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Psychopharmacology: Medications for the Mind

3 Contact Hours including 3 Advanced Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Nurse Midwife, Certified Nurse Practitioner, Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Friday, June 30, 2023

Nationally Accredited

CEUFast, Inc. is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. ANCC Provider number #P0274.

Outcomes

Medications for treating psychiatric disorders are widely used, and a basic level of knowledge about anxiolytics, antidepressants, antipsychotics, mood stabilizers, and psychostimulants is essential for professional nurses. This module will discuss neurotransmitters and their mechanisms of action, adverse effects, and the administration of anxiolytics, antidepressants, antipsychotics, mood stabilizers, and Central Nervous System (CNS) stimulants. The common and less serious adverse effects will be mentioned. The more serious and potentially dangerous adverse effects will be discussed in detail.

Objectives

On completion of this educational activity, participants will be able to:

  1. Describe how psychiatric medications affect neurotransmitter binding, release, and reuptake.
  2. Explain how neurotransmitter binding, agonism, and antagonism cause common adverse effects of psychiatric medications.
  3. Demonstrate knowledge of benzodiazepine withdrawal; MAOI/drug and food interactions; SSRIs and serotonin syndrome, TCAs and QT prolongation/TDP; as well as antipsychotics and NMS.
  4. Describe discontinuation syndrome and techniques used to discontinue the use of psychiatric medications.
  5. Explain the process of switching to or from an MAOI to an antidepressant.
  6. Compare and contrast the signs/symptoms, adverse effects, and laboratory tests used to monitor patients taking anxiolytics, antidepressants, antipsychotics, lithium, and CNS stimulants.
CEUFast Inc. and the course planners for this educational activity do not have any relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
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    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Dana Bartlett (RN, BSN, MA, MA, CSPI)

Introduction

Psychiatric illnesses are quite prevalent in the United States. In fact, the Centers for Disease Control and Prevention (CDC) estimated that > 50% of Americans will be diagnosed with a mental illness at some point in their lives (Centers for Disease Control and Prevention [CDC], 2018). In addition, the CDC also predicted that 1 in 5 children will have or will develop a serious mental illness and 1 in 25 Americans has a severe mental illness like bipolar disorder, major depression, or schizophrenia (CDC, 2018).

Psychotherapy is an important part of treating patients with a mental illness, but for many people, e.g., bipolar disorder or schizophrenia, pharmacotherapy is essential (Reus, 2018a; Reus, 2018b). Antipsychotics, mood stabilizers, antidepressants, and other psycho-pharmacotherapeutic drugs can significantly reduce the severity of the signs and symptoms of a psychiatric illness. For some patients, a combination of psychotherapy and pharmacotherapy is more effective than if either is used alone.

Neurotransmitters

Neurotransmitters are chemical messengers synthesized in neurons, and the neurotransmitters are used to convey messages from a neuron to an adjacent neuron or another type of cell (Costanzo, 2018). Neurotransmitters mediate the therapeutic effects and the adverse effects of anxiolytics, antidepressants, antipsychotics, mood stabilizers, and CNS stimulants.
neurotransmitters

How They Work

The basic process by which neurotransmitters function is described below (Costanzo, 2018; Curry et al., 2018).

  1. The neurotransmitter is synthesized and stored in the presynaptic neuron.
  2. An action potential in the presynaptic neuron causes an influx of Ca2+ into the neuron.
  3. The influx of Ca2+ causes the neurotransmitter to be released into the synapse.
  4. The neurotransmitter binds to neurotransmitter receptors that are located on the membrane of the postsynaptic cell.
  5. Depending on the type of neurotransmitter, they have either an excitatory effect or an inhibitory effect on the postsynaptic cell. An excitatory effect causes depolarization of the postsynaptic cell; an inhibitory effect causes hyperpolarization, making the postsynaptic cell less active.
  6. After release and binding, the neurotransmitter is either degraded by an enzyme or transport molecules bring it back to the presynaptic neuron, a reuptake process.
  7. The specific physiologic effect that occurs depends on the type and location of the postsynaptic cell, and an example is provided below.

Example: Benzodiazepines are used to treat anxiety symptoms, and their therapeutic effect is mediated by Gamma Aminobutyric Acid, otherwise known as GABA.

neurotransmitter_flowchart

Types of Neurotransmitters: Agonists vs. Antagonists

The drugs discussed in this module are agonists or antagonists (and sometimes both) of the neurotransmitters at their binding sites:

  • An agonist increases neurotransmitter binding and neurotransmitter activity.
  • An antagonist prevents neurotransmitter binding and decreases neurotransmitter activity.

Many neurotransmitters have multiple messages they can convey, depending on factors like which area of the nervous system they are released into and what quantities and combinations of neurotransmitters are present. It is important to remember that although the primary therapeutic effect of a psychoactive drug is mediated through a specific neurotransmitter, these medications can and do affect other neurotransmitter systems, and this has clinical significance. For example, the tricyclic antidepressant (TCA) doxepin increases the synaptic concentrations of norepinephrine and serotonin, decreasing the patient’s level of depression. This is how this drug causes its therapeutic effect. But doxepin also affects the activity of the neurotransmitters acetylcholine and histamine, which results in blurred vision, drowsiness, dry mouth, and other common side effects of the TCAs. Although benzodiazepines are used to treat anxiety, their neuroinhibitory effect is the basis of their effectiveness as anticonvulsants and muscle relaxers.

Neurotransmitters

  • Acetylcholine:
    • Acetylcholine (ACh) is the only neurotransmitter that is released at the neuromuscular junction (Costanzo, 2018).
    • ACh is the neurotransmitter released from all preganglionic and many post-ganglionic neurons in the parasympathetic nervous system (Costanzo, 2018).
    • ACh is the only neurotransmitter released from all of the preganglionic neurons in the sympathetic nervous system (Costanzo, 2018).
    • After binding to the nicotinic receptors and muscarinic receptors, ACh is degraded by acetylcholinesterase (Costanzo, 2018).
    • Acetylcholine is an important neurotransmitter for many psychoactive medications.
    • Example: The atypical and typical antipsychotics and the TCAs act as competitive antagonists at the muscarinic ACh receptors, blocking the binding of ACh to these receptor sites. Activation of the muscarinic ACh receptors by ACh produces an inhibitory effect, so the competitive antagonist property of these drugs has an excitatory effect. This, in turn, can cause anticholinergic signs and symptoms (Curry et al, 2018; Jibson, 2021; Jibson, 2020; Jurlink, 2018; Valento & Liebelt, 2018).
  • Dopamine:
    • Dopamine is a biogenic amine, similar in structure (and in some of its physiologic effects) to epinephrine and norepinephrine (Costanzo, 2018). The physiologic effects of dopamine are numerous and complex, and when discussing psychoactive medications, several are particularly important.
      • First, dopamine stimulates β-adrenergic receptors and α-adrenergic receptors, and it can increase blood pressure and heart rate. Methylphenidate, a CNS stimulant drug used to treat attention-deficit/hyperactivity disorder (ADHD), prevents dopamine reuptake into the presynaptic neurons (Curry et al., 2018), and increased blood pressure and heart rate are common adverse effects of this drug.
      • Second, dopamine acts on areas of the brain and neural pathways that control emotions and mood (Curry et al., 2018). The primary action of the atypical and typical antipsychotics is dopamine receptor D2 antagonism (Jibson, 2021; Jibson, 2020).
      • Third, dopamine also acts on areas of the brain and neural pathways that control movement. Dopaminergic blockade by the antipsychotics can cause movement disorders like extrapyramidal symptoms (EPS), akathisia, dystonias, Parkinsonism, tardive dyskinesia (Caroff & Campbell, 2016; Curry et al., 2018; Jibson, 2021; Jibson, 2020; Meyer, 2018; Pringsheim et al., 2018; Simon & Greenberg, 2018) and neuroleptic malignant syndrome (Curry et al., 2018; Kuhlwilm et al, 2020).
      • Fourth, dopamine is degraded by the enzyme monoamine oxidase (MAO) and the MAO inhibitors like selegiline and phenelzine, aka the MAOIs, were the first antidepressants.
  • Epinephrine and norepinephrine:
    • Epinephrine and norepinephrine bind to adrenergic receptors:
      • The ß-adrenergic receptors in the heart, lungs, and peripheral vasculature,
      • The a1-adrenergic receptors in the peripheral vasculature and,
      • The a2-adrenergic receptors in the CNS or the peripheral vasculature (Curry et al., 2018).
      • When epinephrine or norepinephrine binds to the ß-adrenergic receptors in the heart and the peripheral vasculature, the blood pressure and the heart rate are increased, and the pulmonary passages are dilated (Curry et al., 2018).
    • Drugs that mimic the activity of epinephrine or norepinephrine are called sympathomimetics: Methylphenidate is a sympathomimetic drug.
    • The TCAs, bupropion, duloxetine, venlafaxine, and other drugs that are used to treat depression and/or anxiety are thought to be effective, in part, by inhibiting the reuptake of norepinephrine, an effect that has been called the monoamine hypothesis (Harmer et al., 2017; O’ Donnell et al., 2018).
    • Epinephrine or norepinephrine binding to the a1-adrenergic receptors relaxes the smooth muscle of peripheral vasculature relaxes; this decreases peripheral resistance and blood pressure is lowered (Curry et al., 2018).
    • When epinephrine or norepinephrine binds to the peripheral a2-adrenergic receptors, vasoconstriction occurs (Curry et al., 2018). The TCAs and the antipsychotics can cause peripheral a2-adrenergic blockade and orthostatic hypotension (Meyer, 2018; Jibson, 2021; Jibson, 2020).
    • The binding of epinephrine or norepinephrine to the a2-adrenergic receptors in the CNS results in decreased sympathetic outflow and causes sedation and a decrease in blood pressure (Curry et al, 2018).
    • Clonidine is a centrally-acting a2-adrenergic agonist that is used to treat ADHD. Clonidine binds to the a2-adrenergic receptors in the CNS and, as was mentioned, this decreases sympathetic outflow and causes sedation and a decrease in blood pressure.
  • Histamine:
    • The neurotransmitter histamine is a primary mediator of immediate hypersensitivity and allergic reactions (Skidgel, 2018), and it is involved in many other physiologic processes.
    • The atypical antipsychotics, the typical antipsychotics, and the TCAs can act as histamine 1 (H1) receptor antagonists in the CNS and this effect can cause drowsiness and sedation (Jibson, 2021; Jibson, 2020; Meyer, 2018).
  • Serotonin:
    • Serotonin (5-hydroxytryptamine, 5-HT) has many physiologic functions.
    • In the CNS, serotonin modulates emotion, mood, personality, and sexual function (Curry, 2018).
    • There is evidence that suggests that changes in CNS serotonergic activity may be a cause of anxiety and depression (Sibley et al., 2018), and drugs that increase serotonin level are used as a primary treatment for these disorders (Hirsch & Birnbaum, 2020a; Sibley et al., 2018).
    • After serotonin is released from the presynaptic neuron and after it binds to a 5-HT receptor site, transport molecules take it back to the presynaptic neuron or it is degraded by MAO.
    • The selective serotonin reuptake inhibitors (SSRIs) and the TCAs inhibit the reuptake of serotonin, the MAOI antidepressants increase serotonin levels by inhibiting the activity of MAO (Hirsh & Birnbaum, 2020a; O’ Donnell et al., 2018), buspirone is a partial 5-HT1a receptor agonist, and the antidepressants nefazodone and trazodone are serotonin reuptake inhibitors as well as serotonin receptor antagonists (O’ Donnell et al., 2018).

