The Black Book of Psychotropic Dosing and Monitoring

Introduction

Psychotropics continue to be among the most commonly prescribed medications in clinical practice. There are over 380 million outpatient psychotropic prescriptions in the US every year Greenblatt et al. (2018). The majority of these prescriptions are for antidepressants (58%) followed by anxiolytics (22%), hypnotics (14%) and antipsychotics (5%). Since the last edition of this Black Book in 2016, a large number many new psychotropics have been approved by the FDA and are now in clinical use.

Over the past several years, there has been a paradigm shift in antidepressant development. Historically, antidepressants have been oral agents which generally take 4–8 weeks to achieve maximum benefit at therapeutic doses. Two antidepressants have been approved that have been demonstrated efficacy in improving symptoms of major depression in hours or days as opposed to months. One of these, esketamine (Spravato), is the S enantiomer of ketamine which has been used as an anesthetic and for pain management since the 1960’s. While IV ketamine has long been demonstrated to be rapidly effective for treatment resistant depression, IV use require regular visits to a clinic and is generally not covered by insurance. Esketamine (Spravato) is an intranasal preparation which is typically administered twice weekly for 4 weeks, one weekly for 3 weeks, and then every week or two thereafter. Esketamine, like ketamine, is a schedule 3 drug that require a REMs registration of patients and providers and carries some risk of abuse. Like ketamine, the most common symptoms include nausea, dissociation, and increases in blood pressure and heart rate. Thus, patients have to be observed for at least two hours in the clinic after each administration and cannot drive to or from the clinic for each visit. In addition, since ketamine and S ketamine can be habituating, it is important to adhere to the guidelines for frequency and duration of dosing.

Another rapidly acting antidepressant approved in 2019 is brexanolone (Zulresso). Brexanalone is an allosteric modulator of GABA-a approved for the treatment of post partum depression. Like esketamine, it require a REMS registration but unlike esketamine, requires observation in a hospital or overnight clinic over the course of the 60 hour infusion because of the risk of sudden sedation. Another difference from esketamine, whose antidepressant effects typically only last 5–7 days and thus requires repeated administration, brexanolone’s antidepressant effects are observed by 60 hours and have been demonstrated to last at least 30 days from the initiation of treatment. The most common side effects of brexanolone are sedation/drowsiness, dizziness/sensation of spinning, and the sensation that one or the surroundings are moving. Brexanolone is a schedule IV drug.

The class of antipsychotic medications has seen the largest number of new additions of any class of psychotropics in recent years. These have included Cariprazine (Vraylar), Brexpiprazole (Rexulti), and lumataperone (Caplyta). While these second generation do not appear to improve efficacy over other second generation antipsychotics, they do provide additional options for clinician, and may have advantages in side effect profile or ease of use. For example, cariprazine became only the fourth drug approved for the treatment of bipolar depression, and brexpiprazole is only the third drug approved in the adjunctive treatment of major depressive disorder. Lumataperone is unique among antipsychotics in that it has single dose (42 mg) that is both the starting and therapeutic dose. All the newer agents have a somewhat better metabolic profile than older agents such as olanzapine and quetiapine but still require metabolic monitoring.

In addition to newer antipsychotic drugs, there are a number of new formulations of older agents. For example, Invega Trinza is a long acting injectable formulation of paliperidone that last 3 months. As such it is the longest acting injectable antipsychotic that may require only 4 administrations per year. Asenapine, which is a sublingual drug approved for the treatment of schizophrenia, now is also available as the first and only transdermal (Secuado) antipsychotic. Some patients may find the patch more tolerable and convenient than sublingual asenapine including less food and drink restrictions, less hypoesthesia or distortion in the sense of taste, as well as more stable blood levels of the drug. There is even the availability of a smart pill (Abilify Mycite) which has an ingestible sensor embedded in each pill with blue-tooth tooth connection to a wearable patch that allows clinicians and patients to monitor adherence to taking the medication daily. Whether a chronically psychotic patient is likely to agree to swallowing a radio transmitter is not clear. Still, this type of digital monitoring may be useful for some patients who may not want a long acting injectable (Abilify Maintena, Aristada) but have trouble taking a daily medication.

One of the most serious potential long-term side effects of antipsychotics is tardive dyskinesia (TD). There has been no reliable treatment for TD until the approval of VMAT2 inhibitors in the past few years. The VMAT2 inhibitors work by reducing dopamine overstimulation without blocking D2 receptors. Two VMAT2 inhibitors, valbenazine (Ingrezza) and deutetrabenazine (Austedo) have been FDA approved to treat TD since the last edition of the Black Book. While some improvement in TD is often seen in the first 2 weeks of treatment, these drug work in a slow measured way with improvement accumulating over up to 3 years of use. The most common side effects of these drugs are drowsiness and anticholinergic side effects including dry mouth, constipation, urinary retention, and blurred vision. Qt prolongation is also a possible side effect EKG monitoring is suggested.

Among the hypnotics, the most innovative recent advance has been the introduction of Dual Orexin Receptor Antagonists (DORAs). The first of these was approved in 2013 (Suvorexant; Belsomra) for sleep onset and maintenance insomnia, and another, lemborexant (Dayvigo) approved in late 2019 for insomnia. The DORAs appear to work on hypocretin/orexin endogenous system which regulates the sleep cycle. While the mechanism of action is unique, it not clear if this translates to advantages over less expensive, generically available hypnotics such as zolpidem. Possible advantages may include a lower risk of falls and possibly less time awake after falling asleep compared to benzodiazepine hypnotics or agents such as zolpidem and eszopiclone.

In addition to updating the Black Book on new drugs and formulations, we have added a number of new tables to assist with monitoring of antidepressants and antipsychotics. Since monitoring of patients on psychotropics also involves the monitoring of clinical symptoms, we have also included a number of common psychiatric scales available in the public domain for easy reference including the PHQ9 and Quick Inventory of Depressive Symptomatology (QIDs) for depression, the Brief Psychiatric Rating Scale (BPRS) for psychotic disorders, the Generalized Anxiety Disorder (GAD-7) for anxiety, and the Abnormal Involuntary Movement Scale (AIMS) for assessing extrapyramidal symptoms. These scales can help track the progress of patients on psychotropic and are increasingly used in the clinical setting. We hope that this edition of the Black Book proves as useful as some of the earlier editions have been.^1–30

Table 1. Psychotropic Drug Dosage Ranges^30,39–47.

