Florida Best Practice Psychotherapeutic Medication Guidelines for Adults 2017-2018 - Florida Medicaid Drug Therapy Management Program for ...
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2017-2018
Florida Best Practice
Psychotherapeutic Medication
Guidelines for Adults
Florida
Medicaid Drug
Therapy Management
Program for
Behavioral Health
medicaidmentalhealth.org
Please visit our website to view:
n Electronic versions of our
adult and child/adolescent
guidelines (available in full or
in part)
n News and announcements
n Webinars
n Staff publications
n Alerts of recent publications
and related literature
n Resources and tools
Florida
Medicaid Drug
Therapy Management
Program for
Behavioral Health
medicaidmentalhealth.org
For more information, visit us at medicaidmentalhealth.org
These guidelines are available in the public domain and do not require permission from the authors
for use. However, we request when using any of its content that the publication is cited as follows:
2017-2018 Florida Best Practice Psychotherapeutic Medication Guidelines for Adults (2018). The
University of South Florida, Florida Medicaid Drug Therapy Management Program sponsored by the
Florida Agency for Health Care Administration.
For treatment of mood disorders in pregnant and post-partum women visit
medicaidmentalhealth.org and see the Florida Best Practice Recommendations for Women of
Reproductive Age with Serious Mental Illness and Comorbid Substance Use Disorders.
© January 2018
medicaidmentalhealth.org
Table of Contents
Introduction.................................................................................................................................................. 3
Purpose .................................................................................................................................................... 3
Process for Creating the Guidelines.................................................................................................... 3
Organization................................................................................................................................................. 4
Disclaimer .................................................................................................................................................... 5
Principles of Practice ...................................................................................................................... 6-10
Measurement-Based Care .............................................................................................................. 7
List of Antipsychotic Medications Available in the U.S....................................................... 9
Treatment with Antipsychotic Medication.............................................................................. 9
Resources ..................................................................................................................................................11
Bipolar Disorder............................................................................................................................. 14-23
Treatment of Acute Bipolar Disorder – Depression ..........................................................14
Treatment of Acute Bipolar Disorder – Mania .....................................................................16
Bipolar 1 Disorder Continuation/Maintenance Therapy ................................................18
Summary: Pharmacological Treatmeant of Bipolar Disorder........................................21
Major Depressive Disorder...................................................................................................... 25-32
Treatment of Major Depressive Disorder ..............................................................................25
Treatment of Major Depressive Disorder with Mixed Features ...................................27
Treatment of Major Depressive Disorder with Psychotic Features ............................29
Summary: Pharmacological Treatmeant of Major Depressive Disorder...................30
Schizophrenia..................................................................................................................................35-47
Treatment of Schizophrenia ........................................................................................................35
Summary: Pharmacological Treatmeant of Schizophrenia............................................37
Treatment of Schizophrenia with
Long-Acting Injectable Antipsychotic Medications (LAIs)......................................41
Summary: Pharmacological Treatmeant of Schizophrenia with LAIs........................44
List of Abbreviations .......................................................................................................................... 48
References ................................................................................................................................................ 50
medicaidmentalhealth.org
List of Tables
Table 1. Assessment Scales for Behavioral Health Conditions ............................................ 8
Table 2. Medications for the Treatment of Bipolar Disorder: Mood Stabilizers .........19
Table 3. Medications for the Treatment of Bipolar Disorder: Second Generation
Antipsychotics and Antidepressants.......................................................................20
Table 4. Recommended Medications for the Treatment of Schizophrenia
Oral Antipsychotics .........................................................................................................36
Table 5. Recommended Medications for the Treatment of Schizophrenia:
Long-Acting Injectable Antipsychotics .................................................................42
List of Boxes
Box 1. DSM-5 Criteria: Bipolar I Disorder .................................................................................. 12
Box 2. DSM-5 Criteria: Bipolar II Disorder ................................................................................13
Box 3. DSM-5 Criteria: Major Depressive Disorder...............................................................24
Box 4. DSM-5 Criteria: Schizophrenia.........................................................................................34
medicaidmentalhealth.org
Page 2
Purpose of the Guidelines
Introduction
The most recent estimate of the prevalence of any mental illness among adults in the United States
is 43.4 million, or 17.9% of all adults according to the National Institute of Mental Health (NIMH).
Approximately 1 in 25 adults in the U.S.—9.8 million people, or 4.0% of all adults— experiences
a serious mental illness that substantially interferes with or limits one or more major life activities
(National Institute of Mental Health, 2015). Yet, lack of access to behavioral health care has been an
ongoing concern, particularly in areas of critical need, due to increasing shortages in behavioral
health specialists and rising demand for behavioral health services. To help bridge gaps in access to
behavioral health care in the absence of specialists, primary care clinicians are tasked with providing
behavioral health services, as they serve as the first point of contact into the healthcare system.
Given these challenges, providing quality care is especially daunting in the absence of clear, concise
evidence-based treatment recommendations.
Purpose
The goal of the 2017-2018 Florida Best Practice Psychotherapeutic Medication Guidelines
for Adults is to provide a guide to clinicians, including psychiatrists and primary care providers,
who use psychotherapeutic medications to treat adults with behavioral health conditions. The
guidelines are intended as a starting point and provide rational approaches to help address some
very challenging conditions. As always, the clinician and patient partnership prevails in the choice of
treatment.
The guidelines cover a range of conditions that providers encounter in their clinical practice,
including treatment of bipolar disorder, major depressive disorder, and schizophrenia. This year,
the expert panel has also updated the guidelines to include recommendations on the use of long-
acting injectable antipsychotic medications (LAIs) to inform and guide clinicians in the use of these
medications as a treatment option in the management of schizophrenia.
Process for Creating the Guidelines
Every two years, the Florida Medicaid Drug Therapy Management Program brings together a
diverse array of stakeholders to update the Florida Best Practice Psychotherapeutic Medication
Guidelines for Adults. This year’s group of stakeholders, known as the Florida Expert Panel, was
comprised of nationally recognized experts, academicians, medical directors of Florida Medicaid
Managed Medical Assistance (MMA) health plans and community mental health centers (CMHCs),
psychiatrists, primary care providers, and pharmacists.
