine

Beta-blockers:

Propranolol

(40-80 mg/day)

5-HT2A antagonist:
Mirtazapine (15 mg/day)

Anticholinergics (mainly with parkinsonism):

Biperiden (2-6 mg/day)

Benztropine (1.5-8 mg/day)

Trihexyphenidyl (2-10 mg/day)

Amantadine (100 mg/day)
Clonidine (up to 0.15 mg/day)

Benzodiazepines:

Lorazepam (1-2 mg/day)

Clonazepam (0.5-1 mg/day)

Diazepam (5-15 mg/day)

5-HT2A antagonist:
Mianserin (up to 0.15 mg/day)

Cyproheptadine (8-16 mg/day)

Akathisia in schizophrenia and mood disorders

My approach in MDD augmentation:
avoid unapproved antipsychotics

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Expert Recommendations for Treatment Augmentation:
Activation/Akathisia Concerns

Slide credit: clinicaloptions.com

 

 

 

Second-Generation Antipsychotics: Sexual AEs

1. Kristensen E. Dan Med Bull. 2002;49:349. 2. Fava. Prim Care Companion CNS Disord. 2011;13:PCC.10m00994. 3. Pillinger. Lancet Psychiatry. 2020;7:64. 4. Brexpiprazole Prescribing Information.

 

Slide credit: clinicaloptions.com

Symbols: ↓ = inhibits/reduces; ↑ = promotes/increases.

●Review based on few systemic studies[1]

 

 

 

 

 

●Aripiprazole, brexpiprazole also associated with sedation and weight gain,
but no evidence of sexual dysfunction in registration trials[2-4]

Antipsychotic Agent

Libido/Arousal

Orgasm

Sedation

Weight

Other

Clozapine

↓↓

↑↑↑

↑↑↑

Priapism

Olanzapine

↑↑↑

Priapism

Risperidone

Priapism

Ziprasidone

(↑)

 

Sulpiride

↓↓

 

Quetiapine

↑↑

 

 

 

 

Algorithm to Manage Treatment-Emergent
Sexual Dysfunction

Clayton. Psychiatr Clin North Am. 2016;39:427.

Patient warrants
treatment with
antipsychotic

Patient already
has SD or is
concerned about
developing SD?

Choose a
medication with a
more favorable
SD profile

Choose any
appropriate
medication and
monitor for SD

Patient develops
sexual AE

Patient and
physician amenable
to regimen change?

•Watch and wait

•Reduce dose

•Drug holiday

•Nonpharmacologic
options

Is the current regimen
fully effective for the
primary psychiatric
target symptoms?

Add an antidote to
current regimen

Change to a
medication known
to cause fewer
sexual AEs

YES

NO

YES

NO

YES

NO

Slide credit: clinicaloptions.com

 

 

 

Clinical Manifestations of Hyperprolactinemia

●Anxiety, depression, hostility

●Decreased bone mineral density and osteoporosis

●Infertility

●Disturbed menstrual cycles

●Anovulation, amenorrhea, or irregular cycles

●Decreased testosterone levels and sperm mobility

 

●Sexual dysfunction

‒Decreased libido/arousal;
un- or hypo-orgasmia

●Increased risk of cardiovascular disorders

●Breast engorgement and galactorrhea

●Increased risk of breast cancer

●Increased risk of tardive dyskinesia?

●Abnormal function of the immune system?

 

Halbreich. Psychoneuroendocrinology. 2003;28:53.

Slide credit: clinicaloptions.com

 

 

 

Variation in Antipsychotics: Effect on Prolactin Increase

●Meta-analysis of 212 studies of patients with schizophrenia (N = 43,049 )[1]

●Brexpiprazole, not shown, does not generally increase prolactin levels[2]

1. Leucht. Lancet. 2013;382:951. 2. Ivkovic. J Clin Psychopharmacol. 2019;39:13.

Slide credit: clinicaloptions.com

Prolactin Increase, Standardized Mean Difference (95% Cl)

Aripiprazole    -0.22 (-0.46 to 0.03)

Quetiapine    -0.05 (-0.23 to 0.13)

Asenapine     0.12 (-0.12 to 0.37)

Olanzapine     0.14 (0 to 0.28)

Chlorpromazine     0.16 (-0.48 to 0.8)

Iloperidone     0.21 (-0.09 to 0.51)

Ziprasidone     0.25 (0.01 to 0.49)

Lurasidone     0.34 (0.11 to 0.57)

Sertindole     0.45 (0.16 to 0.74)

Halperidol     0.70 (0.56 to 0.85)

Risperidone     1.23 1.06 to 1.40)

Paliperidone     1.30 (1.08 to 1.51)

0

1.0

-0.5

1.5

0.5

More Prolactin Increase
With Placebo

More Prolactin Increase
With Active Drug

 

 

MDD Treatment Augmentation With Second-Generation Antipsychotics: Managing Adverse Events

●Consider potential advantages and disadvantages for individual patients before prescribing

 

McIntyre. J Clin Psychiatry 2017;78:703.

American Psychiatric Association, Practice Guideline for the Treatment of Patients with Major Depressive Disorder; 2010.

Slide credit: clinicaloptions.com

●Dosing in MDD (in combination with antidepressants) is typically lower than in bipolar disorder and psychosis

‒Lower dose may minimize risk of adverse events

 

●Monitor:

‒Adverse events, including sedation, weight gain, akathisia and extrapyramidal symptoms

‒Weight, body mass index, and metabolic indices at baseline and regular intervals

 

 

 

 

Summary

●Goal of treating major depression remains full symptomatic and functional remission and recovery

●4 second-generation antipsychotics are approved by the FDA for use as antidepressant augmentation

‒All have demonstrated efficacy

●Adverse events often manageable with short- and long-term vigilance

‒Weight gain, hyperprolactinemia, sexual dysfunction, tardive dyskinesia, are among the issues to monitor

 

 

Slide credit: clinicaloptions.com

 

 

clinicaloptions.com/internalmedicine

 

Go Online for More CCO
Coverage of Depression!

CME-certified activities with expert faculty commentary

Additional unlocked slidesets with key information

Interactive Decision Support Tool on when to augment or switch MDD treatment

 

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