Generic		Brand Name		Dosage Range* (mg/day)
Alprazolam		Xanax		0.75–10
Amitriptyline		Elavil, Endep, Enovil		50–300
Amoxapine		Asendin		50–600
Armodafinil		Nuvigil		150–250
Asenapine		Saphris		5–10 mg BID sublingual
		Secuado		3.8–7.6 mg patch/24hr
Brexpiprazole		Rexulti		2–4
Bupropion		Wellbutrin, Wellbutrin SR, Zyban†		200–450 150–400 150–300
Buspirone		BuSpar		15–60
Carbamazepine‡		Epitol, Tegretol		400–1,600
Cariprazine		Vraylar		3–6
Chlordiazepoxide§		Librium, Libritabs, Mitran		15–100
Chlorpromazinell		Ormazine, Thorazine		30–800
Citalopram		Celexa		20–60
Clomipramine		Anafranil		25–250
Clonazepam**		Klonopin		0.50–4
Clorazepate§		ClorazeCaps,  ClorazeTabs, Gen-XENE, Tranxene		15–60
Clozapine		Clozaril		12.5–900
Desipramine		Norpramin, Pertofrane		25–300
Desvenlafaxine		Pristiq		50–100
Diazepam		Valium, Valrelease, Zetran		4–40
Doxepin		Adapin, Sinequan		25–300
Droperidol		Inapsine		2.5–15
Duloxetine		Cymbalta		40–120
Eszopiclone		Lunesta		1–3
Fluoxetine		Prozac, Sarafem		20–80
Fluphenazine		Permitil, Prolixin		1–40
Flurazepam		Dalmane		15–30
Fluvoxamine		Luvox		50–300
Gabapentin		Neurontin		300–3,600
Galantamine		Reminyl		16–32
Halazepam		Paxipam		60–160
Haloperidol		Haldol		1–100
Iloperidone		Fanapt		6–12 mg BID
Generic		Brand Name		Dosage Range* (mg/day)
Imipramine		Janimine, Tofranil		50–300
Isocarboxazid		Marplan		20–60
Lamotrigine		Lamictal		25–400
Lemborexant		Dayvigo		5
Levomilnacipran		Fetzima		40–120
Lisdexamfetamine		Vivance		30–70
Lithium		Cibalith-S, Eskalith, Lithane, Lithobid, Lithonate, Lithotabs		600–1,800
Lorazepam		Ativan		1–10
Loxapine		Loxitane		20–250
Lumataperone		Caplyta		42
Lurasidone		Latuda		40–160
Maprotiline		Ludiomil		25–225
Methylphenidate HCl		Concerta Ritalin, Ritalin-SR		18–54 10–60
Mirtazapine		Remeron		15–45
Modafinil		Provigil		100–400
Nefazodone		Serzone		200–600
Nortriptyline		Aventyl, Pamelor		75–150
Olanzapine		Zyprexa		5–20
Oxazepam		Serax		30–120
Oxcarbazepine		Trileptal		600–1,200
Paroxetine††		Paxil		20–60
Perphenazine		Trilafon		12–64
Phenelzine		Nardil		15–90
Pimozide		Orap		1–10
Prazepam		Centrax		30–60
Protriptyline		Vivactil		15–60
Quazepam		Doral		7.5–15
Quetiapine		Seroquel		50–750
Risperidone		Risperdal		2–16
Rivastigmine		Exelon		6–12
Sertraline		Zoloft		50–200
Suvorexant		Belsomra		10–20
Temazepam		Restoril		15–30
Thioridazine		Mellaril		20–800
Thiothixene		Navane		6–60
Tiagabine		Gabitril		4–32
Topiramate		Topamax		50–400
Tranylcypromine		Parnate		30–60
Trazodone		Desyrel		150–600
Triazolam		Halcion		0.125–0.5
Trifluoperazine		Stelazine		2–40
Trimipramine		Surmontil		50–300
Generic		Brand Name		Dosage Range* (mg/day)
Valproic Acid/Divalproex		Depakene, Depakote		750–4,200
Venlafaxine‡‡		Effexor, Effexor XR***		75–375 75–225
Vilazodone		Viibryd		30–40 mg
Vortioxetine		Trintillex		10–20
Zaleplon		Sonata		5–20
Ziprasidone		Geodon		40–160
Zolpidem		Ambien		5–10

*Recommended dosages may vary by indication. Dosage ranges include starting doses that may not represent effective dosages. Some drugs may be contraindicated or may require lower doses in pediatric, geriatric, or debilitated patients. Consult the prescribing information of individual drugs for more detailed information.

^†Zyban is indicated as an aid to smoking cessation.

^‡Although carbamazepine is not approved by the FDA for psychiatric indications, the authors view it as one of the most important agents available for the treatment of bipolar disorder. This view is supported in the medical literature.

^§For alcohol detoxification and withdrawal, doses of up to 300 mg of chlordiazepoxide and 90 mg of clorazepate may be warranted.

^llLabeling suggests that higher doses in severe cases may be appropriate, up to 2,000 mg/day, but little therapeutic gain is achieved by >1,000 mg/day for extended periods. Intramuscular doses may be necessary.

**Starting dosage of clonazepam should not be >1.5 mg/day for PD but doses up to 20 mg/day are approved for seizure disorders.

^††Dosage range for paroxetine adjusted for OCD and PD.

^‡‡Recommended starting dose is 75 mg/day.

***37.5 mg/day for 4–7 days is an initial dosing option.

Table 2. Mood Disorders: Antidepressants^{29,30,40–43,45,46,48–54}.

Drug		Typical Starting Dosage (mg)		Typical Dosage Range* (mg/day)		FDA IndIcatIon(s)		Proposed Therapeutic Plasma Concentration (ng/mL)
Amitriptyline (Elavil, Endep, Enovil)		25 TID or 50 QHS		50–300		Depression		120–250†
Amoxapine (Asendin)		50 BID/TID		50–600		Depression, psychotic depression		—
Brexanalone (Zulresso)		30 mcg/kg/hr IV		30–90 mcg/kg/hr × 60 hrs		Post Partum Depression		—
Bupropion (Wellbutrin)		100 BID		200–450‡		Depression		<100†
Bupropion SR (Wellbutrin SR)		150 QAM		150–400‡		Depression
Bupropion XL (Wellbutrin XL)		150 QD		300–450		Depression
Bupropion SR (Zyban)		150 QD		150–300‡		Smoking cessation
Citalopram (Celexa)		20		20–60		Depression		—
Clomipramine (Anafranil)		25–100 QD in divided doses within first 2 weeks		25–250		OCD		100–250
Desipramine (Norpramin, Pertofrane)		25 TID		100–300		Depression		115–180§
Desvenlafaxine (Pristiq)		50 mg		50–100 mg		Depression, anxiety
Doxepin (Sinequan)		25 TID		75–300		Depression, anxiety, psychotic depressive disorders with associated anxiety		70–250†
Duloxetine (Cymbalta)		20		40–120		Depression, anxiety, neuropathic pain, chronic pain		—
Esketamine intransal (Spravato)		56 mg Intranal		56–84		Depression, Suicidality in Depression		—
Fluoxetine (Prozac, Sarafem)		20 QD		20–80		Depression, OCD, bulimia nervosa, PMDD		—
Fluvoxamine (Luvox)		50 QD		50–300		OCD		—
Imipramine (Janimine, Tofranil)		25 TID		75–300		Depression, childhood enuresis		200–250†,§
Maprotiline (Ludiomil)		25 TID		75–225		Depression		—
Isocarboxazid (Marplan)		10		20–60		Depression		—
Levomilnacipran (Fetzima)		20		40–120		Depression
Milnacipran (Savella)		12.5 mg		50–100 mg BID		Fibromyalgia
Mirtazapine (Remeron)		15 QHS		15–45		Depression		—
Nefazodone (Serzone)		100 BID		200–600		Depression		—
Nortriptyline (Aventyl, Pamelor)		25 TID/QD		75–150		Depression		50–150§
Paroxetine (Paxil)**		20 QAM		10–60		Depression, OCD, PD, social anxiety disorder, GAD		—
Phenelzine (Nardil)		15 TID		15–90		Depression, atypical depression		—
Protriptyline (Vivactil)		5 TID		15–60		Depression		70–250
Sertraline (Zoloft)		50 QAM		50–200		Depression, OCD, PD, PTSD		—
Tranylcypromine (Parnate)		Individualized		30–60		Depression, depression without melancholia		—
Trazodone (Desyrel)		50 TID		150–600		Depression		—
Trimipramine (Surmontil)		25 TID		50–300		Depression		—
Venlafaxine (Effexor)		37.5 BID		75–375		Depression		—
Venlafaxine ER (Effexor XR)††		37.5–75 QD		75–225		Depression, GAD		—
Vilazodone (Vybryd)		10 mg		20–40 mg		Depression		—
Vortioxetine (Trintillex)		10 mg		10–20		Depression		—

*In geriatric patients, the appropriate dosage is widely variable, but in general it is one half the young adult dosage range for TCAs and for compounds with significant cardiovascular toxicity.

^†Parent and metabolite.

^‡Not >150 mg/dose. Zyban is indicated as an aid to smoking cessation.

^§Therapeutic drug monitoring is well established.