The 2017 Florida Expert Panel met in Tampa, Florida on November 3-4, 2017 to review and update
the adult guidelines last published in 2015. For each disorder, a psychiatrist who is a nationally
recognized content expert conducted a full literature review, presented the findings to the expert
panel, and made suggestions to the panel on revising the guidelines based on the state of the
scientific evidence. The panel then discussed the guidelines, proposed revisions, and reached a
consensus about whether or not to revise and adopt a particular set of proposed revisions. Thus,
the final guidelines are a product of an in-depth review of the literature with an emphasis on the
highest level of clinical evidence (e.g., randomized controlled trials, systematic reviews), expert
consensus on the strength of the evidence, and consideration of safety and efficacy. The names of
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Page 3
Organization
the meeting attendees and meeting presentations are available on the program website at
medicaidmentalhealth.org. Financial disclosures are available upon request.
We are grateful to our dedicated panel of experts who have provided their expertise, editorial
comments, and invaluable advice. We also would like to thank all external reviewers who took the
time to make comments and point out areas needing clarity. The Florida Agency for Healthcare
Administration (AHCA) is to be commended for its commitment to improving the behavioral
health and well-being of underserved populations through the use of evidence-based treatment
recommendations.
Organization
The 2017-2018 Florida Best Practice Psychotherapeutic Medication Guidelines for Adults are
based on a thorough review of the research literature by the expert panel. When the scientific
literature is absent or findings are mixed, the guidelines note and explain the absence of clear
findings, and advise caution in treatment. Clinical tools recommended in these guidelines are
available at medicaidmentalhealth.org. Recommended clinical rating scales are available in the
public domain; those that are not are specifically noted.
The guidelines are organized by “levels” of treatment recommendations, beginning with Level 1.
The treatment recommendations for each section (Levels 1, 2, 3, etc.) are categorized hierarchically
based on the strength of the evidence for efficacy and safety regarding a particular agent or
treatment option. Thus, Level 1 treatment has stronger empirical evidence for efficacy and/or safety
than Level 2, and so forth.
A description of the guideline process and assignment of levels of recommendations were recently
published and are adapted here to explain the bases for each Level:
nnLevel 1 is initial treatment for which there is established efficacy and relative safety for the
treatment recommendations (based on replicated, large randomized controlled trials).
nnLevel 2 is considered if Level 1 is ineffective and/or not well tolerated. Compared to
Level 1, the data on treatment efficacy and/or safety in Level 2 are less robust (based on
smaller randomized controlled trials, smaller effect sizes, etc.).
nnLevel 3 is considered if Levels 1 and 2 are ineffective and/or not well tolerated. Treatments
at this level have more limited efficacy data and/or more tolerability limitations than
Levels 1 and 2.
nnLevel 4 is considered if Levels 1 through 3 are ineffective and/or not well tolerated;
however, the treatments are not empirically supported at this time and are listed because
of expert opinion and/or use in clinical practice.
It should be noted that the levels are not algorithms in which specific treatment decisions are
mandatory. Instead, use of these guidelines should take into account the individuality of the patient
and presenting symptoms. Although selecting treatments beginning with Level 1 and moving
sequentially through the levels is encouraged, the treatment choice can start at any level and should
be based on clinical judgment as well as the patient’s individual symptoms, needs, and preferences.
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Page 4
Disclaimer
Disclaimer
The 2017-2018 Florida Best Practice Psychotherapeutic Medication Guidelines for Adults are
based on the current state of scientific knowledge at the time of publication on effective and
appropriate care, as well as on clinical consensus judgments when research is lacking. The inevitable
changes in the state of scientific information and technology mandate that periodic review,
updating, and revisions will be necessary. These guidelines may not apply to all patients; therefore,
each guideline must be adapted and tailored to the individual patient.
Proper use, adaptation, modifications, or decisions to disregard these or other guidelines, in whole
or in part, are entirely the responsibility of the clinician who uses these guidelines. The authors and
expert panel members bear no responsibility for treatment decisions and outcomes based on the use of
these guidelines.
Treatment guidelines are available on
our Program website: medicaidmentalhealth.org
n Best Practice Psychotherapeutic Medication Guidelines for Adults
n Autism Spectrum Disorder & Intellectual Developmental Disorder: Psychotherapeutic
Medication Recommendations for Target Symptoms in Children and Adolescents
n Best Practice Recommendations for Women of Reproductive Age with Severe Mental
Illness and Comorbid Substance Use Disorders
n Best Practice Psychotherapeutic Medication Guidelines for Children and Adolescents
n Monitoring Physical Health and Side-Effects of Psychotherapeutic Medications in
Adults and Children: An Integrated Approach
If you would like hard copies of the guidelines, please email sabrinasingh@usf.edu
medicaidmentalhealth.org
Page 5
Principles of Practice
Comprehensive Assessment
Conduct a comprehensive assessment. Rule out medical causes of behavioral symptoms. Use
validated measures to assess and track psychiatric symptoms and impairment.
nnA comprehensive mental health assessment includes:
FF Risk of harm to self or others
FF An assessment of the full range of psychiatric symptoms and disorders, as well as
impairment from these symptoms and disorders
FF A full medical history
FF A relevant medical work-up and physical examination
FF Assessment of substance use, including tobacco use
FF Assessment of family psychiatric history, which includes psychiatric symptoms/
treatment of family members, including substance use and treatment
nnOngoing management of behavioral health conditions includes:
FF Use of measurement-based care to measure and monitor symptoms and side-effects
FF Assessment of benefits and risks of treatment, including review of boxed warnings
FF Patient education of the benefits and risks of treatment, including review of boxed
warnings
FF Monitoring of physical health parameters (See Program publication titled Monitoring
Physical Health and Side-Effects of Psychotherapeutic Medications in Adults and Children:
An Integrated Approach available at medicaidmentalhealth.org).
FF Assessment of social support system (housing, family, other caregivers)
FF Evaluation of threats to continuity of care (financial burden, housing instability, access
to medication, medication adherence, etc.)
FF Provision of patient tools/support for recovery and self-management
Notes:
• Effort should be made to communicate between primary care providers, psychiatrists, case workers, and other
team members to ensure integrated care.
• Incorporate collaborative/shared treatment decision-making with patients, family and caregivers.
• Written informed consent should be obtained from the patient or the individual legally able to consent to medical
interventions (e.g., pharmacotherapy), and documented in the chart.