Anxiolytics: Benzodiazepines and Buspirone

Anxiety disorders are the most common psychiatric disorder (Garakani et al., 2020; Reus, 2020c). Anxiety disorders affect ~ 15% to 20% of the general population (Reus, 2020c; Terlizzi & Villarroel, 2020) and many people who have an anxiety disorder have a psychiatric co-morbidity like depression (Shelton, 2019). The Diagnostic and Statistical Manual of Mental Disorders describes 12 types of anxiety disorder; this module will focus on the use of anxiolytics for the treatment of Generalized Anxiety Disorder (GAD).

Anxiolytics reduce the severity of the signs and symptoms of anxiety. Benzodiazepines and buspirone are categorized as anxiolytics; Escitalopram, paroxetine, duloxetine, and venlafaxine have a labeled use for the treatment of GAD, but they are categorized as SSRIs and SNRIs, respectively, and they will be discussed later in the module.

Benzodiazepines are the most commonly prescribed anxiolytic that are used to treat GAD (Garankani et al., 2020; Shelton, 2018), and they are effective for short-term and long-term use (Garanaki et al., 2020; Shelton, 2018). The benzodiazepines that are currently available in the US are listed below. The generic name is followed by the trade name.

  • Alprazolam (Xanax®)
  • Chlordiazepoxide (Librium®)
  • Clonazepam (Klonopin®)
  • Clorazepate (Tranxene®)
  • Diazepam (Valium®)
  • Flurazepam (Dalmane®)
  • Lorazepam (Ativan®)
  • Oxazepam (Serax®)
  • Quazepam (Doral®)
  • Temazepam (Restoril®)
  • Triazolam (Halcion®)

Benzodiazepines bind to a specific part of GABAA receptors, and the benzodiazepine – GABAA receptor binding increases the affinity of GABA for GABAA receptors. In simpler terms: The amount of GABA is not increased but the available GABA is more likely to bind to the receptors (Michic et al., 2018). The increased binding of GABA to the GABAA receptors causes an influx of Cl- ions into the postsynaptic neuron (Michic et al., 2018).

The Cl- ion influx hyperpolarizes the postsynaptic neuron, making it less able to respond to an action potential – this is the inhibitory effect of GABA (Michic et al., 2018).

With the benzodiazepines, the neurons and GABA pathways that are affected are in areas of the brain that influence behavior and emotion, hence the anxiolytic effects of these drugs (Michic et al, 2018).

Benzodiazepines all have the same mechanism of action, but they do differ in the onset of action, the duration of action, and the half-life of pharmacologically active metabolites (Bystritsky, 2020; Park, 2020; Strawn et al., 2018a). These pharmacokinetic variables can have clinical implications. They also differ in labeled use: flurazepam, oxazepam, quazepam temazepam, and triazolam have a labeled use as a treatment for insomnia, not for GAD.

Benzodiazepines are useful for treating GAD, but their adverse effects — especially CNS depression — make their use problematic and potentially dangerous for certain patients, e.g., elderly adults. In fact, the American Geriatrics Society advises clinicians to avoid using benzodiazepines for older patients (American Geriatrics Society, 2019). Other concerns when using benzodiazepines are listed below.

  • Adverse effects of the benzodiazepines include (but are not limited to) cognitive impairment, drowsiness, delirium, falls, and rebound anxiety after short-term use (American Geriatric Society, 2019; Bystritsky, 2020; Gomez et al., 2018).
  • Benzodiazepines are Schedule IV medications that can be abused (Garanaki et al, 2020; Shelton, 2018).
  • Long-term and even short-term use, i.e., 3 to 6 weeks, can cause dependence and tolerance (Fluyau et al, 2018; Garanaki et al, 2020; Shelton, 2018).
  • Treatment should be started with a low dose, e.g., 0.25 mg a day of clonazepam, and the dose should be slowly increased as needed, e.g., 1 mg of clonazepam two to three times a day (Bystritsky, 2020).
  • Discontinuation of the use of a benzodiazepine must be done slowly (Greller & Gupta, 2020; Park, 2020). Bystritsky (2020) recommends decreasing the dose by 10% at one-two week intervals. Abrupt discontinuation of use can cause serious adverse effects (Greller & Gupta, 2020), and withdrawal from a benzodiazepine can dangerous and even life-threatening (Soyka, 2017).
  • Benzodiazepine should not be prescribed for a patient who has a substance use disorder (Garanaki et al, 2020).
  • The optimum length of treatment with a benzodiazepine is not known (Gomez et al, 2018).
  • Benzodiazepines alone are unlikely to be effective for treating GAD and using a benzodiazepine and an SSRI or an SNRI together is a better approach (Garanaki et al, 2020). When and for whom a benzodiazepine should be used as a treatment for GAD and if a benzodiazepine should be used alone or with an antidepressant are clinical questions that must be answered on a case-by-case basis (Gomez et al., 2018; Strawn et al., 2018b).
  • There is evidence that benzodiazepines may actually reduce the effectiveness of antidepressants in some cases (Garanaki et al, 2020).

Buspirone, trade name Buspar®, is categorized as a miscellaneous antianxiety agent, and it has a labeled use for treating GAD or for short-term relief of signs and symptoms of anxiety (UpToDate, 2021a). The mechanism of action of buspirone is not completely understood, but its anxiolytic effects are likely mediated by serotonin 5-HT1a and 5-HT2 receptor blockade (Brystritsky, 2020; Shelton, 2018; UpToDate, 2021a) and not by any effect on benzodiazepine-GABA receptors.

Buspirone is as effective as benzodiazepines as a treatment for GAD but unlike benzodiazepines, it does not cause significant adverse CNS effects, nor does it cause dependence or withdrawal (Brystritsky, 2020; Shelton; 2018). The drawback of buspirone, when compared to benzodiazepines, is that the anxiolytic action of buspirone takes three to four weeks to begin (Brystritsky, 2020; Shelton, 2018). Buspirone can be used alone or in combination with an SSRI (Brystritsky, 2020; Garankani); the latter appears to be more common (Garankani et al., 2020; Shelton, 2018). The most common adverse effects of buspirone are dizziness, drowsiness, headache, and nausea (Garakani et al., 2020; UpToDate, 2021a).

Antidepressants

Depression is one of the most common psychiatric illnesses worldwide and in the United States (Munkholm et al., 2020; Villarroel & Terlizzi, 2020).

Major depressive disorder (MDD), which is the primary indication for the use of antidepressants (DeBattista, 2021a), has a lifetime prevalence in the US of ~ 17% (DeBattista, 2021a).

There are five categories of antidepressants:

  1. Monoamine oxidase inhibitors (MAOIs)
  2. Selective serotonin reuptake inhibitors (SSRIs)
  3. Serotonin-norepinephrine reuptake inhibitors (SNRIs)
  4. Tricyclic antidepressants (TCAs)
  5. Atypical antidepressants

Monoamine Oxidase Inhibitors (MAOIs)

The antidepressant action of MAOIs is mediated by their inhibitory effect on monoamine oxidase (MAO). Monoamine oxidase is an enzyme and there are two sub-types of MAO, MAO-A and MAO-B (O’Donnell et al., 2018).

  • Monoamine-A breaks down dietary amines like tyramine that is found in certain foods, e.g., aged cheeses (Hirsch & Birnbaum, 2019a; O’ Donnell et al., 2018).
  • MAO-B degrades dopamine, epinephrine, norepinephrine, and serotonin (Hirsch & Birnbaum, 2019a; O’ Donnell et al., 2018).

The MAOIs are categorized as antidepressants. They have a labeled use as a treatment for major depression.

There are four MAOIs that are available in the US: Generic name (Trade name):

  • Isocarboxazid (Marplan®)
  • Phenelzine (Nardil®)
  • Selegiline (Emsam, Zelapar®)
  • Tranylcypromine (Parnate®)

MAOIs differ in the selectivity of the neurotransmitters that they affect, which of the MAO subtypes they inhibit, and the reversibility of MAO inhibition (Hirsch & Birnbaum, 2019a; O’ Donnell et al., 2018). All MAOIs available in the US are irreversible MAO inhibitors; selegiline is a selective MAO-B inhibitor at low doses — this helps reduce dietary restrictions for patients who take this MAOI — but at high doses, it inhibits MAO-A and MAO-B (Benowitz, 2018a; Hirsch & Birnbaum, 2019a)

MAOIs are effective antidepressants (Hirsch & Birnbaum, 2019; O’ Donnell et al., 2018). However, MAOIs are dangerous when taken in overdose (Benowitz, 2018a). They can cause significant adverse effects (DeBattista, 2021a; Hirsch & Birnbaum, 2019a). Discontinuing their use must be done slowly and carefully and this process can cause a discontinuation syndrome (DeBattista, 2021a; Hirsch & Birnbaum,2019a).

There are MAOI-drug and MAOI-food interactions that can be dangerous and even lethal (Hirsch & Birnbaum,2019a). Because of these concerns, the MAOIs are seldom used, and they are typically prescribed only when other antidepressants have not worked (DeBattista, 2021a; Hirsch & Birnbaum, 2019a).

Adverse Effects of MAOIs: (DeBattista, 2021a; Hirsch & Birnbaum, 2019a).

  • Dizziness
  • Dry mouth
  • GI upset
  • Headache
  • Myoclonic jerks
  • Orthostatic hypotension
  • Insomnia
  • Restlessness
  • Sexual dysfunction
  • Urinary hesitancy

*The MAOIs have a US Boxed Warning on their prescribing information. This warning states that antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies.

Discontinuation of MAOIs:

To discontinue the use of an MAOI, the dose should be gradually tapered down over a two- to four-week period (Hirsch & Birnbaum, 2019b), and at least two weeks should pass before a new antidepressant is started (Boyce et al, 2020; Hirsch & Birnbaum, 2019b). Suddenly stopping the use of an MAOI can cause a discontinuation syndrome (Henzler, et al, 2019) and although for many people the signs and symptoms of a discontinuation syndrome are mild and the duration is brief (Davies & Read, 2019; Gabriel & Sharma, 2017), a serious discontinuation syndrome with a prolonged course can occur (Davies & Read, 2019; Gabriel & Sharma, 2017).

Switching to/from MAOIs:

Switching from another antidepressant to an MAOI or from an MAOI to an antidepressant should be done by:

  1. Tapering the antidepressant or the MAOI.
  2. Waiting two weeks after the last dose and then beginning therapy with the antidepressant or the MAOI (Hirsch & Birnbaum, 2019b).

The two-week waiting period is important because:

  • Some antidepressants have a long half-life and/or pharmacologically active metabolites and waiting two weeks after the last dose before beginning therapy with an MAOI reduces the risk of developing hypertensive crisis and/or serotonin syndrome (Boyce et al., 2020; Hirsch & Birnbaum, 2019b).
  • It takes two weeks for MAO levels to replenish and if an antidepressant is started too soon after an MAOI has been discontinued, high levels of serotonin could occur.

MAOI-Drug Interactions:

There are many potentially serious MAOI-drug interactions.

  • Concurrent use of an MAOI with a drug that increases the circulating levels of dopamine, norepinephrine, or serotonin, e.g., SSRIs or SNRIs, can cause serotonin syndrome (Foon et al., 2018; O’ Donnell et al., 2018; UpToDate, 2021b).
  • Concurrent use of an MAOI with an adrenergic agonist and/or a sympathomimetic can cause severe hypertension (O’ Donnell et al., 2018; UpToDate, 2021b).