**Dosage range for paroxetine adjusted for OCD and PD.

^††37.5 mg/day for 4–7 days is an initial dosing option.

FDA=Food and Drug Administration; OCD=obsessive-compulsive disorder; PMDD=premenstrual dysphoric disorder; PD=panic disorder; GAD=generalized anxiety disorder; PTSD=posttraumatic stress disorder.

Table 3. Pharmacokinetic Comparison of Selected Antidepressants^29,30,55,56.

Sertraline

Fluoxetine

Paroxetine

Esketamine

Fluvoxamine

Half-life (hours)

26

48–72

21 (mean)

7–12

15.6

Metabolite activity

20–30% activity

Equal

Inactive

Low activity

Questionable

Metabolite half-life (hours)

62–104

96–384

—

1–1.3

14–16

Steady state (days)

7–10

28–35

~10

NA

7

Dose-proportional plasma levels

Yes

No

No

No

No

Protein binding (%)

98

94.5

93–95

45

80

Dose reduction in elderly

No

Yes

Yes

No

Yes

EscitaLopram

VenLafaxine

CLomipramine

Amitriptyline

Bupropion

Mirtazapine

Half-life (hours)

27–33

3–7

19–37

9–46

14

20–40

Metabolite activity

Low activity

Equal

Equal

Equal

4 variably active

10% activity

Metabolite half-life (hours)

—

9–13

54–77

16–88

8–24

20–40

Steady state (days)

7–10

3

7–14

4–10

Variable

3–4

Dose-proportional plasma levels

Yes

Yes

No

Yes

Yes

Yes

Protein binding (%)

56

27–30

97

90–97

80

85

Dose reduction in elderly

No

No

Yes

Yes

Yes

No

Table 4. Central Nervous System Neurotransmitters: Selected Antidepressant Effects^29,30,55,57.

		Serotonin		Norepinephrine		Dopamine
Amitriptyline		++++		++++		0
Amoxapine		+++		+++		0
Bupropion		0/+		+*		++
Citalopram		++++		0		0
Desipramine		+		++++		0/+
Doxepin		+++		+		0
Fluoxetine		++++		0		0/+
Fluvoxamine		++++		0		0/+
Imipramine		+++		++		0/+
Lithium		0/++§		0		0
Maprotiline		0		++++		0
Mirtazapine		+++*		++†		0
Nortriptyline		++		+++		0
Paroxetine		++++		0/+		0/+
Protriptyline		+		++++		0
Sertraline		++++		0		0/+
Trazodone		++‡		0		0
Trimipramine		++		++		0
Venlafaxine		++++		+++		0/+
Vortioxetine		****		0		0

++++=high; +++=moderate; ++=low; +=very low; 0=none.

*5-HT₂ and 5-HT₃ antagonist.

^†α₂presynaptic antagonist.

^‡5-HT₂ antagonist.

^§Acutely increases; chronically stabilizes.

Table 5. Substrates, Inhibitors, and Inducers of Some Important Cytochrome p450 (cyp) Isoforms^29,58–62.

CYP % of all CYP*		Substrates				Inhibitors				Inducers
CYPIA2 13		3° amine TCAs (N-demethylation) Acetaminophen Caffeine Clozapine (major) Methadone		Olanzapine Phenacetin Propranolol Tacrine Theophylline		Cimetidine Fluoroquinolines (ciprofloxacin, norfloxacin) Fluvoxamine		Mibefradil Moclobemide Naringenin Ticlopidine		Char-grilled meat Omeprazole Tobacco
CYP2C9 20 (for all 2C)		Celecoxib Fluvastatin Glipizide Irbesartan Losartan		NSAIDs Phenytoin (major) Rosiglitazone S-warfarin Tolbutamide		Amiodarone D-propoxyphene Disulfiram Fluconazole Fluvastatin		Fluvoxamine Miconazole Phenylbutazone Sulphaphenazole Zafirlukast		Phenytoin Rifampin Secobarbital
CYP2CI9† 20 (for all 2C)		3° amine TCAs (N-demethylation) Citalopram (partly) Diazepam (partly) (N-demethylation) Hexobarbital Indomethacin Lansoprazole		Mephobarbital Moclobemide Nelfinavir Omeprazole (5-hydroxylation) Phenytoin (minor) R-warfarin S-mephenytoin		Cimetidine Felbamate Fluoxetine Fluvoxamine Imipramine		Ketoconazole Moclobemide Omeprazole Phenytoin Tranylcypromine		Rifampin
CYP2D6† 2		2° and 3° amine TCAs (2, 8, 10-hydroxylation) Alprenolol Amphetamine Beta blockers Carvedilol		Hydrocodone Mexiletine Mirtazepine (partly) Nortriptyline Oxycodone Paroxetine		Amiodarone Bupropion Celecoxib Cimetidine Fluoxetine Fluphenazine		Hydroxybupropion Methadone Moclobemide Paroxetine Perphenazine Quinidine
		Clozapine (minor) Codeine (hydroxylation, O-demethylation) D-fenfluramine Desipramine Dextromethorphan (O-demethylation) Donezepil (partly) Fluoxetine (partly) Fluphenazine Haloperidol (reduction)		Perphenazine Propafenone (IC antiarrhythmics) Risperidone Tamoxifen Thioridazine Timolol Tramdol Trazodone		Fluvoxamine (weak) Haloperidol		Ritonavir Sertraline (weak) Thioridazine
CYP2EI 7		Acetaminophen Chlorzoxazone Ethanol Halothane		Isoflurane Methoxyflurane Sevoflurane		Diethyldithio-carbamate (Disulfiram metabolite)				Ethanol Isoniazid
CYP3A4 30 (for all 3A)		3° amine TCAs (N-demethylation) Acetaminophen Alfentanil Alprazolam Amiodarone Androgens Atorvastatin Buspirone Carbamazepine Cerivastatin Citalopram (partly) Codeine (demethylation) Cyclophosphamide		Lidocaine Loratadine Lovastatin Midazolam Mirtazapine (partly) Nefazodone Nifedipine Nimodipine Nisoldipine Nitrendipine Omeprazole (sulfonation) Propafenone		Amiodarone Cimetidine Clarithromycin Dexamethasone Diltiazem Erythromycin Fluconazole Fluoxetine Fluvoxamine Gestodene Indinavir (protease inhibitors) Itraconazole		Ketoconazole (azole antifungals) Mibefradil Naringenin (grapefruit) Nefazodone Nelfinavir Ritonavir Saquinavir Sertraline (weak) Troleandomycin (macrolides) Verapamil		Barbiturates Carbamazepine Dexamethasone Phénobarbital Phenytoin Pioglitazone Rifampin St. John’s wort
		Cyclosporine Dexamethasone Diazepam (partly) (hydroxylation and N-demethylation) Diltiazem Disopyramide Donepezil (partly) Erythromycin (macrolides) Estrogens (steroids) Ethosuximide Felodipine Fentanyl Ifosfamide		Protease inhibitors (HMG-CoA reductase inhibitors) Quetiapine Quinidine Sertraline Sildenafil Simvastatin Sufentanil Tacrolimus Tamoxifen Tiagabine Triazolam Verapamil Vinblastine Vincristine Ziprasidone

^†Clinically significant human polymorphism reported.

CYP 450=cytochrome P450; TCAs=tricyclic antidepressants; NSAIDS=nonsteroidal anti-inflammatory drugs.

CYP=cytochrome P450; TCAs=tricyclic antidepressants.

Table 6. Examples of Drugs* That Might Interact with an Antidepressant³¹.