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Principles of Practice (continued)
Adjunctive Psychosocial Treatments (As Indicated)
nnIndividual and family psychoeducation
nnCognitive-behavioral therapy (CBT)
nnInterpersonal psychotherapy (IPT)
nnInterpersonal and social rhythm therapy (IPSRT)
nnFamily-focused therapy
nnGroup psychoeducation (especially for bipolar disorder)
nnSocial skills training (especially in schizophrenia)
nnCognitive remediation/rehabilitation (to improve attention, memory, and/or executive
function)
Note on pharmacogenomics testing: Limited data exist examining whether patient care that integrates
pharmacogenomic test information results in better or safer treatment.
Measurement-Based Care
Questionnaires and rating scales are useful tools for diagnostic assessment and evaluation of
treatment outcomes, and such instruments can be helpful in providing information to supplement
clinical judgement. The integration of measurement scales into routine clinical practice is
suggested for each of the conditions covered in this document. Clinicians should use rating scales
to assess symptom severity during the initial evaluation/treatment, when medication changes are
implemented, and/or when the patient reports a change in symptoms.
nnTreatment targets need to be precisely defined.
nnEffectiveness and safety/tolerability of the medication treatment must be systematically
assessed by methodical use of appropriate rating scales and side-effect assessment
protocols.
Internet links to the following scales are available on the Program website:
medicaidmentalhealth.org.
nnBeck Depression Inventory (BDI)
nnBrief Psychiatric Rating Scale (BPRS)
nnClinical Global Impression (CGI) Scale
nnClinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS)
nnHamilton Rating Scale for Depression (HAM-D)
nnMontgomery-Asberg Depression Rating Scale (MADRS)
nnPatient Health Questionnaire (PHQ-9)
nnPositive and Negative Syndrome Scale (PANSS)
nnQuick Inventory of Depression Symptomatology (QIDS)
nnYoung Mania Rating Scale (YMRS)
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Page 7
Principles of Practice (continued)
Table 1. Assessment Scales for Adult Disorders
Cont/Main Therapy
Major Depression
Major Depression
Major Depression
Acute Depression
with Psychosis
Schizophrenia
Acute Mania
with Mixed
Bipolar 1
Features
Bipolar
Bipolar
Measures
Beck Depression
3 — — 3 3 3 —
Inventory (BDI)
Brief Psychiatric
Rating Scale — — — — — 3 3
(BPRS)
Clinical Global
Impression (CGI) — — — — 3 — 3
Scale
Clinician-Rated
Dimensions
of Psychosis — — — — — 3 3
Symptom Severity
(CRDPSS)
Hamilton
Rating Scale
— 3 — — — 3 —
for Depression
(HAM-D)
Montgomery-
Asberg
3 3 3 — 3 3 —
Depression Rating
Scale (MADRS)
Patient Health
Questionnaire 3 — 3 3 3 — —
(PHQ-9)
Positive and
Negative
— — — — — 3 3
Syndrome Scale
(PANSS)
Quick Inventory
of Depression
3 — 3 3 3 — —
Symptomatology
(QIDS)
Young Mania
Rating Scale 3 3 3 — 3 — —
(YMRS)
medicaidmentalhealth.org
Page 8Principles of Practice (continued)
List of Antipsychotic Medications Available in the United States:
nnFirst Generation Antipsychotics (FGAs): chlorpromazine, fluphenazine*, haloperidol*,
loxapine, molindone, perphenazine, thioridazine, thiothixene, and trifluoperazine
nnSecond Generation Antipsychotics (SGAs): aripiprazole*, asenapine, brexpiprazole†,
cariprazine†, clozapine, iloperidone, lurasidone, olanzapine*, paliperidone*, quetiapine,
risperidone*, and ziprasidone
Notes:
Medications indicated by a single asterisk (*) are available in long-acting injectable formulations (refer to list below).
†
Brexpiprazole and cariprazine were introduced in 2015.
List of Long-Acting Injectable (LAI) Antipsychotic Medications Available in
the United States:
nnFirst Generation Antipsychotics (FGAs): fluphenazine decanoate, haloperidol decanoate
nnSecond Generation Antipsychotics (SGAs): aripiprazole monohydrate, aripiprazole lauroxil,
olanzapine pamoate, paliperidone palmitate, risperidone microspheres
Treatment with Antipsychotic Medication
Selection of antipsychotic medication with well-informed patients should be made on the basis of
prior individual treatment response, side-effect experience, medication side-effect profile, long-
term treatment planning, and should take into account the following:
nnFirst generation antipsychotics (FGAs) and second generation antipsychotics (SGAs) are
heterogeneous within the class and differ in many properties, such as efficacy, side-effects,
and pharmacology.
nnAntipsychotics carry extrapyramidal symptoms (EPS) liability and metabolic effects.
nnCaution should be used in prescribing antipsychotic medication in the context of
dementia, anxiety disorders, and impulse control disorders. For these conditions,
antipsychotic utilization should be:
FF Aimed at target symptoms
FF Prescribed only after other alternative treatments have been tried
FF Used in the short-term
FF Monitored with periodic re-evaluation of benefits and risks
FF Prescribed at the minimal effective dose
Note:
The Food and Drug Administration (FDA) has issued a boxed warning that elderly patients with dementia-
related psychosis treated with FGAs or SGAs have an increased risk of death.
medicaidmentalhealth.org
Page 9Principles of Practice (continued)
Achieving Optimal Outcomes with Currently Available Antipsychotics
STEP 1 – Considerations for selecting the most appropriate antipsychotic for a particular
patient:
FF Equivalent efficacy across agents
FF Individual variability in response
FF No reliable pre-treatment predictor of individual response to different agents
FF Different agents have different side-effects and safety profiles.
FF Individual patients have different vulnerabilities and preferences.
STEP 2 – Proper antipsychotic trial sequence:
FF Begin with systematic 6 to 10 week trial of one antipsychotic with optimal dosing.
FF If inadequate response, follow with systematic trial of monotherapy with one or more
antipsychotics at adequate dose and duration.
FF If inadequate response, follow with a trial of clozapine or a long-acting antipsychotic.
FF Follow with a trial of clozapine, if not tried before.
FF If insufficient response with the previously listed therapies, consider other strategies
(e.g., antipsychotic polypharmacy).