MAOI-Food Interactions:

The MAOIs, except for selegiline at low doses, inhibit MAO-A, and MAO-A breaks down tyramine, a dietary amine that is found in foods like aged cheese. Large amounts of dietary tyramine cause a significant amount of noradrenaline to be released from neuronal synapses in the blood vessels and the heart (Salter & Kenney, 2018). These catecholamines cannot be degraded because of MAO inhibition by the MAOI. The combination of a tyramine-rich food and a MOAI can cause a hypertensive crisis and myocardial infarction (Salter & Kenney, 2018). Patients must be educated about the MAOI-food interactions and they should be given a list of foods that they should not eat and foods that can be eaten only in specific amounts (Hirsch & Birnbaum, 2019a).

Selective Serotonin Reuptake Inhibitors (SSRIs)

The antidepressant effect of SSRIs is mediated by the inhibition of the reuptake of serotonin in the synapses, effectively increasing the serotonin level in the brain. Increased levels of serotonin usually occur quickly after initiation of medication therapy, but the onset of response is usually seen in about two weeks; the full therapeutic effect may not be observed for up to eight weeks after initiation of treatment.

SSRIs have become the first-line treatment for MDD (DeBatista, 2021a; Hirsch & Birnbaum, 2020a; Coryell, 2020). The SSRIs are preferred for treating MDD because they are widely available, they are inexpensive, dose titration may not be needed, their adverse effect/side effect profile is comparatively benign, and compared to the MAOIs and the TCAs, they are much safer when taken in overdose (DeBatista, 2021a; Hirsch & Birnbaum, 2020a). Also, unlike the other antidepressants, the SSRIs have comparatively little effect on other neurotransmitter receptors like the a-adrenergic receptors, cholinergic receptors, and histamine receptors (DeBatista, 2021a; Hirsch & Birnbaum, 2020a). This makes the SSRIs more tolerable – the patient will not have anticholinergic, antihistaminic and adrenergic side effects – and safer.

There are six available SSRIs: Generic name (Trade name):

  • Citalopram (Celexa®)
  • Escitalopram (Lexapro®)
  • Fluoxetine (Prozac®)
  • Fluvoxamine (Luvox®)
  • Paroxetine (Paxil®)
  • Sertraline (Zoloft®)

The SSRIs all have the same mechanism of action. Choosing an SSRI will depend on the patient’s medical co-morbidities and possible drug-drug interactions between the SSRI and the patient’s medication.

Example: Fluoxetine is a strong CYP2D6 enzyme inhibitor and concurrent use of fluoxetine with antipsychotics, certain beta-blockers, and the over-the-counter cough suppressant dextromethorphan can cause an increase in the blood levels of these drugs or increase the risk of developing serotonin syndrome (UpToDate, 2021c).

Adverse Effects of SSRIs: (Hirsch & Birnbaum, 2020a)

  • The most common (≥ 10% occurrence) adverse effects of the SSRIs are:
    • Anxiety
    • Drowsiness
    • Headache
    • Insomnia
    • Sexual dysfunction
    • Weight gain
  • Other less common adverse effects that can occur are:
    • QT prolongation
    • Increased risk for suicidal behavior and suicidal ideation
    • Serotonin Syndrome

Sexual Dysfunction:

  • Sexual dysfunction is a common adverse effect of SSRIs (Atmaca, 2020; DeBatista, 2021a; Hirsch & Birnbaum, 2020a).
  • The true incidence of this adverse effect is difficult to determine, in part because sexual dysfunction in the absence of MDD is relatively common, and sexual dysfunction is common in patients who have MDD (Atmaca, 2020).
  • It has been estimated that ~ 15-80% of patients taking an SSRI develops sexual dysfunction (Atmaca, 2020; Hirsch & Birnbaum, 2019c) with the average being ~ 50% (Hirsch & Birnbaum, 2019c).
  • Sexual dysfunction that can occur include (but are not limited to) decreased arousal, diminished libido, premature ejaculation, and anorgasmia [difficulty in achieving orgasm] (Atmaca, 2020; Hirsch & Birnbaum, 2019c).
  • Sexual dysfunction itself is stressful, but it can also worsen the patient’s level of depression, negatively affect interpersonal relationships, and lead to non-compliance with the medication regimen (Atmaca, 2020).

Suicidal Behavior/Suicidal Ideation:

  • SSRIs have a US Black Box Warning on their prescribing information.
  • This warning states that antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies (Boaden et al, 2020; Kaminski & Bschor, 2020; Yan & Goldman, 2019).
  • These studies did not show an increased risk in adults > age 24.
  • In patients 65 years of age and older the risk was decreased.
  • The level of risk — and if there is a risk — is still a controversial topic (Boaden et al, 2020; Kaminski & Bschor, 2020; Yan & Goldman, 2019).
  • The prescribing information for the SSRIs recommends that clinicians should closely observe all patients who are taking an antidepressant, looking for worsening on depression, unusual changes in behavior, and suicidal behavior and/or ideation (UpToDate, 2021d).

QT Prolongation:

  • All the SSRIs can cause QT prolongation (Hirsch & Birnbaum, 2020).
  • The risk of this adverse effect varies between the SSRIs (Beach et al., 2018; Campleman et al., 2020; Hirsch & Birnbaum, 2020a).
  • It appears that the highest risk of QT prolongation is from citalopram and escitalopram (Campleman et al, 2020; Hirsch & Birnbaum, 2020a).
  • Other factors that increase the risk of SSRI-induced prolonged QT include (but are not limited to) advanced age, cardiovascular disease, hypokalemia, the use of other drugs that prolong the QT, and overdose of an SSRI (Hirsch & Birnbaum, 2020a; Groot et al., 2018; Zolezzi & Cheung, 2018).
  • Prolonged QT is a risk factor for torsades des pointes (TDP), but TDP associated with/caused by an SSRI is unusual (Hirsch & Birnbaum, 2020a) and the risk appears to be drug-dependent.
  • CredibleMeds® categorizes citalopram and escitalopram as having a known risk for causing TDP and the other SSRIs are categorized as being drugs that may cause TDP only if certain risk factors are in place or if the patient has congenital long-T syndrome (CredibleMeds®, 2021a).
  • The prescribing information for Prozac® states: “Post-marketing cases of QT interval prolongation and ventricular arrhythmia including torsades de pointes have been reported in patients treated with PROZAC®. PROZAC® should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Consider ECG assessment and periodic ECG monitoring if initiating treatment with PROZAC® in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing PROZAC® and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.” (Prozac®, 2020).

Serotonin Syndrome:

  • Serotonin Syndrome is a group of autonomic, cognitive, and neuromuscular signs and symptoms that are caused by an excess of serotonin (Bartlett, 2017).
  • The defining signs are: (Bartlett, 2017)
    • Clonus (spontaneous and induced)
    • Diaphoresis
    • Tremor
    • Hyperreflexia
    • Agitation
    • Elevated temperature > 100.4° F
  • Serotonin Syndrome can be mild, e.g., with agitation, diaphoresis, and clonus, but a severe case can cause (Bartlett, 2017; Hirsch & Birnbaum, 2020a):
    • Acidosis
    • Coma
    • Hyperthermia
    • Seizures
    • Death
  • The onset of Serotonin Syndrome typically occurs within six hours of an increased dose, initiation of SSR therapy, or an SSRI overdose (Bartlett, 2017).
  • The use of a single SSRI can cause Serotonin Syndrome (Foong et al., 2018), but most cases of serotonin syndrome are caused when two or more serotonergic drugs are used concurrently (Foong et al., 2018; Hirsch & Birnbaum, 2020a).
  • Serotonin syndrome can also happen if a drug-drug interaction inhibits the metabolism of an SSRI (Bartlett, 2017).
  • It is not known if any of the SSRIs is more likely to cause serotonin syndrome (Hirsch & Birnbaum, 2020a).

Discontinuation of SSRIs:

To discontinue the use of an SSRI, it is recommended to taper the dose over several weeks to avoid causing discontinuation syndrome (Hirsch & Birnbaum, 2019b). Some of the SSRIs, e.g, fluoxetine can be tapered more quickly and others, like paroxetine, must be tapered more slowly (Hirsch & Birnbaum, 2019b). Clinicians should be aware that tapering the SSRI dose does not always prevent discontinuation syndrome from happening (Cosci & Chouinard, 2020; Massabki & Abi-Jaoude, 2021).

Signs and symptoms of discontinuation syndrome include (but are not limited to) agitation, anxiety, dizziness, fatigue, headache, and nausea (Hirsch & Birnbaum, 2019b; Massabki & Abi-Jaoude, 2021).

The risk of discontinuation syndrome with SSRIs has been estimated to be 27% to 86% (Massabki & Abi-Jaoude, 2021). The onset can begin 36 hours to 10 days after the last dose or a decrease in dose (Cosci & Chouinard, 2020). The duration has been estimated to be several hours to 6 weeks and longer (Cosci & Chouinard, 2020; Massabki & Abi-Jaoude, 2021). Massabki & Abi-Jaoude (2021) reported that 46% of patients rated the signs and symptoms of their discontinuation syndrome as severe. Fluoxetine appears the least likely and paroxetine the most likely to cause discontinuation syndrome (Hirsch & Birnbaum, 2019b; Massabki & Abi-Jaoude, 2021).

Switching to/from SSRIs:

Switching from one SSRI to another can typically be done by simply starting the new drug (Hirsch & Birnbaum, 2019b). Switching from an SSRI to another class of antidepressant may involve tapering, a washout period, cross-tapering (the dose of the first drug is slowly tapered down, and the new drug is started at a low dose and slowly tapered up), and the preferred method may be specific to the SSRI and the new drug (Hirsch & Birnbaum, 2019b).

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

The antidepressant effects of serotonin-norepinephrine reuptake inhibitors (SNRIs) are mediated by inhibition of the reuptake of serotonin and norepinephrine (DeBattista, 2021a). SNRIs do not have strong binding to other neurotransmitter receptor sites (DeBattista, 2021a; Nelson, 2020).

SNRIs are considered a primary treatment for MDD, preferable to the TCAs and the MAOIs (DeBattista, 2021a). They appear to be equally as effective as other antidepressants for treating depression (Rush, 2020), and they appear to have a more rapid onset of antidepressant effects than the SSRIs (Li et al., 2020).

There are five SNRIs available in the US: Generic name (Trade name):

  • Desvenlafaxine (Pristiq®)
  • Duloxetine (Cymbalta®)
  • Levomilnacipran (Fetzima®)
  • Milnacipran (Savella®)
  • Venlafaxine (Effexor®)

*Milnacipran is categorized as an antidepressant, but its labeled use is as a treatment for fibromyalgia; using milnacipran for treating MDD is an off-label use.

These drugs all have the same mechanism of action (Nelson, 2020) and as always, choosing which SNRI to prescribe will depend on the patient’s co-morbidities and possible drug-drug reactions.

Adverse Effects of SNRIs: (DeBattista, 2021a; O’ Donnell et al, 2018; Nelson, 2020):

  • Anxiety
  • Constipation
  • Headache
  • Insomnia
  • Nausea
  • Sexual dysfunction
  • Increased blood pressure and heart rate

Venlafaxine® can cause prolonged QT. There is no evidence that the other SNRIs can cause this adverse effect (Credible Meds, 2021b). The SNRIs can also cause Serotonin Syndrome (Bartlett, 2017).