CYP IA2		CYP 2CI9		CYP 2C9		CYP 2D6		CYP 3A4
Acetaminophen Caffeine Clozapine Haloperidol Olanzapine Phenacetin Phenothiazines R-warfarin (minor) Tacrine 3°TCAs Theophylline Thiothixene		Barbiturates Citalopram Diazepam Mephenytoin Moclobemide Propranolol 3° TCAs		Diclofenac Ibuprofen Naproxen Omeprazole Phenytoin Piroxicam S-Warfarin Tolbutamide		Amphetamines Chlorpheniramine Codeine/hydrocodone Desipramine other 2° TCAs Dextromethorphan Fiecainide/encainide Haloperidol (minor) Phenothiazines Propranolol, timolol, metoprolol Reduced haloperidol Risperidone Quinidine† Tamoxifen Tramadol		Androgens Benzodiazepines (alprazolam, triazolam, clonazepam, diazepam) Calcium channel blockers Carbamazepine Corticosteroids Cyclosporine Dapsone Estrogens HMG-CoA reductase inhibitors Ketoconazole, itraconazole Macrolide antibiotics Nonsedating antihistamines†† Paclitaxel Quinidine Tamoxifen Zolpidem

*Drug can be a substrate and/or an inhibitor of a given enzyme system.

^†Inhibitor at 2D6, not a substrate.

^††Loratadine not contraindicated.

CYP=cytochrome P450; TCA=tricyclic antidepressant.

Table 7. Examples of Drug Interactions^{29,30,58,61–67}.

Drug		Interaction		Mechanism
TCA Interactions
Alcohol		sedation, ataxia		CNS depression synergism
Calcium channel blockers		TCA levels		Inhibit oxidation of TCAs
Carbamazepine		TCA levels		Hepatic enzyme induction
Clmetidine		TCA levels		Inhibit TCA metabolism
Clonidine		Antagonize antihypertensive effects		Norepinephrine reuptake
Estrogen		TCA levels		Inhibit oxidation of TCAs
Guanethidine		Reverse antihypertensive effects		Block norepinephrine reuptake
Haloperidol/phenothiazines		antipsychotic levels		CYP 2D6 inhibition
Methadone		TCA levels		Inhibit TCA metabolism
MAOIs		Serotonin syndrome		Serotonin synergism
Quinidine		TCA levels, arrhyth mia		Inhibit CYP 2D6
SSRIs		TCA levels		Inhibit various CYP systems
Stimulants		TCA levels		Inhibit TCA metabolism
SSRI Interactions
Cyproheptadine		Reverse antidepressant effect		Serotonin antagonism
Dextromethorphan		Serotonin syndrome		Serotonin synergism
Hallucinogens		LSD flashbacks		5-HT2 agonism
MAOIs		Serotonin syndrome		Serotonin synergism
TCAs		TCA toxicity		Inhibit various CYP systems
Tryptophan		Serotonin syndrome		Serotonin synergism
Theophlline		Theophylline toxicity		Inhibit theophylline metabolism (fluvoxamine)
Warfarin		warfarin levels		Inhibit CYP 2C
MAOI Interactions
Barbiturates		sedation		Inhibit barbiturate metabolism
Hypoglycemics		effects of hypoglycemics		MAOIs lower blood sugar
Meperidine		Serotonin syndrome		Serotonin synergism
SSRIs		Serotonin syndrome		Serotonin synergism
Succinylcholine		Prolonged apnea in surgery		Decreased cholinesterase levels
Sympathomimetics		Hypertensive crisis		indirect pressor effect
TCAs		Serotonin syndrome		Serotonin synergism
Tyramine (dietary)		Hypertensive crisis		indirect pressor effects
Venlafaxine Interactions
Clmetidine		venlafaxine levels		CYP P450 inhibition
Haloperidol		haloperidol levels Haloperidol elimination half-life unchanged		Unknown
MAOIs		Serotonin syndrome		Serotonin synergism
SSRIs		Potential venlafaxine levels		2D6 inhibition
		Serotonin syndrome		Serotonin synergism
Nefazodone Interactions
Glucocorticoids		steroid		Inhibit 3A4

TCA=tricyclic antidepressant; =increased; CNS=central nervous system; =decreased; CYP=cytochrome P450; MAOIs=monoamine oxidase inhibitors. =incr eased; TCAs=tricyclic antidepressants; CYP=cytochrome P450; SSRIs=selective serotonin reuptake inhibitors; LSD=lysergic acid diethylamide; MAOIs=monoamine oxidase inhibitors.

Table 8. TCA Monitoring^29,30.

Baseline		At Therapeutic dose steady state		Annually or PRN
		(Steady state at 5 x half life (t1/2) of drug)
EKG, HR, BP (with orthostasis)		EKG, HR, BP with orthostasis		EKG, BP, HR
		Serum levels		Serum levels
Serum Level Monitoring		10–14 hour after last dose for once daily dosing 4–6 hours after last dose of split dosing
TCA		Therapeutic serum level (μ/L)		TOXIC LEVEL (μ/L)
Amitriptyline		120–250		>500
Desipramine		115–250		>500
Nortriptyline		50–150		>300
Imipramine		180–350		>500

Table 9. Intranasal Esketamine BP/HR Monitoring^4,29,30.

Esketamine may cause increases in BP and Heart rate.
For baseline BP >140/90 the risks of an increase in BP should be weighed against potential benefit. Food and drink discouraged for 2 hours prior to drug to reduce nausea/vomiting.
	Prior to Administration		40 minutes		120 minutes
	BP and HR		BP and HR		BP and HR
BP should be stable or reducing to baseline to discharge home. Patients should not drive to or from visits and should abstain from driving until the following day. (PDR 2020)

Table 10. Brexanalone IV Monitoring^5,6,30.

Brexanalone is associated with a risk of excessive sedation and loss of consciousness in some patients.

Before Administration Counsel the patient on signs and symptoms of excessive sedation, loss of consciousness, and the importance of immediately reporting to a healthcare provider any signs and symptoms of excessive sedation using the Patient Information Guide. Provide a copy of the material to the patient.

During treatment, every 2 hours: • Assess the patient’s health status for signs and symptoms pf excessive sedation and loss of consciousness.

During treatment: • Assess the patient’s oxygen saturation using continuous pulse oximetry.

After treatment discontinuation, prior to discharge: • Assess the patient’s level of sedation

After treatment discontinuation, within 3 business days of completion date: • Report excessive sedation or loss of consciousness to the REMS Program using the Excessive Sedation and Loss of Consciousness Adverse Event Form

Table 11. Mood Stabilizers^29,30,68,73.

		Lithium*		Valproic Acid*		Carbamazepine*,‡
		(Cibalith-S, Eskalith, Lithane, Lithobid, Lithonate, Lithotabs)		(Depakene, Depakote)		(Carbitrol, Tegretol)
Serum plasma levels		0.6–1.2 mEq/L (acute)		50–100 (μ/mL)		4–12 (μg/mL)
Usual adult daily dosage		600–1,800 mg		750–4,200 mg		400–1,600 mg
Onset of action		5–14 days		5–15 days		3–15 days
Protein binding		Not bound to plasma proteins		90% concentration dependent with high concentration (variable due to saturation)		76%
t1/2		24 hours (average) with age and/or with decreased renal function		6–16 hours (average) with age and/or decreased hepatic function		Initial range 26–65 hours; with repeated dosing, 12–17 hours
Metabolic pathway(s)		Not metabolized, primarily excreted unchanged in urine		Hepatic (glucuronidation, mitochondrial boxidation, microsomal oxidation)		Hepatic: CYP 3A, 2D6
Route(s) of elimination		Renal		Glucuronidation, renal		Renal (72%), fecal (28%)
Common drug interactions		lithium serum concentrations (fluoxetine,† ACE inhibitors, diuretics, NSAIDs) lithium serum concentrations (acetazolamide, osmotic diuretics, theophylline, urinary alkalinizers)		Interacts with drugs that are hepatically metabolized; enzyme inducers can decrease concentrations of valproic acid; valproic acid can increase		Induces metabolism of CYP 3A4-dependent drugs; decreases phenobarbital, phenytoin, sex steroids, haloperidol, valproic acid, calcium channel blockers, etc.
		Lithium*		Valproic Acid*		Carbamazepine*,‡
		Antipsychotics may increase lithium neurotoxicity		phenobarbital by impairment of nonrenal clearance (severe CNS depression)		(see Table 6). Valproate increases 10, 11 epoxide metabolite of carbamazepine.
Common adverse effects		Nausea, vomiting, diarrhea, polyuria, polydipsia, tremor, hypothyroidism		GI distress, diplopia, sedation, tremor, edema, weight gain, alopecia, and thrombocytopenia		Dizziness, drowsiness, ataxia, and weight gain
Indication(s)		Manic episodes of bipolar disorder, bipolar disorder maintenance		Bipolar disorder, acute mania (and seizure disorders)		Partial complex seizures

=decreased; =increased; CYP=cytochrome P450; ACE=angiotensin-converting enzyme; NSAIDs=nonsteroidal anti-inflammatory drugs; CNS=central nervous system; GI=gastrointestinal.