STEP 3 - Good practice guidelines for ongoing antipsychotic treatment:
FF Measurement-based individualized care
FF Repeated assessment of efficacy using reliably defined treatment targets (use
standard rating scales - e.g., CRDPSS, CGI, BPRS, PANSS)
FF Careful assessment and measurement of adverse effects
FF Care consistent with health monitoring protocols
FF Standard protocols customized to individual vulnerabilities/needs and specific agent
FF Ongoing collaboration with patient in decision-making
Notes:
CRDPSS = Clinician-Rated Dimensions of Psychosis Symptom Severity; CGI = Clinical Global Impressions Scale; BPRS
= Brief Psychiatric Rating Scale; PANSS = Positive and Negative Syndrome Scale
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Page 10Resources
Below is a list of national and local resources for adults with serious mental illness (SMI).
National Resources:
nnAmerican Psychiatric Association: https://www.psychiatry.org/
nnBrain and Behavior Research Foundation: http://bbrfoundation.org/
nnNational Alliance on Mental Illness (NAMI): http://www.nami.org/
nnNational Council for Behavioral Health: https://www.thenationalcouncil.org/
nnNational Depressive and Manic Depressive Association (NDMDA):
http://www.dbsalliance.org/
nnNational Institute of Mental Health: http://nimh.nih.gov/
nnMental Health America (MHA): http://www.mentalhealthamerica.net/
nnSubstance Abuse and Mental Health Services Administration (SAMHSA):
http://www.samhsa.gov/
Local Resources:
nnFlorida Academy of Family Physicians (FAFP): http://www.fafp.org/
nnFlorida Association of Nurse Practitioners (FLANP): http://flanp.org/
nnFlorida Council for Community Mental Health (FCCMH): http://www.fccmh.org/
nnFlorida Medical Association (FMA): http://www.flmedical.org/
nnFlorida Osteopathic Medical Association (FOMA): http://www.foma.org/
nnFlorida Psychiatric Society (FPS): http://www.floridapsych.org/
nnFlorida Society of Neurology (FSN): http://fsn.aan.com/
nnNational Alliance on Mental Illness (NAMI) Florida: http://www.namiflorida.org/
For updated links to resources, visit medicaidmentalhealth.org.
medicaidmentalhealth.org
Page 11DSM-5 Criteria: Bipolar Disorders
Box 1.
DSM-5 Diagnosis: Bipolar I Disorder
Bipolar I Disorder:
For a diagnosis of bipolar I disorder, it is necessary to meet the following criteria for a
manic episode. The manic episode may have been preceded by and may be followed by
hypomanic or major depressive episodes.
Manic Episode:
FF A distinct period of abnormally and persistently elevated, expansive, or irritable mood
and abnormally and persistently increased goal-directed activity or energy, lasting
at least 1 week and present most of the day, nearly every day (or any duration if
hospitalization is necessary).
FF During the period of mood disturbance and increased energy or activity, 3 (or more)
of the following symptoms (4 if the mood is only irritable) are present to a significant
degree and represent a noticeable change from usual behavior:
Inflated self-esteem or grandiosity
Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
More talkative than usual or pressure to keep talking
Flight of ideas or subjective experience that thoughts are racing
Distractibility (i.e., attention too easily drawn to unimportant or irrelevant
external stimuli), as reported or observed
Increase in goal-directed activity (either socially, at work or school, or sexually) or
psychomotor agitation (i.e., purposeless, non-goal-directed activity)
Excessive involvement in activities that have a high potential for painful
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions,
or foolish business investments)
FF The mood disturbance is sufficiently severe to cause marked impairment in social or
occupational functioning, or to necessitate hospitalization to prevent harm to self or
others, or there are psychotic features.
FF The episode is not attributable to the physiological effects of a substance (e.g., a drug
of abuse, a medication, or other treatment) or to another medical condition.
Note: A full manic episode that emerges during antidepressant treatment [e.g., medication,
electroconvulsive therapy (ECT)], but persists at a fully syndromal level beyond the physiological effect of
treatment is sufficient evidence for a manic episode, and therefore, a bipolar I diagnosis.
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Page 12DSM-5 Criteria: Bipolar Disorders (continued)
Box 2.
DSM-5 Diagnosis: Bipolar II Disorder
Bipolar II Disorder:
FF Criteria have been met for at least one hypomanic episode and at least one major
depressive episode
FF There has never been a manic episode
FF The occurrence of the hypomanic episode(s) and major depressive episode(s) is
not better explained by schizoaffective disorder, schizophrenia, schizophreniform
disorder, delusional disorder, or other specified or unspecified schizophrenia
spectrum and other psychotic disorder.
FF The symptoms of depression or the unpredictability caused by frequent alternation
between periods of depression and hypomania causes clinically significant distress or
impairment in social, occupational, or other important areas of functioning.
For a diagnosis of bipolar II disorder, it is necessary to meet the following criteria for a
current or past hypomanic episode and the criteria for a current or past major depressive
episode (See Box 3 on page 24 for Major Depressive Episode criteria).
Hypomanic Episode:
FF A distinct period of abnormally and persistently elevated, expansive, or irritable
mood and abnormally and persistently increased activity or energy, lasting at least 4
consecutive days and present most of the day, nearly every day.
FF During the period of mood disturbance and increased energy and activity, 3 (or more)
of the above symptoms (4 if the mood is only irritable) have persisted, represent
a noticeable change from usual behavior, and have been present to a significant
degree.
FF The episode is associated with an unequivocal change in functioning that is
uncharacteristic of the individual when not symptomatic.
FF The disturbance in mood and the change in functioning are observable by others.
FF The episode is not severe enough to cause marked impairment in social or
occupational functioning or to necessitate hospitalization. If there are psychotic
features, the episode is, by definition, manic.
FF The episode is not attributable to the physiological effects of a substance (e.g., a drug
of abuse, a medication, or other treatment).
Note: A full hypomanic episode that emerges during antidepressant treatment (e.g., medication, ECT)
but persists at a fully syndromal level beyond the physiological effect of that treatment is sufficient
evidence for a hypomanic episode diagnosis. However, caution is indicated so that one or two symptoms
(particularly increased irritability, edginess or agitation following antidepressant use) are not taken as
sufficient for a diagnosis of a hypomanic episode nor necessarily indicative of a bipolar diathesis.
medicaidmentalhealth.org
Page 13Treatment of Acute Bipolar Disorder - Depression
Conduct comprehensive assessment and use measurement-based care. Refer to Principles of
Practice on pages 6-10.