SNRIs have also been associated with an increased risk for bleeding, bone resorption, hyponatremia, suicidal behavior and ideation, sexual dysfunction, and weight gain (Nelson, 2020):

  • Bone Resorption:
    • SNRIs duloxetine and venlafaxine have been associated with bone loss and bone resorption (Nelson, 2020; Rawson et al., 2017), but it is not known if these changes are clinically significant (Rawson et al., 2017).
    • Depression has been identified as a risk factor for bone loss and fractures (Wu et al., 2018).
  • Bleeding:
    • Serotonergic drugs reduce the activity of the 5-HTT transport molecule that moves serotonin into platelets.
    • Because of this effect, SNRIs can reduce platelet activation and aggregation and impair hemostasis (Smith et al., 2018).
    • The clinical implications of this effect are not completely understood (Smith et al., 2018), but the Lexicomp® drug information database notes that the use of an SNRI and antiplatelet drugs like aspirin or low-molecular-weight heparin may cause bleeding (UpToDate, 2021e).
  • Hyponatremia:
    • SNRIs have been associated with hyponatremia (Gandhi et al., 2017; Nelson, 2020; Oliver et al, 2020; Yoshida et al, 2019), particularly in patients > age 65, patients who take diuretics, or patients who have a history of hyponatremia (Nelson, 2020).
    • This adverse effect is likely caused by the syndrome of inappropriate diuretic hormone [SIADH] (Oliver et al., 2020).
    • Duloxetine seems to be the SNRI with the highest level of risk (Nelson, 2020), but there is little published information on this topic (Gandhi et al., 2017; Nelson, 2020).
    • Letmaier et al. (2012) found that in > 16,000 patients taking venlafaxine, the incidence of hyponatremia (serum sodium < 130 mmol/L) was 0.08%.
  • Suicidal Behavior/Suicidal Ideation:
    • Antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies.
    • These studies did not show an increased risk in adults > age 24.
    • In patients 65 years of age and older, the risk was decreased.
    • Clinicians should closely observe all patients who are taking an antidepressant, looking for worsening of depression, unusual changes in behavior, and suicidal behavior and/or ideation.
  • Sexual Dysfunction:
    • Sexual dysfunction has been associated with all the currently available SNRIs (Clayton et al., 2015; Fetzima, 2019; Hudson et al., 2005; Savella, 2017; Serretti & Chiesa, 2009).
    • The sexual dysfunction side effects associated with milnacipran were reported during clinical trials involving fibromyalgia patients (Savella, 2017).

Discontinuation of SNRIs:

Discontinuation signs/symptoms can occur after stopping the use of any of the SNRIs (Fava et al., 2018; Nelson, 2020). The signs and symptoms are like those of SSRI discontinuation, e.g., agitation, anxiety, fatigue, headache, and nausea (Hirsch & Birnbaum, 2019b; Massabki & Abi-Jaoude, 2021). The onset typically begins within several days after the last dose and the duration was several weeks (Fava et al., 2018).

Abruptly discontinuing the use of an SNRI can cause discontinuation syndrome (Fava et al., 2018; Nelson, 2020), and the prescribing information and authoritative sources recommend that the dose of SNRIs should be gradually tapered down over several weeks before completely stopping use (Nelson, 2020). However, discontinuation signs and symptoms can occur even if a tapering protocol had been used (Fava et al., 2018).

Switching to/from SNRIs:

Switching from an SNRI to an antidepressant from another class should be done by cross-tapering (Hirsch & Birnbaum, 2019b). Switching from an SNRI to an MAOI is done by tapering the SNRI for two to four weeks and then waiting two weeks before starting the MAOI (Hirsch & Birnbaum, 2019b). This waiting period should be five weeks for fluoxetine because of its long half-life (Hirsch & Birnbaum, 2019b). The prescribing information for the SRNIs recommend a waiting period for starting an SNRI after stopping use of an MAOI. A waiting period of 14 days is often recommended but this varies from drug to drug (O’ Donnell et al., 2018).

Tricyclic Antidepressants (TCAs)

The antidepressant effects of the TCAs are mediated by inhibition of serotonin and norepinephrine reuptake (O’Donnell et al., 2018). The TCAs also have antagonist activity at histaminic, muscarinic, and peripheral a-adrenergic receptors (Benowitz, 2018c; DeBattista, 2021a; O’Donnell et al., 2018; Hirsch & Birnbaum, 2020b). This causes many of the adverse effects of the TCAs.

Example: Antagonism at histamine and muscarinic receptors causes drowsiness and sedation, antagonism at muscarinic receptors causes anticholinergic effects like blurred vision, constipation, and flushed skin, and antagonism at the peripheral a-adrenergic receptors causes orthostatic hypotension (Benowitz, 2018c; DeBattista, 2021a; Hirsch & Birnbaum, 2020b; O’Donnell et al., 2018).

As with many antidepressants, there is a lag time of several weeks between starting therapy with a TCA and a change in the signs and symptoms of MDD (Hirsch & Birnbaum, 2020b).

TCAs are second-line or third-line therapy for treating MDD (DeBattista, 2021a; O’ Donnell et al., 2018). Although TCAs are effective antidepressants, their adverse effect profile and the serious and lethal effects they have when taken in overdose make them a less attractive choice, compared to SSRIs and other antidepressants (DeBattista, 2021a; O’Donnell, et al, 2018).

TCAs that are currently available in the US are listed below. Many of the trade name TCAs are no longer produced. Generic name (Trade name):

  • Amitriptyline
  • Amoxapine
  • Clomipramine (Anafranil®)
  • Desipramine (Norpramin®)
  • Doxepin (Silenor®)
  • Imipramine
  • Maprotiline
  • Nortriptyline (Pamelor®)
  • Protriptyline
  • Trimipramine

There are structural and pharmacokinetic differences between the TCAs, but choosing which TCA will depend on patient demographics, especially age, the patient’s comorbidities, the drug-drug interaction profile of the TCA, how the TCA’s adverse effect profile will affect the patient, and how immediate the need for therapeutic effect is (Hirsch & Birnbaum, 2020b).

Adverse Effects of TCAs: (DeBattista, 2021a; Hirsch & Birnbaum, 2020b; O’ Donnell et al, 2018).

  • Blurred vision
  • Confusion
  • Constipation
  • Delirium
  • Dry mouth
  • Difficulty urinating/urinary retention
  • Orthostatic hypotension
  • Weight gain

The TCAs can also cause CV complications, fractures, QT prolongation, they can lower the seizure threshold and, they can cause sexual dysfunction (Hirsch & Birnbaum, 2020b). The TCAs can cause serious adverse effects and death when taken in overdose (Benowitz, 2018c).

  • Cardiovascular complications:
    • The use of TCAs, particularly moderate to high doses (Wu et al., 2017) and/or long duration of use (Jang et al., 2020) has been associated with an increased risk for sudden cardiac death, ventricular arrhythmias, and other major CV events (Almuwqqat et al., 2019; Jang et al., 2020; Hirsch & Birnbaum, 2020b; Wu et al., 2017).
    • These adverse effects have occurred in patients with and without preexisting CVD (Hirsch & Birnbaum, 2020b; Jang et al., 2020).
    • TCAs by themselves can affect the myocardium and the cardiac conduction system in ways that could increase the risk of serious CV events (Hirsch & Birnbaum, 2020b; Jang et al., 2020).
    • However, MDD itself may be a risk factor for developing CVD (Tang et al., 2020 and although it has not been conclusively established that therapeutic use of the TCAs is a cause of significant CV adverse effects (Almuwqqat et al, 2019; Hirsch & Birnbaum, 2020b), prescribing information and authoritative sources recommend that the TCAs should be used cautiously in patients who have CVD.
  • Fractures:
    • An association between TCAs and an increased risk for fractures has been reported (Hirsch & Birnbaum, 2020b; Power et al., 2020; Wu et al., 2020).
    • The level of risk and why it occurs have not been established, and Power et al. (2020) neatly summarized the issue: “The relationship between depression, antidepressants, and bone health is a complex interplay of multiple factors.”
    • Fractures could be due to bone loss, bone loss caused by the drug or bone loss as a complication of MDD itself (Wu et al, 2018), or TCA-related fractures could be caused by common adverse effects of the TCAs, i.e., drowsiness and orthostatic hypotension (Wu et al, 2020).
    • Older adults are more susceptible to bone loss and fractures and orthostatic hypotension from TCAs.
    • The American Geriatrics Association Beers Criteria identifies TCAs as a drug that should not be used for older adults (American Geriatrics Society, 2019).
  • QT Prolongation:
    • Therapeutic use of TCAs can cause QT prolongation (Hirsch & Birnbaum, 2020b; Rochester et al., 2018).
    • QT prolongation is a risk factor for torsades de pointes.
    • QT prolongation has been associated with an increase in all-cause mortality and cardiovascular mortality death rates (Aronow & Shamliyan, 2020).
    • The risk of developing prolonged QT and torsades de pointes from the use of a TCA has not been quantified, but CredibleMeds® notes that TCAs can cause torsades pointes in specific circumstances, including (but not limited to) an overdose, concurrent use of a drug that inhibits metabolism of the TCA, and/or hypokalemia (Credible Meds, 2021c).
    • Before beginning therapy with a TCA, patients should be evaluated for the presence of cardiac disease, particularly any pathologies of the cardiac conducting system. Potential drug-drug interactions should be evaluated as well (Hirsch & Birnbaum, 2020b).
  • Seizure Threshold:
    • TCAs can lower the seizure threshold (Cardamone et al., 2013; Hirsch & Birnbaum, 2020b), but the evidence of this adverse effect is limited and inconsistent (Bloechliger et al., 2016; Chiao et al., 2020; Ribot et al., 2017).
    • It appears that the risk of seizures is associated only with high doses of some of the TCAs, e.g., amoxapine, clomipramine, and maprotiline (Hirsch & Birnbaum, 2020b; Bloechlinger et al., 2016; Ribot et al., 2017).
  • Sexual Dysfunction:
    • The risk of sexual dysfunction with the use of TCAs appears to be less than that of SSRIs and the level of risk has been described as medium (Rothmore, 2020).
    • An exception is clomipramine: for this TCA, the level of risk has been described as high and equivalent to that of the SSRIs (Rothmore, 2020).
    • There is, however, little published information on sexual dysfunction and the TCAs. Rothmore (2020) wrote: “. . . very few studies have evaluated risk with TCAs and how the incidence compares with SSRIs. Results to date have been inconsistent. “

Discontinuation of TCAs:

Discontinuation of a TCA can cause discontinuation syndrome, even when the dose is tapered (Henssler et al., 2017). Most of the reported cases were mild, although severe cases have occurred (Henssler et al., 2017). There is little published information on this issue (Henssler, 2017).

Switching to/from TCAs:

Hirsch & Birnbaum (2019b) have these recommendations for switching antidepressants to or from a TCA:

  • Switching from one TCA to another or to another type of antidepressant, except an MAOI:
    • Cross-tapering over one to two weeks.
  • Switching from an SSRI to a TCA:
    • Cross tapering.
  • Switching from an SNRI to a TCA:
    • Cross tapering over one to four weeks.
  • Switching from a TCA to an MAOI:
    • Taper the TCA over two to four weeks, wait two weeks and then begin the MAOI. If the patient was taking fluoxetine, wait five weeks before starting the MAOI.
  • Switching from an MAOI to a TCA:
    • Taper the MAOI over two to four weeks, wait two weeks and begin the TCA.

Atypical Antidepressants

The term atypical antidepressant is used to describe drugs that have a labeled use as a treatment for MDD, but they have mechanisms of action that make them distinct from the MAOIs, SSRIs, SNRIs, and TCAs.

Medications that will be discussed in this section are listed below: Generic name (Trade name):

  • Bupropion (Aplenzin®,Forfivo® XL, Wellbutrin®): Antidepressant, dopamine/norepinephrine reuptake inhibitor
  • Mirtazapine (Remeron®): Antidepressant, a2 adrenergic antagonist
  • Nefazodone: Antidepressant, serotonin reuptake inhibitor/antagonist
  • Trazodone: Antidepressant, serotonin reuptake inhibitor/antagonist
  • Vilazodone (Viibryd®): Antidepressant, selective serotonin reuptake inhibitor, 5-HT1A receptor partial agonist
  • Vortioxetine (Trintellix®): Antidepressant, selective serotonin reuptake inhibitor, serotonin 5-HT1A receptor agonist, serotonin 5-HT3 receptor antagonist

These antidepressants can be used as first-line treatment for MDD, but they are typically prescribed if an SSRI or an SNRI was ineffective. Many of these drugs do not have the adverse effects of SSRIs, SNRIs, and TCAs that many patients find intolerable like anticholinergic signs and symptoms, sexual dysfunction, and weight gain. They are prescribed for this reason. They are also not as restrictive to use as the MAOIs.