*Women taking a mood stabilizing agent should be given a pregnancy test at baseline and then as clinically indicated.

^†Both increases and decreases have been reported and lithium levels should be monitored when used together.

^‡Carbamazepine may decrease the efficacy of oral contraceptives through enzyme induction.

Table 12. Baseline and Routine Monitoring Parameters for Mood Stabilizers^{29,30,34–36,69,72–73}.

Laboratory Parameters		Lithium*		Carbamazepi ne*,†,‡		VaLproic Acid*
Serum plasma concentrations		Weekly × 4 weeks, then monthly × 3 months, then every 3 months or as clinically indicated		2 weeks after initiation, then every 3 months or as clinically indicated		2 weeks after initiation, then every 3 months or as clinically indicated
Complete blood count		Baseline, monthly × 3 months, then as clinically indicated		Baseline, then monthly × 3 months, then as clinically indicated		Baseline, then monthly × 6 months, then every 6 months or as clinically indicated (include differential and platelets)
Blood chemistries		Baseline, then every 12 months or as clinically indicated (eg, serum creatinine, renal function, and electrolytes)		Baseline, then annually as indicated		Baseline, monthly then × 6 months, then every 6 months or as clinically indicated (eg, hepatic and renal function)
ECG (in patients 45 years or with preexisting cardiac disease)		Baseline, then every 12 months or as clinically indicated		Baseline, then every 12 months		Baseline, then as clinically indicated
Urinalysis		Baseline, then as clinically indicated		Baseline, then as clinically indicated		Baseline, then every 6 months or as clinically indicated
PT/PTT		—		—		Baseline, then every 6 months or as clinically indicated
Thyroid function tests (T3 ,T4,TSH, FTI )		Baseiine, then every 12 months		Baseline, then every 12 months		—

*Women taking a mood stabilizing agent should be given a pregnancy test at baseline and then as clinically indicated.

^†Although carbamazepine is not approved by the FDA for psychiatric indications, the authors view it as one of the most important agents available for the treatment of bipolar disorder. This view is supported in the medical literature.

^‡Carbamazepine may decrease the efficacy of oral contraceptives through enzyme induction.

ECG=electrocardiogram; PT/PTT=prthrombin time;

TSH=thyroid stimulaing hormone; FTI=free thyroid index;

FDA=Food and Drug Administration.

Table 13. Benzodiazepine Anxiolytics*^{29,30,40,53,54}.

Approved Oral Adult Dosage Range (mg/day)

Approximate Equivalent Dosages (mg/day)

Half-life of Parent Drug (hrs)

Peak Plasma Level tmax(hrs)

Half-life for Major Active Metabolites (hrs)

Metabolic Pathway

Pregnancy Risk Category

Alprazolam†,‡ (Xanax)

General: 0.75–4.0 Panic disorder: 1–10

0.5

6.3–26.9

1–2

None

Oxidation

D

Chlordiazepoxide†,ll (Librium, Libritabs, Mitran)

15–100

10

24–48

Several hours

Desmethyl- chlordiazepoxide (18) Demoxepam (14–95) Desmethyldiazepam (30–200) Oxazepam (3–21)

N-dealkylation

D (not FDA specified)

Clonazepam†,‡ (Klonopin)

1.5–20

0.25

18–50

1–2

None

Reduction, hydroxylation, oxidation

D (not FDA specified)

Clorazepate†,ll (ClorazeCaps, ClorazeTabs, Gen-XENE, Tranxene)

15–60

7.5

Prodrug

1–2

Oxazepam (3–21) Desmethyldiazepam (30–200)

Oxidation, hydroxylation, conjugation

D (not FDA specified)

Diazepam† (Valium, Valrelease, Zetran)

4–40

5

20–80

0.5–2

Desmethyldiazepam (30–200) 3-Hydroxydiazepam (5–20) Oxazepam (3–21)

Oxidation, hydroxylation, demethylation

D (not FDA specified)

Lorazepam† (Ativan)

1–10

1

12

2

None

Conjugation

D

Oxazepam† (Serax)

30–120

15

5.7–10.9

3

None

Conjugation

D (not FDA specified)

Prazepam† (Centrax)

20–60

10

Prodrug

6

—

Oxidation

D (not FDA specified)

*Adverse events commonly seen with the benzodiazepines include drowsiness, ataxia, confusion, fatigue, anterograde amnesia, light-headedness, and dizziness.

^†Single doses provide sedation and calming; chronic dosing reduces symptoms of generalized anxiety disorder.

^‡Clonazepam and alprazolam are FDA approved for PD.

^llFor alcohol detoxification and withdrawal, doses of up to 300 mg of chlordiazepoxide and 90 mg of clorazepate may be warranted.

D=relatively contraindicated; FDA = Food and Drug Administration; PD=panic disorder.

Table 14. Nonbenzodiazepine Anxiolytics^{29,30,75–77}.

Drug		Brand Name		Dosage (mg)		Indications
Buspirone*		BuSpar		5–20 mg TID or 15–30 mg BID		GAD
Hydroxyzine†		Vistaril, Atarax		50–100 mg QD		Anxiety, tension

*Adverse events commonly seen with buspirone include dizziness, nausea, headache, nervousness, lightheadedness, and excitement.

^†Second-agent.

GAD=generalized anxiety disorder.

Table 15. Benzodiazepine Drug Interactons^{29,30, 61,62}.

Drug		Interaction		Mechanism
Antacids		absorption and benzodiazepine levels		gastric pH
Carbamazepine		benzodiazepine levels		CYP induction
Cimetidine		benzodiazepine levels		CYP inhibition
Digoxin		digoxin levels		Unknown
Erythromycin		alprazolam levels		3A4 inhibition
Ethanol		sedation/respiratory depression		CNS depression synergism
Nefazodone		alprazolam, triazolam levels		3A4 inhibition
Opioids		sedation, respiratory depression		CNS additive
SSRIs		diazepam, alprazolam levels		2D6 and 3A4 inhibition
Valproic acid		benzodiazepine levels		metabolism

=decreased; CYP=cytochrome P450; =increased; CNS=central nervous system; SSRIs=selective serotonin reuptake inhibitors.

Table 16. Hypnotic Agents^{29,30,40–53}.