The primary therapeutic objectives of bipolar disorder care are remission, maintenance of
remission, prevention of recurrence, and full functional recovery.
nnSelection of acute treatment should take maintenance treatment goals into account.
nnBe aware of safety and tolerability concerns, evidence for maintenance use, and acute
efficacy.
Strongly recommend psychiatric consultation prior to initiation of therapy + psychotherapeutic
medication using a multi-disciplinary approach if treated by a non-psychiatrist.
Level 1 Established efficacy:
FF Optimize index mood stabilizer if already prescribed a mood stabilizer. Check blood
levels if appropriate.
FF Quetiapine or lurasidone monotherapy*
*Notes: Only quetiapine has established efficacy for bipolar II disorder. Lurasidone has a better
metabolic profile than quetiapine.
FF Lamotrigine monotherapy
FF Lurasidone or lamotrigine** adjunctive to lithium or divalproex if index mood stabilizer
has been optimized.
**Caution: There is a drug-drug interaction with use of lamotrigine and divalproex together
that requires reducing the lamotrigine dose by 50% of the typical lamotrigine dose. For dosing
recommendations, refer to Table 2 on page 19.
FF Do not utilize conventional antidepressants (e.g., SSRIs, SNRIs, TCAs, MAOIs) as a first-line
therapy.
Level 2A Established efficacy, but with safety concerns*:
FF Olanzapine + fluoxetine (bipolar I disorder)
*Note: Tolerability limitations include weight gain and metabolic concerns.
Level 2B Better tolerability, but limited efficacy*:
FF Lithium (bipolar 1 disorder)
FF 2 drug combination of above medications. Drugs may include either a first
generation antipsychotic (FGA) or second generation antipsychotic (SGA) but
NOT TWO antipsychotic medications
*Note: Efficacy limitations, relatively few positive randomized controlled trials.
Level 3 If Levels 1 and 2 are ineffective and/or not well tolerated*:
FF Electroconvulsive therapy (ECT)
*Note: Consideration is merited due to clinical need, despite even greater efficacy/
tolerability limitations than Level 1 and 2 treatments.
medicaidmentalhealth.org
Page 14Treatment of Acute Bipolar Disorder - Depression (continued)
Level 4 If Levels 1 – 3 are ineffective and/or not well tolerated:
FF Cariprazine
FF FDA-approved agent for bipolar disorder + conventional
antidepressant (e.g., SSRI)*
FF Pramipexole
FF Adjunctive: modafinil, thyroid hormone (T3), or stimulants
FF 3 drug combination
FF Transcranial magnetic stimulation (TMS)
*Notes:
• There is inadequate information (including negative trials) to recommend
adjunctive antidepressants, aripiprazole, ziprasidone, levetiracetam,
armodafinil, or omega-3 fatty acids for bipolar depression.
• Preliminary evidence is available for cariprazine in the treatment for bipolar I
depression.
•A ntidepressant monotherapy is not recommended in bipolar I depression;
recommendation is for adjunctive mood stabilizer with antidepressant.
• Superiority (in other words, efficacy and safety) of antidepressant
monotherapy versus adjunctive mood stabilizer with antidepressant for
treatment of bipolar II depression is uncertain.
medicaidmentalhealth.org
Page 15Treatment of Acute Bipolar Disorder - Mania
Conduct comprehensive assessment and use measurement-based care. Refer to Principles of
Practice on pages 6-10.
The primary therapeutic objectives of bipolar disorder care are safety, symptomatic
improvement, and patient psychoeducation.
nnSelection of acute treatment should take maintenance treatment goals into account.
nnBe aware of safety and tolerability concerns, evidence for maintenance use, and acute
efficacy.
Strongly recommend psychiatric consultation prior to initiation of therapy + psychotherapeutic
medication using a multi-disciplinary approach if treated by a non-psychiatrist.
Level 1A Established efficacy:
Mild to moderate severity and/or not requiring hospitalization
FF Optimize mood stabilizer (lithium*, divalproex*, or carbamazepine*) if already
prescribed. Check blood levels if appropriate.
FF Lithium* monotherapy
FF Monotherapy with aripiprazole, asenapine, divalproex*, quetiapine, risperidone,
ziprasidone, or cariprazine.
Severe and/or requiring hospitalization
FF Lithium* or divalproex* + aripiprazole, asenapine, quetiapine, or risperidone
FF Electroconvulsive therapy (ECT) is recommended if medical emergency/patient welfare
at risk and pharmacotherapy is insufficient.
Level 1B Established efficacy, but with safety concerns**:
Mild to moderate severity and/or not requiring hospitalization
FF Monotherapy with either haloperidol or olanzapine
Severe and/or requiring hospitalization
FF Lithium* or divalproex* + either haloperidol or olanzapine
Level 2 If Levels 1A and 1B are ineffective and/or not well tolerated:
FF Combination treatment with lithium* + divalproex*
FF Combination with lithium* and/or divalproex* + second generation
antipsychotic (SGA) other than clozapine
FF Carbamazepine* monotherapy
Level 3 If Levels 1 and 2 are ineffective and/or not well tolerated:
FF Electroconvulsive therapy (ECT)
FF Clozapine + lithium* or divalproex*
FF Lithium* + carbamazepine*
FF Divalproex* + carbamazepine*
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Page 16Treatment of Acute Bipolar Disorder - Mania (continued)
Level 4 If Levels 1 – 3 are ineffective and/or not well tolerated:
FF A three-drug combination of Level 1, 2, and 3. Drugs
may include first generation antipsychotic (FGA) or
second generation antipsychotic (SGA) but NOT TWO
antipsychotic medications.
Example: lithium* + (divalproex* or carbamazepine*) +
antipsychotic
Notes:
*Caution should be used when prescribing lithium, lamotrigine, divalproex or carbamazepine to women of
reproductive age due to increased risks to the fetus with use during pregnancy, including neural tube and other
major birth defects. Please see Florida Best Practice Recommendations for Women of Reproductive Age with Serious
Mental Illness and Comorbid Substance Use Disorders and online guideline on the Pharmacological Treatment of
Mood Disorders During Pregnancy.