Atypical Antidepressants -Bupropion

The antidepressant effects of bupropion are mediated by inhibition of the reuptake of dopamine and norepinephrine (Hirsch & Birnbaum, 2020c; O’Donnell et al., 2018). It appears to have little effect on other neurotransmitter receptors (Hirsch & Birnbaum, 2020c).

Bupropion has been proven to be an effective treatment for MDD (Dhillon et al., 2008a; Dhillon, 2008b) as well as a suitable first-line treatment or a second-line treatment if another type of antidepressant were tried first and were unhelpful (DeBattista, 2021a). Bupropion is also an attractive alternative to the other antidepressants because it does not cause weight gain (Gill et al., 2020). In fact, it may cause weight loss (Gill et al., 2020; Hirsch & Birnbaum, 2020c). In addition, the risk of sexual dysfunction side effects is low, compared to placebo (Rothman, 2020).

Adverse Effects of Bupropion: (Hirsch & Birnbaum, 2020c; O’ Donnell et al., 2018)

  • Anxiety
  • Constipation
  • Dizziness
  • Dry mouth
  • Headache
  • Insomnia
  • Mild elevations of blood pressure and heart rate
  • Seizures

Abuse of bupropion has been reported.

  • Bupropion inhibits the reuptake of norepinephrine.
  • Some patients report that the drug has a CNS stimulant effect, and bupropion abuse is a well-documented phenomenon (Hu et al., 2016; Stall et al., 2016; Stassinos & Klein-Schwartz, 2016).

Bupropion overdose can be dangerous.

  • Bupropion overdose can cause serious and deadly outcomes (Murray et al., 2020; Overberg et al., 2016; Weerdenburg et al., 2015).
  • There are several aspects of bupropion overdose that are notable.
  • These effects are common after bupropion overdose and include: (Hartford et al., 2019; Murray et al., 2020; Overberg et al., 2016; Weerdenburg & Finklstein, 2015)
    • Hallucinations
    • Seizures
    • Toxic psychosis
    • QRS prolongation
    • QT prolongation
    • Arrhythmias
    • Agitation
    • Tachycardia

Typical Antidepressant adverse effects associated with Bupropion include:

  • Suicidal Behavior/Suicidal Ideation:
    • Antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies.
    • These studies did not show an increased risk in adults > age 24.
    • In patients 65 years of age and older, the risk was decreased.
    • Clinicians should closely observe all patients who are taking an antidepressant, looking for worsening of depression, unusual changes in behavior, and suicidal behavior and/or ideation.
  • Seizures:
    • Bupropion lowers the seizure threshold at therapeutic and supratherapeutic doses (Overberg et al., 2016).
    • Bupropion is contraindicated for patients who have a seizure disorder (Wellbutrin SR, 2019).
    • Bupropion is also contraindicated for patients who have anorexia nervosa, bulimia, or who are undergoing abrupt discontinuation from alcohol, barbiturates, benzodiazepines, or anti-epileptics (Hirsch & Birnbaum, 2020c; Wellbutrin SR, 2019).
    • The use of bupropion in these patients increases the risk for seizures.
    • Sleep-deprivation, head injury, and a family history of seizure disorder can increase the risk of bupropion-induced seizures as well (Mishra et al., 2017; Saffei et al., 2020).
    • Seizures caused by bupropion are dose-related (Hirsch & Birnbaum, 2020c; Mishra et al., 2017; O’Donnell et al., 2018; Saffei et al., 2020).
    • The higher the dose the higher the risk.
    • With sustained-release preparation doses of 100 mg – 300 mg a day, the risk of seizures has been estimated to 0.1%.
    • At 400 to 450 mg a day the risk has been estimated to be 0.4% to 0.44% (Hirsch & Birnbaum, 2020c; Mishra et al., 2017). Also, the sustained-release preparation can cause a seizure if it is not swallowed whole, i.e., cut into sections and then ingested (Chouu et al., 2019).
    • The onset of seizures can be delayed, from six to 24 hours (Ayers & Tobias, 2001; Hartford et al., 2019; Starr et al., 2009), and single and multiple seizures are possible (Hartford et al., 2019).
    • The toxic dose of bupropion is not known, but the highest daily dose is 450 mg.
    • The risk of seizures is increased at 600 mg (Hartford et al., 2019), and seizure has been reported after ingestion of 1-3 grams (Ayers & Tobias, 2001).

Discontinuation of Bupropion:

There are no recommendations for a discontinuation protocol for bupropion (Wellbutrin SR, 2019). There are only two case reports that have described withdrawal signs and symptoms associated with bupropion (Berigan, 2020).

Switching to/from Bupropion:

Switching to bupropion from SSRIs, SNRIs, TCAs, or other atypical antidepressants should be done by cross-tapering over one to three weeks (Hirsch & Birnbaum, 2019b). The tapering period should be adjusted depending on the drug, i.e., as antidepressants are likely to cause discontinuation issues like SSRIs (aside from than fluoxetine), duloxetine and venlafaxine (Hirsch & Birnbaum, 2019b). Switching from bupropion to an MAOI or bupropion from an MAOI requires 14 days after the last dose of either drug (Wellbutrin SR, 2019).

Atypical Antidepressant - Mirtazapine

Mirtazapine is an a2 adrenergic antagonist. Its primary mechanism of action is causing an increased release of norepinephrine and serotonin in the CNS. Mirtazapine is also an antagonist at peripheral a1 adrenergic receptors, histamine receptors, and muscarinic receptors. Mirtazapine is effective for treating MDD and its efficacy compares well with other antidepressants (Khoo et al., 2015; Watanabe et al., 2011).

Adverse Effects of Mirtazapine: (Hirsch & Birnbaum, 2020c)

  • Drowsiness
  • Dry mouth
  • Increased appetite
  • Sedation
  • Weight gain

The sedating effects of mirtazapine have been reported to occur more often at lower doses of 15mg than at doses of 30 mg (UpToDate, 2021f). Serotonin Syndrome has been associated with mirtazapine, but this is a rare adverse effect of the drug (UpToDate, 2021f). QT prolongation and arrhythmias have been reported after mirtazapine overdose (UpToDate, 2021f), but therapeutic use does not appear to cause QT prolongation (Allen et al, 2020).

Typical Antidepressant adverse effects associated with Mirtazapine include:

  • Sexual Dysfunction:
    • Mirtazapine is considered to have a low to medium risk of causing sexual dysfunction (Rothmore, 2020), which is much less of a risk than SSRIs and possibly no greater than placebo (UpToDate, 2021f).
    • Mirtazapine has been used to reduce signs and symptoms of sexual dysfunction caused by SSRIs (Jing & Straw-Wilson, 2016).
  • Suicidal Behavior/Suicidal Ideation:
    • Antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies.
    • These studies did not show an increased risk in adults > age 24.
    • In patients 65 years of age and older, the risk was decreased.
    • Clinicians should closely observe all patients who are taking an antidepressant, looking for worsening of depression, unusual changes in behavior, and suicidal behavior and/or ideation.
  • Weight Gain:
    • Mirtazapine can cause significant weight gain (UpToDate, 2021f).

Discontinuation of Mirtazapine:

Discontinuation signs and symptoms have occurred after abrupt discontinuation and gradual tapering of mirtazapine (Cosci & Chouinard, 2020; Cosci, 2017; UpToDate, 2021f).

Switching to/from Mirtazapine:

Switching between mirtazapine and SSRIs, SNRIs, TCAs, and other atypical antidepressants should be done by cross-tapering (Hirsch & Birnbaum, 2019b). When switching to an MAOI, taper and decrease the mirtazapine dose over two to four weeks, wait two weeks, and then start the MAOI (Hirsch & Birnbaum, 2019b). Mirtazapine should not be started with two weeks of the last dose of an MAOI.

Atypical Antidepressant - Nefazodone

Nefazodone is a serotonin reuptake inhibitor and 5-HT2a receptor antagonist (DeBattista, 2021a; O’Donnell et al., 2018). Antagonism at the 5-HT2a receptors is thought to work synergistically to increase activity at 5HT-1a receptors (Hirsch & Birnbaum, 2020c). Nefazodone can be used as a first-line or second-line treatment for MDD (“Drugs for Depression,” 2020; O’Donnell et al., 2018)

Adverse Effects of Nefazodone: (UpToDate, 2021g) (Common in > 10%)

  • Drowsiness
  • Dizziness
  • Headache
  • Insomnia
  • Constipation
  • Nausea
  • Xerostomia
  • Weakness

The risk of orthostatic hypotension and QT prolongation with nefazodone is low. Nefazodone does not cause weight gain (“Drugs for Depression,” 2020), and although there is little published information on the topic, it appears that nefazodone is less likely than SSRIs to cause sexual dysfunction (Clayton et al., 2014). The risk is comparable to placebo (Hirsch & Birnbaum, 2020c).

Typical Antidepressant adverse effects associated with Nefazodone include:

  • Hepatic Failure:
    • The prescribing information for nefazodone has a Black Box Warning about nefazodone and hepatic failure.
    • The use of nefazodone has been linked to several cases of liver failure and several deaths (LiverTox, 2020; UptoDate, 2012g).
    • Reviews of the data suggested that the incidence of hepatic failure from nefazodone is 1 per 250,000 to 300,000 patient-years of exposure (LiverTox, 2020; UpToDate, 2021g).
    • There is no evidence that pre-existing liver disease increases the risk of developing hepatic failure from nefazodone (UpToDate, 2021g), but nefazodone should not be prescribed for patients who have active liver disease, who have elevated serum transaminases, or who had liver damage from nefazodone (Hirsch & Birnbaum, 2020c; UpToDate, 2021g).
  • Suicidal Behavior/Suicidal Ideation:
    • Antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies.
    • These studies did not show an increased risk in adults > age 24.
    • In patients 65 years of age and older the risk was decreased.
    • Clinicians should closely observe all patients who are taking an antidepressant, looking for worsening of depression, unusual changes in behavior, and suicidal behavior and/or ideation.

Discontinuation from Nefazodone:

Discontinuation signs and symptoms have been reported after abrupt discontinuation and tapering of nefazodone (Hirsch & Birnbaum, 2020c). It is recommended to taper the drug over seven days before stopping use (Hirsch & Birnbaum, 2020c).

Switching to/from Nefazodone:

When switching between nefazodone and similar antidepressants (trazodone, vilazodone, vortioxetine), or other antidepressants except for the MAOIs, it is recommended to cross-taper over one to two weeks (Hirsch and Birnbaum, 2019b). When switching from an SSRI, SNRI, or TCA to nefazodone, cross-tapering is recommended (Hirsch & Birnbaum, 2019b). For the SNRIs, the cross-tapering should be done over one to three weeks and for TCAs, one to two weeks (Hirsch and Birnbaum, 2019b). When switching from an MAOI to nefazodone, at least two weeks should pass after the last dose of the MAOI before starting nefazodone (Hirsch & Birnbaum, 2019b). When switching from nefazodone to an MAOI, taper nefazodone over two to four weeks, wait two weeks, and then start the MAOI (Hirsch & Birnbaum, 2019b).