Daily Adult Dosage (mg/day)

Time to Peak Plasma Level (hours)

t1/2 (hours)

Metabolic Pathway

Pharmacokinetic Parameters Active Metabolites

Protein Binding (%)

Benzodiazepines

Estazolam (ProSom)

0.5–2

0.5–6

10–24

Oxidation

None

93

Flurazepam (Dalmane)

15–30

0.5–1 4.7–100†

2.3 36–120†

Oxidation, N-dealkylation

N-desalkylflurazepam, hydroxyethylflurazepam, flurazepam aldehyde

97

Quazepam (Doral)

7.5–15

2 73†

39 36–120†

Oxidation

N-desalkylflurazepam, 2-oxoquazepam

>95

Temazepam (Restoril)

7.5–30

1.2–1.6

3.5–18.4

Conjugation

None

96

Triazolam (Halcion)

0.125–0.5

2

1.5–5.5

Conjugation

None

89

Nonbenzodiazepines

Chloral hydrate (Noctec, Aquachloral Supprettes)

500–2,000

0.5–12†

8–11†

Oxidation, reduction

Trichloroethanol

35–41†

Zaleplon (Sonata)

5–20

1

1

Oxidation

5-oxo-zaleplon

92

Zolpidem (Ambien)

5–10

1.6

2.6 1.4–4.5

Oxidation, hydroxylation

None

92.5

*Quitken FM. Current Psychotherapeutic Drugs. 2nd ed. Washington, DC: American Psychiatric Press; 1998.

^†Values given for active metabolite.

Table 17. First Generation Antipsychotic Dosages and Adverse Effects^{29,30,40,41,44}.

		Class		Traditional Equivalents		Dosage* Range (mg/day) PO		Usual Maximum Dosage for Organic Mental Syndrome (mg/day)		Usual Dosage for Patients >65 Years of Age (mg/day)*
Chlorpromazine† (Ormazine, Thorazine)		Aliphatic phenothiazine		100		30–800		400		400
Thioridazine (Mellaril)		Piperidine phenothiazine		100		20–800		200		200
Mesoridazine (Serentil)		Piperidine phenothiazine		50		30–400		—		—
Fluphenazine (Permitil, Prolixin)		Piperazine phenothiazine		2		1–40		10		10
Perphenazine (Trilafon)		Piperazine phenothiazine		8		12–64		16		16
Trifluoperazine (Stelazine)		Piperazine phenothiazine		5		2–40		20		20
Thiothixene (Navane)		Thioxanthene		4		6–60		15		15
Haloperidol (Haldol)		Butyrophenone		2		1–100		15		15
Loxapine (Loxitane)		Dibenzoxazepine		10		20–250		60		60
Molindone (Moban)		Dihydroindolone		10		15–225		55		55
Pimozide (Orap)		Piperidine		—		1–10		—		—
Droperidol (Inapsine)		Butyrophenone		—		2.5–15		—		—
		Adverse Effects‡				Adverse Effects‡
		Extrapyramidal		Sedation		Anticholinergic		Orthostatic Hypotension
Chlorpromazine		++		+++		+++		+++
Thioridazine		+		+++		++++		+++
Mesoridazine		+		+++		++++		++
Fluphenazine		++++		++		++		++
Perphenazine		+++		++		++		++
Trifluoperazine		+++		++		++		++
Thiothixene		+++		++		++		++
Haloperidol		++++		+		+		+
Loxapine		+++		++		++		++
Molindone		+++		++		++		++
Pimozide		+++		+		+		+
Droperidol		++++		+++		+		++

*In elderly patients, doses should be lowered and tailored to the patient.

^†Labeling suggests higher doses may be appropriate, noting intramuscular doses up to 2,000 mg (using >1,000 mg only in severe cases).

^‡Severity: ++++=extremely high; +++=high; ++=moderate; +=low.

Table 18. Second Generation Antipsychotic Dosages and Adverse Effects^{29,30,32,33,47,78–81}.

		Starting Dose		Dosage* Range (mg/day) PO		Recommended Dosage for Patients >65 Years of AGE mg/day*
Aripiprazole (Abilify)		2–5		10–30		2–15
Asenapine (Saphris, Secuado)		10–20		10–20		5–20
Brexpiprazole (Rexulti)		0.5–1		2–3		1–2
Cariprazine (Vraylar)		1.5		3–6		1.5–3
Clozapine (Clozaril)		12.5–25		300–900		25–100
Ileoperidone (Fanapt)		1–2		12–24		6–12
Lumateperone (Caplyta)		42		42		42
Lurasidone (Latuda)		20–40		60–120		20–60
Olanzapine (Zyprexa)		5–10		5–20		5–10
Pimavanserin (Nuplazid)		17		17–34		10–17
Quetiapine (Seroquel)		25–50		50–750		Slower rate of dose titration, lower target dose
Risperidone (Risperdal)		0.5–1		2–16		0.5 to start
Ziprasidone (Geodon)		20–40		40–160		Slow rate of dose titration, lower target dose
		Adverse Effects†				Adverse Effects†
		Extrapyramidal		Sedation		Weight Gain		Anticholinergic		Orthostatic Hypotension
Aripiprazole		++		+		++		+		+
Asenapine		+		++		+		+		+++
Brexpiprazole		++		+		+		+		+
Cariprazine		++		+		+		+		+
Clozapine		0		++++		++++		++++		++++‡
Ileoperidone		+		+		++		++		++
Lurasidone		+		++		+		+		+
Olanzapine		+		++++		++++		++		+
Risperidone		+++§		++		+		+		++‡
Quetiapine		0/+		++/++		+++		++		++
Ziprasidone		++		++		+/0		+		++

*In elderly patients, doses should be lowered and tailored to the patient.

^†Severity: ++++=extremely high; +++=high; ++=moderate; +=low; 0=none.

^‡Tolerance develops; slow dose titration is necessary.

^§Dose-dependent extrapyramidal effects.

N/A=not available.

Table 19. Pharmacokinetic Parameters and Dosing of Depot and Long Acting Antipsychotics*^29,30,82,83.

First Generation Antipsychotics

Drug

Starting Dosage

Maintenance Dosage

tmax (days)

t1/2 Single Dose (days)

t1/2 Multiple Dose (days)

Time to Steady State (weeks)

Haloperidol decanoate

20 × oral haloperidol 100–450 mg/28 days

10–15 × oral haloperidol 50–300 mg/28 days

4–11

21

21

12

Fluphenazine decanoate

1.2 × oral fluphenazine 12.5–75 mg/7–14 days

Based on starting dose and clinical response

0.3–2

6–10

14

4–8

Fluphenazine enanthate

12.5–100 mg/7–21 days

Based on starting dose and clinical response

2–3

3.5–4

N/A

3

Second Generation Long Acting Injectable Antipsychotics

Drug

Starting Dose

Maintenance Dosage

T1/2

Steady State

Aripiprazole (Abilify Maintena)

400 mg/monthly

300–400 mg/monthly

30–46 days

4 months

Aripiprzole Lauroxil (Aristada)

441 mg/monthly

441–882 mg/month. Or 882 mg/every 6 weeks or 1064 mg/every 8 weeks

29–35 days

4 months

Paliperidone

Invega Sustenna

234 mg on day 1, and 156 mg 1 week later

39 mg to 234 mg (average maintenance dose 117 mg)/monthly

25–49 days

4–5 months

Invega Trinza

273 mg

273–829/ every three months

84–95 days

12–15 Months

Risperidone Consta

25 mg for 2 weeks

25–50 mg/every 2 weeks

3–6 day

4 weeks

Olanzapine Relprevv

150 mg for 2 weeks

150–300 mg/every 2 weeks or 405 mg/every 4 weeks

30 days

3 months

*Patients maintained for 1 year or longer demonstrated a very long time to wash out drug (terminal observed half-life exceeding 60 days).

N/A=not available.

Table 20. Antiparkinsonian Agents^{29,30,42,84,86}.

Drug		Approximate Dose Equivalent (mg)		Dosage Range (mg/day)		Dose Forms
Antimuscarinics
Benztropine (Cogentin)		1		1–8		T, I
Biperiden (Akineton)		2		2–8		T, I
Ethopropazine (Parsidol)		50		50–600		T
Orphenadrine (Various)		50		50–250		T
Procyclidine (Kemadrin)		2		7.5–20		T
Trihexyphenidyl (Artane)		2		2–15		T, C-SR, L
Antihistaminic
Diphenhydramine (Various)		50		50–400		C,T, L, I
Dopamine Agonists
Amantadine (Symadine, Symmetrel)		N/A		100–400		C, L
Ropinirole (Requip)		N/A		0.75–24*		T
Pramipexole (Mirapex)		N/A		1.5–4.5*		T

*Maintenance dose for Parkinson’s disease.