**Side-effect concerns with these agents include weight gain, metabolic syndrome, and extrapyramidal symptoms
(EPS). Side-effects warrant vigilance and close monitoring on the part of the clinicians.
Data for use of paliperidone to treat bipolar mania are mixed. Paliperidone >6 mg has some data supporting
efficacy.
Benzodiazepines may be used as an adjunct treatment for acute treatment of bipolar mania.
Florida Clozapine Hotline
727-562-6762
Rhemsath@aol.com
The Clozapine Hotline is operated by Randolph Hemsath, M.D., Medical Director of Boley
Centers, a CARF-accredited community mental health center in St. Petersburg, FL. Dr.
Hemsath has over 30 years’ experience as a psychiatrist and extensive experience utilizing
clozapine as an option for individuals with treatment-refractory schizophrenia.
The hotline is funded by the Florida Medicaid Drug Therapy Management Program for
Behavioral Health through a contract with the Florida Agency for Healthcare Administration.
Calls and emails will be answered on non-holiday weekdays between 8:00am and 5:00pm.
No registration is required and the service is free.
medicaidmentalhealth.org
Page 17Bipolar 1 Disorder Continuation / Maintenance Therapy
Conduct comprehensive assessment and use measurement-based care. Refer to Principles of
Practice on pages 6-10.
The list of possible treatments in the prevention of bipolar disorder is comprised of many
treatment options; therefore, the regimen that stabilizes a patient should be strongly
considered for continuation and maintenance (monitoring for efficacy and adverse events).
Strongly recommend psychiatric consultation prior to initiation of therapy + psychotherapeutic
medication using a multi-disciplinary approach if treated by a non-psychiatrist.
Level 1 Established efficacy:
FF Periodic evaluation: frequency based on clinical needs
FF Continue with effective and well-tolerated treatment
FF Lithium* monotherapy
FF Quetiapine monotherapy
FF Lamotrigine* (evidence strongest for prevention of depression)
FF If initially stabilized on divalproex*†, maintain.
FF Aripiprazole or aripiprazole long-acting injectable, long-acting risperidone
monotherapy
FF Quetiapine (for recurrence prevention) or ziprasidone (for relapse prevention) adjunctive
to (lithium* or divalproex*†)
FF Asenapine monotherapy
†Note: Be aware that there are limited data on long-term efficacy of divalproex.
Level 2A Established efficacy, but with safety concerns**:
FF Olanzapine monotherapy
FF Olanzapine adjunctive to lithium* or divalproex*†
Level 2B If Level 1 is ineffective and/or not well tolerated:
FF Continue effective and well-tolerated acute treatment(s) if not listed in Level 1
FF Lithium* and divalproex*† combination
FF Follow acute mania/bipolar depression guidelines to achieve remission or
partial remission
Level 3 If Levels 1 and 2 are ineffective and/or not well tolerated:
FF Adjunctive clozapine (avoid combining with another antipsychotic)
FF Electroconvulsive therapy (ECT)†
Notes:
* Caution should be used when prescribing lithium, lamotrigine, divalproex or carbamazepine to women of
reproductive age due to increased risks to the fetus with use during pregnancy, including neural tube and other
major birth defects. Please see Florida Best Practice Recommendations for Women of Reproductive Age with Serious
Mental Illness and Comorbid Substance Use Disorders and online guideline on the Pharmacological Treatment of
Mood Disorders During Pregnancy.
**Side-effect concerns with these agents include weight gain, metabolic syndrome, and extrapyramidal symptoms
(EPS). Side-effects warrant vigilance and close monitoring on the part of the clinician.
†Long-term efficacy data are limited for the following: divalproex monotherapy, carbamazepine (drug interaction
risk), antidepressants, and electroconvulsive therapy (inconvenience/expense).
medicaidmentalhealth.org
Page 18Table 2. Recommended Medications for the Treatment of
Bipolar Disorder – Mood Stabilizers
Medication Dosage Comments
Lithium In acute mania: Initial titration for tolerability - start 600-900 mg/day,
1,200 - 2,400 mg/day increase 300 mg/day every 5 days. Check levels 5 days
(serum level 0.8 - 1.2 mEq/L) after initiation/dose change. Check levels frequently
if clinical toxicity. Monitor renal and thyroid functions.
Lower doses/levels may be necessary in non-manic
compared to manic patients. For maintenance, some
patients require serum levels of 0.8 to 1.2 mEq/L,
others can be maintained with lower levels, but not
below 0.6 mEq/L. In older individuals, start with lower
lithium dose, titrate more slowly, and target lower
serum lithium levels.
Divalproex In acute mania: Initial loading may be tolerated, but some patients
5 - 60 mg/kg/day; need initial titration for tolerability. Check levels 48
1,000 - 2,500 mg/day hours after initiation and adjust dose accordingly. Side-
(serum level 85 - 125 µg/mL) effects (especially gastrointestinal) are more evident
above 100μg/ml.
More teratogenic than other mood stabilizers.
Lower doses/levels may be necessary in non-manic
compared to manic patients.
Carbamazepine In acute mania: Initial titration for tolerability due to hepatic auto-
200 - 1,600 mg/day induction:
(serum level 6 - 12 µg/mL) Start 200 - 400 mg/day and increase 200 mg/day every
3 days. Lower doses/levels may be necessary in non-
manic compared to manic patients. Monitor for blood
dyscrasias and serious rash. Screen individuals of Asian
descent for HLA-B*1502 (serious rash risk indicator)
due to high risk for Stevens-Johnson Syndrome (SJS)
and Toxic Epidermal Necrolysis (TEN). Patients testing
positive for the HLA-B*1502 allele should not be
treated with carbamazepine unless benefits clearly
outweigh risks.
Carbamazepine decreases serum levels of multiple
other CYP450-metaboized drugs due to induction of
CYP450 enzymes 3A4, 1A2, 2C19, and 2C19.
Lamotrigine In bipolar maintenance: Initial titration to reduce risk of Stevens-Johnson
100 - 400 mg/day syndrome (serious rash): Start 25 mg/day (12.5 mg/day
if taken with divalproex).
Increase by 25mg/day (12.5 mg/day if taken with
divalproex) after 2 and 4 weeks and weekly thereafter.