Atypical Antidepressant - Trazodone

Trazodone is a serotonin reuptake inhibitor and 5-HT receptor antagonist. It is an α-adrenergic receptor antagonist (Hirsch & Birnbaum, 2020c; Khouzam, 2017). Trazodone is also a histamine 1 receptor antagonist (Hirsch & Birnbaum, 2020c). It has a labeled use as a treatment for MDD, and it is equally as effective as the SSRIs, SNRIs, and TCAs (Khouzam, 2017).

Adverse Effects of Trazodone: (Hirsch & Birnbaum, 2020c; Khouzam, 2017)

  • Constipation
  • Diarrhea
  • Headache
  • Nausea
  • Orthostatic hypotension
  • Vomiting
  • Sedation

Trazodone does not appear to cause weight gain (Hirsch & Birnbaum, 2020c). The risk of sexual dysfunction adverse effects has been reported to be low (Khazaie et al., 2015). As with any of the serotonergic medications, trazodone can (usually in combination with other serotonergic drugs) cause Serotonin Syndrome. Trazodone can cause prolonged QT (Hirsch & Birnbaum, 2020c; Khazaie, 2017) and in patients who have CV disease, electrolyte abnormalities, or other risk factors, the use of trazodone can cause torsade de pointes and other arrhythmias (Hirsch & Birnbaum, 2020c; Khazaie, 2017).

  • Orthostatic Hypotension:
    • Orthostatic hypotension is a common adverse effect of trazodone (Hirsch & Birnbaum, 2020c; Khazaie, 2017).
    • Orthostatic hypotension is an abnormal decrease in blood pressure after moving from a lying to a standing position.
    • Five minutes of being supine, blood pressure is measured after the patient has been standing for two to five minutes.
    • Orthostatic hypotension is present if the systolic blood pressure has decreased by ≥ 20 mm Hg, the diastolic blood pressure has decreased by ≥10 mm Hg, or both.
    • Orthostatic hypotension can cause syncope, falls, and fractures.
    • Older patients are particularly at risk. In fact, the American Geriatrics Society recommends that antidepressants that can cause orthostatic hypotension should be avoided in older patients (American Geriatrics Society, 2019).
  • Priapism:
    • Priapism is a rare but potentially serious complication of trazodone (Hirsch & Birnbaum, 2020c; Khazaie, 2017).
  • Suicidal Behavior/Suicidal Ideation:
    • Antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies.
    • These studies did not show an increased risk in adults > age 24.
    • In patients 65 years of age and older the risk was decreased.
    • Clinicians should closely observe all patients who are taking an antidepressant, looking for worsening of depression, unusual changes in behavior, and suicidal behavior and/or ideation.

Discontinuation of Trazodone:

Abrupt discontinuation of trazodone can cause discontinuation signs and symptoms (Hirsch & Birnbaum, 2020c; Khazaie, 2017). Trazodone should be tapered over a two to four week before topping use (Hirsch & Birnbaum, 2020c; Khazaie, 2017).

Switching from/to Trazodone:

When switching between trazodone and similar antidepressants (nefazodone, vilazodone, vortioxetine), or other antidepressants except for the MAOIs, it is recommended to cross-taper over one to two weeks (Hirsch and Birnbaum, 2019b). When switching from an SSRI, SNRI, or TCA to trazodone, cross-tapering is recommended (Hirsch & Birnbaum, 2019b). For SNRIs, the cross-tapering should be done over one to three weeks and for TCAs, one to two weeks (Hirsch and Birnbaum, 2019b). When switching from an MAOI to trazodone, at least two weeks should pass after the last dose of the MAOI before starting trazodone (Hirsch & Birnbaum, 2019b). When switching from trazodone to an MAOI, taper trazodone over two to four weeks, wait two weeks, and then start the MAOI (Hirsch & Birnbaum, 2019b).

Atypical Antidepressant - Vilazodone

Vilazodone inhibits the presynaptic reuptake of serotonin. It is also a partial agonist at postsynaptic 5-HT1a receptors (Hirsch & Birnbaum, 2020c). Vilazodone has a labeled use for the treatment of MDD, and its effectiveness as a treatment for MDD is well established (Stuivenga et al, 2019).

Adverse Effects of Vilazodone: (Hirsch & Birnbaum, 2020c; Stuivenga et al., 2019)

  • Diarrhea
  • Dizziness
  • Dry mouth
  • Headache
  • Sexual dysfunction in men

Vilazodone does not cause weight gain (Hirsch & Birnbaum, 2020c; Stuvienga et al., 2019) or QT prolongation (Hirsch & Birnbaum, 2020c), and Serotonin Syndrome caused by vilazodone is rare (Hirsch & Birnbaum, 2020c).

Typical Antidepressant adverse effects associated with Vilazodone include:

  • Sexual Dysfunction:
    • The incidence of sexual dysfunction caused by vilazodone is not clear and the available information is conflicting and difficult to interpret.
    • During clinical trials, the incidence of sexual dysfunction was low and not much higher than placebo-treated patients.
    • Post-marketing, researchers have found that vilazodone is and is not a significant cause of sexual dysfunction.
    • Vilazodone can actually improve depression-related dysfunction in some cases (Clayton et al., 2013).
    • In additional, the incidence of sexual dysfunction caused by placebo and vilazodone are essentially the same (Citrome, 2012; Clayton et al., 2013).
  • Suicidal Behavior/Suicidal Ideation:
    • Antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies.
    • These studies did not show an increased risk in adults > age 24.
    • In patients 65 years of age and older, the risk was decreased.
    • Clinicians should closely observe all patients who are taking an antidepressant, looking for worsening of depression, unusual changes in behavior, and suicidal behavior and/or ideation.

Discontinuation of Vilazodone:

Discontinuation signs and symptoms after withdrawal from vilazodone have not been reported (Hirsch & Birnbaum, 2019c). Hirsch & Birnbaum (2019c) recommend tapering vilazodone over one to two weeks before stopping the use of the drug.

Switching to/from Vilazodone:

When switching between vilazodone and similar antidepressants (nefazodone, trazodone, vortioxetine), or other antidepressants except for the MAOIs, it is recommended to cross-taper over one to two weeks (Hirsch and Birnbaum, 2019c). When switching from an SSRI, SNRI, or TCA to vilazodone, cross-tapering is recommended (Hirsch & Birnbaum, 2019b). For SNRIs, the cross-tapering should be done over one to three weeks and for TCAs, one to two weeks (Hirsch and Birnbaum, 2019b). When switching from an MAOI to vilazodone at least two weeks should pass after the last dose of the MAOI before starting vilazodone (Hirsch & Birnbaum, 2019b). When switching from vilazodone to an MAOI, taper vilazodone over two to four weeks, wait two weeks, and then start the MAOI (Hirsch & Birnbaum, 2019b).

Atypical Antidepressant - Vortioxetine

Vortioxetine inhibits presynaptic reuptake of serotonin. It is an antagonist at several 5-HT receptors and as with the other atypical antidepressants, inhibition of serotonin reuptake and 5H- receptor antagonism likely have a synergistic effect that explains, in part, the antidepressant effect of the drug (Hirsch & Birnbaum, 2020c). Vortioxetine has a labeled use as a treatment for MDD, it is an effective treatment for MDD (De Carlo et al., 2020; Ostuzzi et al., 2020), and its effectiveness seems comparable to the SSRIs and the SNRIs (Ostuzzi et al, 2020).

Adverse Effects of Vortioxetine: (De Carlo et al, 2020)

  • Constipation
  • Diarrhea
  • Nausea

Vortioxetine is typically well-tolerated. Adverse effects common to other atypical antidepressants and other antidepressants e.g., orthostatic hypotension, QT prolongation are either rare or do not happen with vortioxetine (Ostuzzi et al., 2020; UpToDate, 2021h). In addition, the incidences of sexual dysfunction and weight gain appear to be low (De Carlo et al., 2020; Jacobsen et al., 2015).

Typical Antidepressant adverse effects associated with Vortioxetine include:

  • Suicidal Behavior/Suicidal Ideation:
    • Antidepressants increased the risk of suicidal behavior and ideation in children, adolescents, and young adults in short-term studies.
    • These studies did not show an increased risk in adults > age 24.
    • In patients 65 years of age and older. the risk was decreased.
    • Clinicians should closely observe all patients who are taking an antidepressant, looking for worsening of depression, unusual changes in behavior, and suicidal behavior and/or ideation.

Discontinuation of Vortioxetine:

The prescribing information for Trintellix states that Trentellix® can be abruptly discontinued, but it is recommended that doses of 15 mg to 20 mg be tapered to 10 mg a day for a week before stopping use of the drug (Trentellix®, 2021).

Switching to/from Vortioxetine:

When switching between vortioxetine and similar antidepressants (nefazodone, trazodone, vortioxetine), or other antidepressants except for the MAOIs, it is recommended to cross-taper over one to two weeks (Hirsch and Birnbaum, 2019c). When switching from an SSRI, SNRI, or TCA to vortioxetine, cross-tapering is recommended (Hirsch & Birnbaum, 2019b). For SNRIs, the cross-tapering should be done over one to three weeks and for TCAs, one to two weeks (Hirsch and Birnbaum, 2019b). When switching from an MAOI to vilazodone at least two weeks should pass after the last dose of the MAOI before starting vilazodone (Trentellix, 2021).

Antipsychotics

Antipsychotics are primarily used to treat:

  • Acute agitation associated with bipolar disorder or anxiety.
  • Major Depressive Disorder.
  • Psychosis associated with other psychiatric illnesses.
  • Schizophrenia.

The antipsychotics are divided into two categories:

  1. Typical antipsychotics (also called first-generation)
  2. Atypical antipsychotics (also called second-generation)

The second-generation antipsychotics were developed after the first-generation drugs and they were named atypical because they were less likely to cause specific CNS adverse effects that were typical of the first-generation drugs.

The primary mechanism of action of both types of antipsychotics is dopamine-2 receptor blockade (DeBattista, 2021; Jibson, 2021; Jibson, 2020; Meyer, 2018), but the atypical antipsychotics also have significant binding at serotonin receptors (DeBattista, 2021b; Jibson, 2021; Jibson, 2020; Meyer, 2018).

The exception is the atypical antipsychotic pimavanserin (Nuplazid®). This antipsychotic is a serotonin agonist and antagonist, and it does not affect dopamine, histamine, muscarinic, or adrenergic receptors. The typical and the atypical antipsychotics also, to varying degrees, have activity at histaminic, muscarinic, and adrenergic receptors.

The labeled uses of the typical and atypical antipsychotics are generally the same and, pharmacologically, they are quite similar. The primary difference is that the atypical antipsychotics are less likely to cause extrapyramidal side effects (EPS) and tardive dyskinesia (DeBattista, 2021b; Jibson, 2021; Meyer, 2018).

The typical antipsychotics currently available in the US are: Generic name (Trade name):

  • Chlorpromazine
  • Fluphenazine
  • Haloperidol (Haldol®)
  • Loxapine (Adasuve®)
  • Perphenazine
  • Pimozide
  • Thioridazine
  • Thiothixene
  • Trifluoperazine

The atypical antipsychotics that are currently available in the US are: Generic name (Trade name)

  • Aripiprazole (Abilify®)
  • Asenapine (Saphris®)
  • Brexpiprazole (Rexulti®)
  • Cariprazine (Vraylar®)
  • Clozapine (Clozaril®, FazaClo®, Versacloz®)
  • Iloperidone (Fanapt®)
  • Lumateperon (Caplyta®)
  • Lurasidone (Latuda®)
  • Olanzapine (Zyprexa®)
  • Paliperidone (Invega®)
  • Pimavanserin (Nuplazid®)
  • Quetiapine (Seroquel®)
  • Risperidone (Risperdal®)
  • Ziprasidone (Geodon®)

Adverse Effects of Antipsychotics: (Jibson, 2021; Jibson, 2020)

  • Sedation
  • Anticholinergic effects
  • Sexual dysfunction
  • Weight gain
  • Orthostatic hypotension

The adverse effect profiles of the antipsychotics differ depending on the class, the affinity of each drug for adrenergic, histaminic, muscarinic, and serotonin receptors, and the effect of each drug on the heart.