T=tablet; I=injection; C=capsule; SR=sustained release; L=liquid solution, elixir, or suspension;

N/A=not available.

Table 21. Antipsychotic Drug Interactions^{29,30,61–79,86}.

Interacting Medication		Mechanism		Clinical Effect
Drug interactions assessed to have major severity
Anticholinergics		Pharmacodynamic effects Additive anticholinergic effect		Decreased antipsychotic effect
Barbiturates		Phenobarbital induces antipsychotic metabolism		Decreased antipsychotic concentrations
Beta-blockers		Synergistic pharmacologic effect; antipsychotic inhibits metabolism of propranolol; antipsychotic increases plasma concentrations		Severe hypotension
Carbamazepine		Induces antipsychotic metabolism		Up to 50% reduction in antipsychotic concentrations
Charcoal		Reduces GI absorption of antipsychotic and absorbs drug during enterohepatic circulation		May reduce antipsychotic effect or cause toxicity when used during overdose or for GI disturbances
Cigarette smoking		Induction of microsomal enzymes		Reduced plasma concentrations of antipsychotic agents
Epinephrine, norepinephrine		Antipsychotic antagonizes pressor effect		Hypotension
Ethanol		Additive CNS depression		Impaired psychomotor skills
Fluvoxamine		Fluvoxamine inhibits metabolism of haloperidol and clozapine		Increased concentrations of haloperidol and clozapine
Guanethidine		Antipsychotic antagonizes guanethidine neuronal uptake		Impaired antihypertensive effect
Lithium		Unknown		Rare reports of neurotoxicity
Meperidine		Additive CNS depression		Hypotension and sedation
Interacting Medication		Mechanism		Clinical Effect
Amphetamines, anorexiants		Decrease pharmacologic effect of amphetamine; drug-disease state interaction		Diminished weight-loss effect; amphetamines may exacerbate psychosis; treatment-refractory patients may improve
ACE inhibitors		Additive hypotensive effect		Hypotension, postural intolerance
Antacids containing aluminum		Insoluble complex in GI tract formed		Possible reduced antipsychotic effect
Antidepressants (antidepressant, nonspecific)		Decreases metabolism of antidepressant through competitive inhibition		Increased antidepressant concentration
Benzodiazepines		Increases pharmacologic effect of benzodiazepine		Respiratory depression, stupor, hypotension
Bromocriptine		Antipsychotic antagonizes dopamine receptor stimulation		Increased prolactin
Caffeinated beverages		Form precipitate with antipsychotic solutions		Possible diminished antipsychotic effect
Cimetidine		Reduces antipsychotic absorption and inhibits clearance		Increased or decreased antipsychotic effect
Clonidine		Antipsychotic potentiates α-2-adrenergic hypotensive effect		Hypotension
Disulfiram		Impairs antipsychotic metabolism		Increased antipsychotic concentrations
Methyldopa		Unknown		Blood pressure elevations
Phenytoin		Induction of antipsychotic metabolism; increases phenytoin metabolism		Decreased antipsychotic concentrations; decreased phenytoin levels
SSRIs		Impair antipsychotic metabolism; pharmacodynamic interaction		Sudden onset of extrapyramidal symptoms
Valproic acid		Antipsychotic inhibits valproic acid metabolism		Increased valproic acid half-life and levels

ACE=angiotensin-converting enzyme; GI=gastrointestinal; CNS=central nervous system SSRIs=selective serotonin reuptake inhibitors.

Table 22. Acute Neurologic Side Effects of Antipsychotic Medications^{29,30,79,86,87}.

Reaction		Clinical Features		Approximate Onset		Treatment
Acute dystonia		Spasm of tongue, throat, face, jaw, eyes, neck, or back muscles		<1 week		Injectable benztropine or diphenhydramine, followed by oral anticholinergics or benzodiazepines
Akathisia		Motor restlessness, inability to stay still		<1 week– 2 weeks		If possible, reduce dose of antipsychotic; add beta-blockers, benzodiazepines, or anticholinergics
Pseudoparkinsonism		Bradykinesia, rigidity, resting tremor, rabbit syndrome, sialorrhea, flat affect		~1 week		Add anticholinergics or amantadine; diphenhydramine and lorazepam may also be effective

Table 23. Pharmacokinetic Parameters of Selected Oral Antipsychotics^{29,30,40,41,79,84–88}.

Bioavailability (%)

Protein Binding (%)

vd (L/kg)*

Plasma t1/2 (hours)

Active Metabolites

therapeutic plasma concentration (ng/ml)

Chlorpromazine

10–33

90–95

7–20

8–35

7-hydroxy

100–300†

Clozapine

—

95

4–66

4–66

Desmethyl

350

Haloperidol

40–70

92

10–35

12–36

Reduced haloperidol

3.0–30 5–12‡

Fluphenazine

10–50

90–95

—

14–24

Hydroxy

0.2–3

Olanzapine

–60

93

10–20

21–54

—

9–20†

Perphenazine

25

—

10–35

8–21

None known

—

Quetiapine

100

83

6–14

–6

7-hydroxy 7-hydroxy-N-dealkylated

—

Risperidone

70

90

—

3–20

9-hydroxy

—

Thioridazine

25–33

99

—

9–30

Mesoridazine, sulphoridazine

200–800†

Thiothixene

50

90–95

—

34

None known

1.0–5.0*,§ 10–30*,**

*Range given includes mean +/– standard deviation.

^†Data inconclusive regarding therapeutic range for these drugs.

^‡Optimal concentration for response not emcompassing neuroleptic threshold (3–5 ng/mL).

^§Trough concentration, predose.

**Peak concentration 2–3 hours postdose.

Table 24. APA/ADA Recommendations for Patients Who Are Taking Antipsychotics*.

Prior to starting an antipsychotic Screen for personal of family history of diabetes, high blood pressure, heart disease, high cholesterol Weight and height (BMI ·25) Waist circumference (>40 inches in males, 35 inches in females) Blood pressure >130/85 Fasting glucose >110 Fasting cholesterol (HDL <40, total >200) Fasting triglyceride levels (>175) Reassess weight at weeks 4, 8, 12 and quarterly thereafter. Weight gain >5% consider switching antipsychotics. Reassess glucose, lipids and blood pressure 3 months after starting the antipsychotic. Thereafter, check BP annually or as needed. Lipids checked at 5 year intervals or as needed. Assessing EPS symptoms (place after table 19) Extrapyramidal symptoms may be checked at every visit or every 6 months.

*Diabetes Care 2004; 27(2): 596–601.

Table 25. VMAT Inhibitors for the Treatment of Tardive Dyskinesia^19,20,29,30.

VMAT2 Inhibitor

Starting dose

Therapeutic Dose

Valbenazine (Ingrezza)

40 mg

40–80 mg

Deutetrabenzaine (Austedo)

6 mg bid

12–24 mg bid

ADA/APA Monitoring protocol for patients on Second Generation Antipsychotics (SGA)s

Baseline

4 weeks

8 weeks

12 weeks

Quarterly

Annually

Every 5 years

Personal/family history

X

X

Weight (BMI)

X

X

X

X

X

Waist circumference

X

X

Blood pressure

X

X

X

Fasting plasma glucose

X

X

X

Fasting lipid profile

X

X

X

Table 26. Clozapine Monitoring by Acute Neutrophil Count (ANC) Level for the General Population. (For patients with Benign Ethnic Neutropenia, please see clozapine REMs).