Initial target dose 200 mg/day, but final doses may
be 100 - 400 mg/day. May be used in some patients
with acute bipolar depression (despite acute efficacy
limitation) due to good tolerability and depression
prevention efficacy.
*mg/day = milligrams per day; mEq/L = milliequivalents per Liter; mg/kg/day = milligram per kilogram per day; μg/
ml = microgram per milliliter
Page 19Table 3. Recommended Medications for the Treatment of
Bipolar Disorder – Second Generation Antipsychotics (SGAs)
and Antidepressants
Medication Dosage Comments
Second In acute mania: Initial titration may be necessary for tolerability.
Generation Lower doses may be necessary in depressed
• Aripiprazole: 15 - 30 mg/day
Antipsychotics patients (e.g., quetiapine 300 mg/day).
(SGA) • Asenapine: 10 - 20 mg/day Ziprasidone should be taken with food.
• Olanzapine: 6 - 20 mg/day Asenapine is sublingual.
• Paliperidone 3 - 12 mg/day Monitor for side effects, including sedation
• Quetiapine: 400 - 800 mg/day (especially with quetiapine and clozapine),
weight gain (especially with olanzapine and
• Risperidone: 2 - 6 mg/day
clozapine), akathisia (especially with aripiprazole
• Ziprasidone: 80 - 160 mg/day and ziprasidone) and extrapyramidal symptoms
(EPS), especially with risperidone. Monitor
weight and body mass index (BMI) at each visit
In acute bipolar depression: and laboratory metabolic indices at baseline, 3
• Quetiapine: 200 - 600 mg/day months, and yearly thereafter.
• Olanzapine/Fluoxetine:
3 mg/12.5 mg - 12 mg/50 mg
per day
• Lurasidone: 40 - 120 mg/day
• Clozapine: 50 - 400 mg/day
(if treatment resistant)
Antidepressants In acute bipolar depression: Larger trials have not found a benefit of
antidepressants when added to mood
As dosed for major depression.
stabilizers/antimanics for bipolar depression
(No specific dosing
(other than olanzapine/fluoxetine combination).
recommendations can be given
May be used in combination with antimanic
for bipolar depression.)
drugs in some patients with acute bipolar
depression, but should not be prescribed as
monotherapy in patients with bipolar I disorder
due to manic switch risk.
Serotonin-norepinephrine reuptake inhibitors
(SNRIs) and tricyclic antidepressants (TCAs) may
have greater manic switch risk.
Antidepressants carry an FDA boxed warning for
increased suicidality risk in pediatric and young
adult patients (under age 25). May be continued
in patients who are on them and have stable
mood.
*mg/day = milligrams per day
medicaidmentalhealth.org
Page 20Pharmacological Treatment of Bipolar Disorder:
2017-2018 Update Summary
Roger S. McIntyre, M.D., FRCPC
Professor of Psychiatry and Pharmacology, University of Toronto
Head, Mood Disorders Psychopharmacology Unit (MDPU), University Health Network
Chairman and Executive Director, Brain and Cognition Discovery Foundation (BCDF)
Director, Depression and Bipolar Support Alliance (DBSA), Chicago
Introduction
Bipolar disorders (BD) are associated with high rate of non-recovery, inter-episodic dysfunction, and
chronicity. Mortality studies indicate that the rate of premature mortality is significantly elevated
in bipolar disorder with a widening chasm in the mortality rate between affected individuals and
persons in the general population. Convergent and replicated evidence indicates that utilization of
a chronic disease model is an integral component to improving health outcomes in bipolar disorder,
with salutary effects on both morbidity and mortality outcomes. Moreover, by improving precision,
consistency, and appropriateness of treatment selection, decision support with evidence informed
guidelines have demonstrated to reduce both individual and societal costs attributable to bipolar
disorder.
The update of the 2017-2018 Florida Best Practice Psychotherapeutic Medication Guidelines
for Adults represents the most up-to-date treatment recommendations and decision support for
multiple stakeholders involved with, and who provide care for, individuals diagnosed with bipolar
disorder. This current iteration provides a further refinement, in some cases differential emphasis,
from the previous published version (Ostacher, Tandon, and Suppes 2016). In contradistinction from
most treatment guidelines in bipolar disorder, the 2017-2018 Florida Best Practice Psychotherapeutic
Medication Guidelines for Adults represents a synthesis of evidence and multi-disciplinary opinion
from multiple stakeholders, including, but not limited to academicians, clinicians, and experts
in private and public healthcare policy. The current portrait sketched of bipolar disorder as a
common, complex, and lifelong disorder that significantly curtails human capital invites the need
for multi-disciplinary consensus on pragmatic and scalable interventions. The updated version of
the 2017-2018 Florida Best Practice Psychotherapeutic Medication Guidelines for Adults provides an
update of pharmacologic, psychosocial, and neurostimuatory treatment approaches for symptom
management.
Principles of Treatment
There are several guiding principles of treatment that are emphasized in the 2017-2018 guidelines.
A particular emphasis is made on the importance of timely and accurate diagnosis. It remains
a modifiable deficiency in bipolar disorder that the majority of affected individuals continue to
be misdiagnosed and/or diagnosed long after observable characteristics and service utilization
related to bipolar disorder have appeared. Safety assessment continues to be a priority and
guiding principle in bipolar disorder, with emphasis not only on suicide and risk reduction, but
also an urgency given to risk factor modification for common and chronic non-communicable
comorbid physical health conditions (e.g., cardiovascular disease, metabolic syndrome). A third
guiding principle is the importance of careful calculus of benefit of treatment expected compared
to the holistic appraisal of treatment-related side effects and safety concerns. It is the view of the
medicaidmentalhealth.org
Page 21Pharmacological Treatment of Bipolar Disorder:
2017-2018 Update Summary (continued)
authorship of the guideline, that collective treatments for acute-based management (i.e., acute
mania, acute bipolar depression) need to anticipate both short- and long-term side effects and
safety concerns (e.g., weight gain). Priority is always given to safe, well-tolerated treatments that are
supported by rigorous, randomized, double-blind, placebo-controlled trials.
Moreover, the guiding principle of integrating multimodality treatments in bipolar disorder is
emphasized in light of the evidence supporting and the rationale for considering manualized-based
psychosocial treatments (e.g., cognitive behavioral therapy, interpersonal social rhythm therapy).