Other adverse effects associated with Antipsychotics include:

  • US Black Box Warning:
    • The prescribing information for antipsychotics has a US Black Box Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
    • These deaths are typically caused by myocardial infarction and stroke.
    • There is considerable and consistent evidence that antipsychotics are associated with an increased risk of mortality from other causes, as well, and people of all age groups are at risk (Jibson, 2021; Jibson, 2020).
  • Extrapyramidal Side Effects:
    • Extrapyramidal side effects are movements disorders that are caused by an imbalance between dopaminergic and cholinergic activity in an area of the brain that is involved in movement control (DeBattista, 2021b; Stepnicki et al., 2018).
    • EPS are one of the most distressing adverse effects of the antipsychotics.
    • Both typical and atypical antipsychotic can cause EPS.
    • These symptoms include: (DeBattista, 2021b; Jibson, 2021; Meyer, 2018)
      • Akathisia
      • Parkinsonism
      • Dystonic reactions
      • Tardive dyskinesia
  • QT Prolongation:
    • The typical and the atypical antipsychotics can cause prolonged QT and torsade de pointes (Jibson, 2021; Jibson, 2020; Meyer, 2018; Ruiz Diaz et al., 2020).
    • The use of antipsychotics has been associated with an increased risk for sudden cardiac death (SCD) (Jibson 2021; Jibson, 2020; Ruiz Diaz et al., 2020).
    • The risk for SCD from an antipsychotic is higher for the typical antipsychotics.
    • The risk is also drug-specific, e.g., chlorpromazine and quetiapine are more likely to cause this adverse effect, and factors like advanced age, electrolyte abnormalities, and congenital long QT syndrome increase the risk (Ruiz Diaz et al., 2020).
  • Orthostatic Hypotension:
    • Orthostatic hypotension is a common adverse effect of typical and atypical antipsychotics (Jibson, 2020; Jibson, 2021; Meyer, 2018).
    • Orthostatic hypotension typically does not cause problems, but the dose may need to be decreased (Jibson, 2020), and the risk of orthostatic hypotension is one of the reasons why the American Geriatric Society recommends that clinicians should avoid prescribing antipsychotics in older patients (American Geriatric Society, 2019).
  • Falls:
    • The typical and the atypical antipsychotics are sedating.
    • They can cause orthostatic hypotension and instability.
    • These are factors that increase the risk for falls and fractures.
    • Both types of antipsychotics are associated with an increased risk for falls and fractures (Jibson, 2021; Jibson 2020) and for this reason, the American Geriatric Society recommends that clinicians should avoid prescribing antipsychotics in older patients (American Geriatric Society, 2019).
  • Neuroleptic Malignant Syndrome (NMS):
    • Neuroleptic malignant syndrome is a rare, potentially fatal adverse effect of antipsychotics.
    • NMS is characterized by hyperthermia, muscle rigidity, and diaphoresis after exposure to a dopamine antagonist (Kuhlwilm et al., 2020).
    • The incidence of NMS has been reported to be 0.01% to 0.04% (Kuhlwilm et al., 2020).
    • The onset of NMS is usually one to weeks after starting treatment with the drug, but NMS can occur at any time during therapy with an antipsychotic (Kuhlwilm et al., 2020).
    • NMS can cause rhabdomyolysis, seizures, multisystem organ failure, and other serious complications.
    • The mortality rate can be as high as 22% (Kuhlwilm et al., 2020).
    • The pathophysiologic mechanism of NMS is unknown.
    • All the antipsychotics can cause NMS.
    • The biggest risk factor is a previous episode of NMS (Jibson, 2021; Jibson, 2020).
  • Seizure:
    • The antipsychotics do not cause seizures, but they lower the seizure threshold (Jibson, 2021; Jbson, 2020).
    • This is especially true of the typical antipsychotics: chlorpromazine, haloperidol, thioridazine, and trifluoperazine (Bloechliger et al., 2015).
  • Sexual Dysfunction:
    • Sexual dysfunction, e.g., erectile problems, problems with libido, and problems with orgasms, is a common adverse effect of antipsychotics (Jibson, 2021; Jibson, 2020; Montejo et al., 2021).
    • Sexual dysfunction is common even in patients who do not have a decreased prolactin level (Jibson, 2021).
    • The exact incidence is not known, but ~ 40% to 60% of patients taking an antipsychotic have some type of sexual dysfunction (Montejo et al., 2021).
    • The risk differs for each drug and it appears to be the highest for olanzapine (40%), risperidone (43%), haloperidol (45%), clozapine (52%), and thioridazine (60%) (Montejo et al., 2021).
    • Patients who develop a sexual dysfunction from an antipsychotic may benefit from reducing the dose, switching to another drug of the same class, waiting for remission, or using a phosphodiesterase-5 (PDE-5) inhibitor like sildenafil (Montejo, 2021).

The risk of these adverse effects is more common with the typical antipsychotics (DeBattista, 2021b; Jibson, 2021; Meyer, 2018) and within both categories the risk is drug-specific (DeBattista, 2021b; Jibson, 2021; Meyer, 2018). For example, fluphenazine, haloperidol, loxapine, pimozide, and thiothixene are more likely to cause EPS than the other typical antipsychotics (Jibson, 2021). The exact incidence of EPS with the antipsychotics is not known and it can vary considerably. For example, the reported incidence of akathisia is 0.1% to 76% (Caroff & Campbell, 2016; Shams-Alizadeh et al., 2018).

Possible Systemic Effects of Antipsychotics:

  • Hematologic:
    • Agranulocytosis, leukopenia, and neutropenia are rare and potentially fatal adverse effects of the typical and atypical antipsychotics (Jibson, 2021; Jibson, 2020).
    • Chlorpromazine is the typical antipsychotic most likely to cause these adverse effects (Jibson, 2021) and clozapine is the atypical antipsychotic most likely to cause agranulocytosis (Jibson, 2020; Mijovic & MacCabe, 2020).
    • These hematologic adverse effects occur in approximately 1% to 4% of patients taking an antipsychotic (Jibson, 2020; Fryer & Billings, 2020), but progression to severe hematologic abnormalities is rare (Fryer & Billings, 2020; Mijovic & MacCabe, 2020), except for clozapine (Mijovic & MacCabe, 2020).
    • Patients who have had drug-induced agranulocytosis, leukopenia and neutropenia and patients who have an abnormality on the complete blood count (CBC) should be closely monitored during the use of antipsychotics.
  • Ocular:
    • Typical and atypical antipsychotics are associated with an increased risk for cataracts (Fang et al., 2019).
    • The mechanism of action of this adverse effect is not known, but the antipsychotics increase the risk of developing diabetes mellitus and dyslipidemia.
    • This may explain, in part, the increased risk of cataracts (Fang et al., 2019). A recent (2019) review concluded that the risk is greater with atypical antipsychotics (Fang et al., 2019).
  • Metabolic:
    • The relationship between antipsychotics and glucose disorders is complex and bidirectional.
    • Serious psychiatric disorders like bipolar disorder and schizophrenia are often complicated by the presence of DM and fasting hyperglycemia, impaired glucose tolerance, and pre-diabetes are common in these people (Cernea et al., 2020).
    • Typical and atypical antipsychotics can cause weight gain.
    • They are also associated with impaired glucose control and the development of metabolic syndrome (Jibson, 2021; Jibson, 2020; Meyer, 2018).
  • Endocrine- Prolactin:
    • An elevated prolactin level is a common adverse effect of antipsychotics, occurring in approximately ~ 70% of all patients who are on long-term therapy with an antipsychotic (Labad et al., 2020).
    • Hyperprolactinemia can cause: (Jibson, 2021; Jibson, 2020; Labad et al., 2020)
      • Amenorrhea
      • Decreased libido
      • Erectile dysfunction
      • Ejaculatory problems
      • Galactorrhea
      • Infertility
      • Osteoporosis
    • All of the typical antipsychotics can cause hyperprolactinemia (Jibson, 2021).
    • While the atypical antipsychotics, paliperidone, and risperidone are the most likely to elevate the prolactin level, aripiprazole, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, and quetiapine have little to no effect on the prolactin level (Jibson, 2020).
    • An elevated prolactin level does not necessarily cause reproductive and sexual adverse effects (Labad et al., 2020), but patients should be closely monitored and a prolactin level measure if they become symptomatic.
  • Anticholinergic Effects:
    • Many of the antipsychotics are competitive antagonists at muscarinic receptors, and patients can develop anticholinergic effects like: (Jibson, 2021; Jibson, 2020).
      • Blurred vision
      • Constipation
      • Dry mouth
      • Urinary retention
    • The anticholinergic effects are one of the reasons the American Geriatric Society recommends that these drugs not be used in elderly patients (American Geriatric Society, 2019).

Mood Stabilizers

Mood stabilizers are used to treat and prevent mood episodes in patients who have bipolar disorder.

Lithium, anticonvulsants, e.g., carbamazepine, valproic acid, chlorpromazine, and several atypical antipsychotics are used as mood stabilizers, but lithium, unlike anticonvulsants and antipsychotics, has a labeled use only for treating mood disorders in bipolar patients.

Lithium has been the mainstay of treatment for bipolar disorder for decades (Janicak, 2021; Meyer, 2018; Reus, 2018a). It is effective at treating acute mood episodes (Reus, 2018a). Lithium is also effective in preventing suicide in bipolar patients (Meyer, 2018). In addition, lithium is the only drug that has consistently been effective in preventing suicide in bipolar patients (Miller & Black, 2020). The mechanism of action of lithium is not completely understood (Meyer, 2018).

Prescribing lithium requires gradually increasing the dose until the desired response is attained and then carefully monitoring the patient’s clinical condition as well as the serum lithium level.

Lithium levels are closely correlated with both effectiveness and adverse effects (Janicak, 2021; Meyer, 2018):

  • Low levels are associated with relapse.
  • High levels increase the risk of adverse effects.

A starting dose is 300 mg once or twice a day and the dose is increased 300 to 600 mg a day at intervals of one to five days (Janicak, 2021). The amount and the frequency of dose increases will depend on the response and the serum level. The goal for maintenance treatment is a serum level of 0.8 to 1.2 mEq/L (Janicak, 2021), but levels of 0.6 mEq/L and 1.5 mEq/L can be safe and effective (Meyer, 2018). The level should not be > 1.5 mEq/L (Janicak, 2021).

A lithium level should be measured five to seven days after a dose increase (Janicak, 2021). Lithium levels should be measured 10 to 12 hours after the last dose (Janicak, 2021; Meyer, 2018). After the patient has reached a stable, effective dose, the level should be measured every six to 12 months (Janicak, 2021).