ANC Level		Recommendation		ANC Frequency
Normal Range for a New Patient (ANC ≥1500/μL)		• Initiate treatment • If treatment interrupted:  – <30 days, continue monitoring as before  – ≥30 days, monitor as if new patient (Patient interrupted treatment for any reason other than low ANC)		• Weekly from initiation to 6 months • Every 2 weeks from 6 to 12 months • Monthly after 12 months
Mild Neutropenia (1000 to 1499/μL)*		• Continue treatment		• Three times weekly until ANC ≥1500/μL • Once ANC ≥1500/μL, return to patient’s last normal range ANC monitoring interval
Moderate Neutropenia (500 to 999/μL)*		• Hematology consultation • Suspend treatment for suspected clozapine induced neutropenia • Resume treatment once ANC normalizes to ≥1000/μL		• Daily until ANC ≥1000/μL, then • Three times weekly until ANC ≥1500/μL • Once ANC ≥1500/μL, check ANC weekly for 4 weeks, then monthly as appropriate
Severe Neutropenia(less than 500/μL)*		• Hematology consultation • Suspend treatment for suspected clozapine induced neutropenia • Consider discontinuing unless the benefits clearly outweigh the risks		• Daily until ANC ≥1000/μL • Three times weekly until ANC ≥1500/μL • If patient is restarted on clozapine, monitor as a new patient or as needed

*Confirm all initial reports of ANC less than 1500/μL (ANC < 1000/μL for BEN patients) with a repeat ANC measurement within 24 hours.

Source: Adapted from Clozapine and the Risk of Neutropenia: An Overview for Healthcare Providers, 2014 (www.clozapinerems.com).

Table 27. Anorexiants^{29,30,64–71,89–91}.

Agent		dosage range (mg/day)		indication
Amphetamine (Biphetamine)		5–40		Obesity
Naltrexone + Bupropion 8/90 mg (Contrave)		1–2 tablets BID		Obesity
Methamphetamine (Desoxyn)		10–15		Obesity
Orlistat (Xenical)		120 TID with meals		Obesity
Phendimetrazine (various)		70–105		Obesity
Phentermine (Adipex-P, various)		18.75–37.5		Obesity
Phentermine + Topiramate 3.75/23 mg (Qsmia)		1–2 tablets Daily		Obesity

Table 28. Psychostimulants^29,30,92.

Agent		Dosage Range (mg/day)		Indication
Dextroamphetamine (Dexedrine)		5–40 5–60		ADHD Narcolepsy
Dextroamphetamine + amphetamine (Adderall)		5–40 5–60		ADHD Narcolepsy
Methamphetamine (Desoxyn)		5–25*		ADHD
Methylphenidate (Ritalin, Ritalin LA, Aptenso XR)		10–40 10–60		ADHD Narcolepsy
Methylphenidate HCI (Concerta)		18–54		ADHD
Modafinil (Provigil)		200–400		Narcolepsy, idiopathic hypersomnia
Armodafinil (Nuvigil)		150–250
Lisdexamfetamine (Vyvanse)		30–70		ADHD, Binge Eating

ADHD=attention-deficit/hyperactivity disorder. *20–25 mg is effective dosage range; can be titrated up from 5 mg.

Table 29. Drugs for Alzheimer’s Disease^{29,30,38,40,93,97} (Cholinesterase Inhibitors).

Drug

Dosage

Peak Plasma

Elimination Half-life

steady State

Protein Binding

Metabolism

Donepezil (Aricept)

5–10 mg/day

3–4 hours

70 hours

15 days

96%

2D6, 3A3/4

Galantamine (Reminyl)

16–32 mg/day

1 hour

7 hours

–

18%

2D6, 3A4

Rivastigmine (Exelon)

6–12 mg/day

1.4–2.6 hours

1.5–3 hours

24–48 days

40%

Not CYP dependent

CYP=cytochrome P450.

Table 30. Adverse Effects of Cholinesterase Inhibitors^{29,30,37,39,93–96,98,99}.

Symptom		Donepezil		Galantamine		Rivastigmine		Tacrine
GI
Nausea, vomiting		+		++++		++		+++
Weight loss		+		+		++ (dose dependent)		+
LFTs rise		–		–		–		+++
CNS
Insomnia		+/-		+		+/-		+
Fatigue		+/-		+		+/-		+/-
Depression		+/-		+		+/-		+/-
Miscellaneous
Syncope		+/-		+		+		+/-
Increased urination		+/-		+		+/-		+/-
Rhinitis		+/-		+		–		–

++++=high; +++=moderate; ++=low; +=very low; –=none. GI=gastrointestinal; LFTs=liver function tests; CNS=central nervous system.

Appendix

The Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR₁₆)²⁵

Patient Health Questionnaire (PHQ-9)²⁹

For physician use only

Scoring:

Count the number (#) of boxes checked in a column. Multiply that number by the value indicated below, then add the subtotal to produce a total score. The possible range is 0-27. Use the table below to interpret the PHQ-9 score.

* PHQ-9 is described in more detail at the McArthur Institute on Depression & Primary Care website www.depression-primarycare.org/clinicians/toolkits/materials/forms/phq9/

Abnormal Involuntary Movement Scale (AIMS)²⁷

AIMS Examination Procedure

Either before or after completing the Examination Procedure, observe the patient unobtrusively, at rest (e.g., in the waiting room)

The chair to be used in this examination should be a hard, firm one without arms.

1. Ask the patient whether there is anything in his/her mouth (i.e., gum, candy, etc.) And if there is, remove it.

2. Ask patient about the current condition of his/her teeth. Do teeth bother patient now?

3. Ask the patient whether he/she notices any movements in mouth, face, hands, or feet. If yes, ask to describe and to what extent they currently bother patient or interfere with his/her activities.

4. Have patient sit in chair with hands on knees, legs slightly apart, and feet flat on floor. (Look at entire body for movements while in this position).

5. Ask patient to sit with hands hanging unsupported. If male, between legs; if female and wearing a dress, hanging over knees. (Observe hands or other body areas).

6. Ask patient to open mouth. (Observe tongue at rest within mouth). Do this twice.

7. Ask patient to protrude tongue. (Observe abnormalities of tongue movement). Do this twice.

8. Ask patient to tap thumb, with each finger as rapidly as possible for 10 to 15 seconds; first with right hand, then with left hand. (Observe facial and leg movements).

9. Flex and extend patient’s left and right arms (one at a time).

10. Ask patient to stand up. (Observe in profile. Observe all body areas again, hips included).

11. Ask patient to extend both arms outstretched in front with palms down. (Observe trunk, legs, and mouth).

12. Have patient walk a few paces, turn, and walk back to chair. (Observe hands and gait). Do this twice.

Guy W: ECDEU Assessment Manual for Psychopharmacology - Revised (DHEW Publ No ADM 76-338), US Department of Health, Education and Welfare; 1976.

Generalized Anxiety Disorder 7-item (GAD-7) scale²⁸

If you checked off any problems, how difficult have these made it for you to do your work, take care of things at home, or get along with other people?

Not difficult at all ____________

Somewhat difficult ____________

Very difficult ____________

Extremely difficult ____________

Scoring

Scores of 5, 10, and 15 are taken as the cut-off points for mild, moderate and severe anxiety, respectively. When used as a screening tool, further evaluation is recommended when the score is 10 or greater.

Using the threshold score of 10, the GAD-7 has a sensitivity of 89% and a specificity of 82% for GAD. It is moderately good at screening three other common anxiety disorders—panic disorder (sensitivity 74%, specificity 81%), social anxiety disorder (sensitivity 72%, specificity 80%) and post-traumatic stress disorder (sensitivity 66%, specificity 81%).

Source: Spitzer RL, Kroenke K, Williams JBW, Lowe B. A brief measure for assessing generalized anxiety disorder. Arch Inern Med. 2006;166:1092–1097.

YOUNG MANIA RATING SCALE (YMRS)¹⁰⁰