The 2017-2018 guideline further presses the principle on the importance of giving equal priority to
somatic health (e.g., cardiovascular disease) as is given to conventional treatment targets in bipolar
disorder (e.g., mania, sleep, cognitive impairment). Finally, patient health management, locus of care
(e.g., medical home), and the importance of functional recovery and positive mental health and
resiliency, are emphasized.
Pharmacological Treatment of Acute Bipolar Depression
Bipolar depression is the predominant therapeutic target in bipolar disorder in most early and
later phases of the illness. Furthermore, depressive symptoms as part of bipolar disorder are often
chronic, and highly associated with risk, comorbidity (e.g., cardiovascular disease), functional
impairment, and suicidality. The United States Food and Drug Administration (FDA) has approved
three psychotherapeutic agents of bipolar depression (i.e., lurasidone, quetiapine, and olanzapine-
fluoxetine combination). The expert panel for the Florida Guidelines consensually agree to
also list lamotrigine as a possible first-line treatment strategy in bipolar depression. The expert
panel recognizes that lamotrigine has not received regulatory approval for marketing in bipolar
depression. Notwithstanding, results conducted in large academic centers, as well as meta-analyses,
indicate that lamotrigine is an effective agent for both acute and recurrence prevention of bipolar
depression (lamotrigine is currently FDA-approved for recurrence prevention in bipolar disorder).
Cariprazine, a D3 preferring D2/D3 partial agonist is currently approved for mania and mixed states
in bipolar disorder, but not for bipolar depression. At the time of completing the 2017-2018 Florida
Guidelines, results from two pivotal registration trials in adults with bipolar I depression indicate that
cariprazine is efficacious in the acute treatment of bipolar I depression. The 2017-2018 guidelines
re-emphasize the ubiquity and hazards posed by mixed features in bipolar disorder. Hitherto, no
safe and reliable treatment is unequivocally established and efficacious in mixed bipolar depression
(McIntyre, 2017). Notwithstanding, select atypical antipsychotics are likely the initial treatments of
choice for many individuals with bipolar depression and mixed features. Select second generation
antipsychotics are also recommended as first-line treatment for mania with mixed features.
Antidepressant utilization remains an understudied and controversial issue in bipolar disorder. No
single antidepressant or class of antidepressants are approved for bipolar disorder. It is recognized
by the Florida Expert Panel that antidepressants continue to be utilized at a high rate in adults
with bipolar disorder. The guiding principle of utilizing antidepressants in bipolar disorder is that
they should not be prioritized over better established and FDA-approved treatment, and should
be utilized as adjunctive treatment strategies. The use of antidepressant monotherapy is highly
discouraged in bipolar I disorder, while the safe and effective use of antidepressants in bipolar
II disorder remains a possibility, but still requires replicated empirical evidence. Psychosocial
treatments, like pharmacotherapeutic treatments for bipolar disorder, are recognized to be more
effective earlier in the illness course. For treatment-resistant bipolar depression, electroconvulsive
Page 22Pharmacological Treatment of Bipolar Disorder:
2017-2018 Update Summary (continued)
therapy (ECT) remains the recommended treatment option, with evidence also supporting alternate
neurostimuatory approaches (e.g., rTMS).
Pharmacological Treatment of Acute Bipolar Mania
The expert panel recognizes that mania is not only a defining feature of bipolar I disorder, but is
a medical emergency requiring urgent detection, establishment of safety, appropriate setting
assignment for care, and evidence-based treatments. No substantive changes were made to
the acute mania guidelines when compared to the 2015 iteration, with an ongoing emphasis on
FDA-approved second-generation antipsychotics, lithium, and divalproex, as the most commonly
recommended first-line strategies.
Continuation and Maintenance Pharmacological Treatment of Bipolar
Disorder
Bipolar disorder is a highly progressive condition, as evidenced by greater episode frequency,
duration, and complexity, as well as diminished treatment response across the illness trajectory.
It is also recognized in bipolar disorder that best practices utilizing integrated multimodality
therapies reduce and forestall risk of recurrence, and speculatively, neurobiological progression
and cumulative illness load. Since the publication of the 2015 guidelines, the FDA has approved
aripiprazole long-acting injectable (LAI) as a recurrence prevention treatment in bipolar disorder.
The FDA has also approved aripiprazole proteus (Abilify MyCite®), which may be extrapolated to
the bipolar population. Aripiprazole proteus (Abilify MyCite®) is a combination product comprised
of oral aripiprazole embedded with an ingestible digital sensor to record and communicate
medication ingestion events. Whether digital sensory detection improves compliance and health
outcomes in bipolar disorder, however, is not well known. As per the previous guidelines, key
therapeutic targets during long-term treatment of bipolar include subsyndromal depression,
affective instability, cognitive impairment, sleep disturbance, comorbidity (e.g., substance use
disorder, anxiety disorder, cardiovascular disease, obesity), as well as interpersonal, social and
workplace dysfunction (Miskowiak et al., 2017). Multimodality interventions incorporating
pharmacotherapy, psychosocial treatment, cognitive remediation, lifestyle modification (e.g.,
exercise), are critical components of long term care. As with major depressive disorder (MDD), it is
also recommended by the expert panel that advocacy, for example, the Depression and Bipolar
Support Alliance (DBSA), can play a critical role in education support service access and illness/
treatment literacy and should be considered an integral component of care for any person affected
by bipolar disorder.
References:
McIntyre, Roger S. 2017. “Mixed Features and Mixed States in Psychiatry: From Calculus to Geometry.”
CNS Spectrums 22 (2):116–17.
Miskowiak, K. W., K. E. Burdick, A. Martinez-Aran, C. M. Bonnin, C. R. Bowie, A. F. Carvalho, P. Gallagher,
et al. 2017. “Methodological Recommendations for Cognition Trials in Bipolar Disorder by the
International Society for Bipolar Disorders Targeting Cognition Task Force.” Bipolar Disorders 19
(8):614–26.
Ostacher, Michael J., Rajiv Tandon, and Trisha Suppes. 2016. “Florida Best Practice Psychotherapeutic
Medication Guidelines for Adults With Bipolar Disorder: A Novel, Practical, Patient-Centered
Guide for Clinicians.” The Journal of Clinical Psychiatry 77 (7):920–26.
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