Adverse Effects of Lithium: (DeBattista, 2021b; Janicak, 2021; Meyer, 2018)

  • Nausea
  • Polydipsia
  • Polyuria
  • Tremor
  • Weight gain

Important components of these adverse effects include:

  • Tremor:
    • Tremor occurs in ~ 10% to 65% of all patients taking lithium (Alves et al., 2017; Janicak, 2021).
    • Tremor usually affects the hands (Alves et al., 2017) and it a common reason for non-compliance with the medication regimen and for discontinuing the use of lithium (Alves et al., 2021).
    • Lithium-induced tremor usually begins after the patient has started taking lithium or when the dose is increased, but it can occur at any time (Janicak, 2021).
    • The tremor may spontaneously resolve, or the patient may need to change the dose, change from a long-acting preparation to a short-acting (or the reverse), use lithium citrate instead of lithium carbonate (or the reverse), or a specific intervention like a beta-blocker can be used to reduce the intensity of the tremor (Janicak, 2021).
  • Cognitive Impairment:
    • Cognitive impairment is an often-reported adverse effect of lithium (Janicak, 2021; Malhi et al., 2016; Paterson & Parker, 2017).
    • The true incidence of this adverse effect in bipolar patients who are treated with lithium is difficult to determine as cognitive impairment is, itself, a common feature of bipolar disorder (Janicak, 2021; Malhi et al., 2016; Paterson & Parker, 2017).
    • Research has shown that lithium therapy has a negative effect on creativity, psychomotor performance, verbal fluency, learning, and memory (Janicak, 2021; Malhi et al., 2016; Paterson & Parker, 2017).
    • It does not appear to affect attention (Paterson & Parker, 2017).
    • Lithium therapy may preserve other aspects of cognitive ability (Janicak, 2021; Malhi et al., 2016).
    • Malhi et al (2016) wrote: “Disentangling the components of neurocognition modulated by lithium in the context of a fluctuating and complex illness such as bipolar disorder is a significant challenge.”
  • Cardiovascular:
    • Lithium is directly toxic to the myocardium (Lorgovenau et al., 2019).
    • But unless an overdose of lithium is taken, or the serum lithium level is high, serious CV adverse effects do not occur.
    • Most of the CV complications, even ones that might be alarming for clinicians like AV blocks, bundle branch blocks, and sinus bradycardia, may persist for years and are often benign (Lorgovenau et al., 2019; Mehta & Vannozzi, 2017).
    • Cardiovascular effects of lithium therapy include (but are not limited to): (Lorgovenau et al., 2019; Mehta & Vannozzi, 2017):
      • AV blocks
      • Bundle branch blocks
      • Sinus bradycardia
      • Sinus node dysfunction
      • QT prolongation
      • T wave depression/inversion
    • T wave depression/inversion is the most common finding, followed by sinus node dysfunction characterized by sinus bradycardia, with an average decrease in heart rate of 10 beats per minute (Mehta & Vannozzi, 2017).
    • The longer the duration of treatment and the higher the serum lithium level the greater the risk for CV complications from lithium (Mehta & Venozzi, 2016).
    • However, the adverse effects can happen when the serum lithium level is changing rapidly (Mehta & Vannozzi, 2016) and at therapeutic lithium levels, as well (Lorgovenau et al., 2019; Mehta & Vannozzi, 2017).
    • Unless there is a serious adverse effect, lithium therapy does not need to be discontinued if there are adverse CV effects (Mehta & Vannozzi, 2016).
    • Sick sinus syndrome is a contraindication to the use of lithium, however (DeBattista, 2021b).
  • Polydipsia and Polyuria:
    • Lithium decreases the responsiveness of the collecting ducts in the kidneys to antidiuretic hormone (ADH) (DeBattista, 2021b; Janicak, 2021; Meyer, 2018).
    • Because of this, the kidneys lose the ability to concentrate urine, water is not reabsorbed, and large amounts of dilute urine are produced.
    • Polydipsia and polyuria (usually defined as a urine output > 3 liters in 24 hours) are common adverse effects of lithium therapy (Davis et al., 2018; DeBattista, 2021b; Janicak, 2021; Meyer, 2018; Schoot et al., 2020).
    • It has been estimated that 20% to 87% of patients taking lithium develop Nephrogenic Diabetes Insipidus (NDI) (Davis et al., 2018).
    • The risk for this adverse effect is correlated to the duration of treatment, i.e., the longer the treatment, the greater the risk (Schoot et al., 2020).
    • Although there are treatments, NDI may become irreversible (Schoot et al., 2020).
    • NDI is difficult to tolerate and it can cause dehydration, electrolyte disturbances, and elevated serum lithium levels (Schoot et al., 2020).
    • Long-term lithium therapy may or may not cause end-stage kidney disease (ESKD), but if it occurs, it happens after decades of treatment and the incidence is < 1.0% (Davis et al., 2018; DeBattista, 2021b).
  • Sexual Dysfunction:
    • Sexual dysfunction is common in patients on long-term lithium therapy (Grover et al., 2015; Elanzer et al., 2014). There is little published information on the topic, but a study by Elanzer et al (2014) found that one-third of the patients who were on long-term lithium therapy (the mean duration of treatment was almost 10 years) had some form of sexual dysfunction.
  • Thyroid Dysfunction:
    • Thyroid dysfunction affects approximately 14% to 35% of patients taking lithium (Lieber et al., 2020).
    • Most patients (19-35%) have subclinical hypothyroidism (Lieber et al., 2020), 14% to 17% have overt diseases (Lieber et al., 2020), and women have a three to nine times greater risk than men (Meyer, 2018).
    • Lithium-induced hypothyroidism can be easily treated with thyroid supplements (Meyer, 2018).
    • In fact, it should be reversible once the use of lithium is discontinued (Lieber et al., 2020).

CNS Stimulants

Central nervous system (CNS) stimulants are the primary treatment for attention deficit/hyperactivity disorder (ADHD) in children (> age 6 and who meet specific criteria), adolescents, and adults (Searight & Severance, 2020).

Amphetamines and methylphenidate, commonly called by its trade name, Ritalin, are the two types of CNS stimulants used for treating ADHD (Searight & Severance, 2020).

Amphetamines and methylphenidate are sympathomimetics. These drugs cause a release of catecholamines (primarily dopamine and norepinephrine) at the synapses, and block the reuptake of catecholamines.

The CNS stimulants currently available in the US that are used to treat ADHD are listed below: Generic name (Trade name)

  • Dexmethylphenidate (Focalin®)
  • Dextroamphetamine and amphetamine (Adderall®)
  • Lisdexamfetamine (Vyvanse®)
  • Methylphenidate (Ritalin®)

Prescribing:

Before prescribing a CNS stimulant, a pretreatment evaluation should be done. This should include measurement of blood pressure, pulse, weight, and height (for children), determination of the patient’s personal and family history of CV disease, determining if the patient has or is at risk for a substance-use disorder and when needed, a consultation with a cardiologist (Bukstein, 2021; Krull, 2020a).

These CNS stimulants should not be used or should be used cautiously if the patient has symptomatic CV disease, a history of a substance-use disorder, moderate to severe hypertension, hyperthyroidism, concurrent use or use in the prior 14 days of an MAOI, anxiety, agitation, glaucoma, motor tics, or Tourette’s syndrome (Krull, 2020b)

Therapy should start with a low dose and the dose should be increased over weeks or months until the desired effect is reached (Bukstein, 2021; Krull, 2020a).

Adverse Effects of CNS Stimulants: (Bukstein, 2021; Krull, 2020a; Searight & Severance, 2020)

  • Dizziness
  • Dry mouth
  • Insomnia
  • Irritability
  • Mood lability
  • Weight loss

Less common and more serious adverse effects are: (Bukstein, 2021; Krull, 2020a; Searight & Severance, 2020)

  • Elevations of blood pressure and heart rate
  • CV events
  • Psychosis
  • Priapism
  • Tics
  • Abuse and/or diversion

Important components of these adverse effects include:

  • Cardiovascular:
    • The CNS stimulants can increase blood pressure and heart rate (Bukstein, 2021; Krull, 2020b; Searight & Severance, 2020).
    • There is no evidence that the use of CNS stimulants in children, adolescents, and adults who do not have cardiac disease, increases the risk for serious CV events. (Berger, 2021; Houghton et al, 2020).
  • Psychosis:
    • Psychosis is a well-known complication of CNS stimulant overdose and abuse.
    • Psychosis has been reported in patients who have ADHD and are taking a CNS stimulant (Bukstein, 2021; Krull, 2020b).
    • However, this is not a common adverse effect.
    • Moran et al (2019) found that in patients aged 13 to 25, with or without a previous history of psychosis, new-onset psychosis occurred in 1 of 660 patients, and amphetamines were more likely to cause this adverse effect than methylphenidate (Moran et al., 2019).
    • A study by Hollis et al, found that in patients with or without a previous history of psychosis, methylphenidate use did not increase the risk of developing psychosis (Hechtman, 2019).
  • Priapism:
    • Priapism is a rare adverse effect of methylphenidate and amphetamines. (Bukstein, 2021; Eiland et al., 2014; Karayagmurlu & Coskun, 2020).
    • There are a few published case reports (Eiland et al., 2014), and a US Food and Drug Administration (FDA) Safety Warning published in 2013 that identified 15 cases (Eiland et al., 2014; US Food and Drug Administration [FDA], 2013).
    • Most of the patients have been children, but in the FDA report, the age range was 8 to 33 years (FDA, 2013).
    • The FDA Safety warning read: “In our review, the median age of patients taking a methylphenidate product who experienced priapism was 12.5 years (range 8 to 33 years). In a few patients, priapism occurred after an increase in the dosage of methylphenidate, but priapism has also occurred under other conditions, such as during short periods when the drug was stopped temporarily, when there was a longer than the typical time between doses, or after stopping the drug permanently.”
    • Patients taking methylphenidate or amphetamine for ADHD who develop priapism should immediately seek medical attention (Eiland et al., 2014).
  • Poor Growth:
    • Children with ADHD who are treated with a CNS stimulant may be at risk for poor growth, decreased body weight, decreased body mass index, and decreased height when reaching adulthood (Ghaiar & DeBoer, 2020).
    • There is research that supports and research that refutes that CNS stimulants can cause these adverse effects (Ghaiar & DeBoer, 2020).
    • Krull (2020a) notes that a drug holiday – a short period of abstinence from the drug – may be helpful in children who are taking a CNS stimulant and who are having growth problems.
  • Abuse and Diversion:
    • Amphetamines and methylphenidate are controlled substances, Schedule II drugs.
    • These medications have addiction potential, and they can be and are abused and diverted (Chamakalayil et al., 2020; Krull, 2020a; Krull, 2020b).
    • Adults who have ADHD are more likely to have a substance-use disorder than adults who do not have ADHD (Chamakalayil et al., 2020), and using a CNS stimulant drug for an adult who has ADHD and has a substance-use disorder can be done, but must be done carefully (Chamakalayil et al., 2020).
    • It appears that the use of CNS stimulants for adult ADHD patients does not cause a substance-use disorder to develop, but the evidence on this topic is not conclusive for or against (Chamakalayil et al., 2021).
    • Clinicians should keep in mind the possibility that if a patient is not having an adequate response to a CNS stimulant or if he/she is having serious adverse effects, the patient may be diverting (i.e., selling) the medication or abusing it i.e., taking excess amounts.

Summary

For many people who have a psychiatric illness, pharmacotherapy is an essential treatment. The anxiolytics, antidepressants, antipsychotics, lithium, and CNS stimulants are effective, but they are also complex. These drugs are agonists and antagonists of many of the neurotransmitters. They affect the binding, release, and reuptake of dopamine, norepinephrine, serotonin, and other neurotransmitters. This is the basis of their therapeutic effects, but it is also the cause of (some) of their adverse effects. For example, the antipsychotics are designed to be dopamine-2 receptor blockers, but they also have an effect – and unwanted effect – on cholinergic and adrenergic receptors. In addition, there are adverse effects and administration and patient monitoring issues specific to the anxiolytics, antidepressants, antipsychotics, lithium, and CNS stimulants that healthcare professionals must know about in order to use these medications safely and provide good patient education.

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