Psychopharmacology: Medications for the Mind

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 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.

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 classified as SSRIs and SNRIs, respectively, and they will be discussed later in the module.

Benzodiazepines are the most commonly prescribed anxiolytic that is 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 trade name follows the generic 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 binding of benzodiazepine–GABAA receptors 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 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 label used 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 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 be 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-HT_1a 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).

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

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 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 movement 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 is one of the most distressing adverse effects of antipsychotics.
  • Both typical and atypical antipsychotics 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 of 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 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 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 to 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 is 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, adverse effects can happen when the serum lithium level changes 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).

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

Amphetamines and methylphenidate, commonly called by their 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 had 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 they have serious adverse effects, the patient may be diverting (i.e., selling) the medication or abusing it, i.e., taking excess amounts.

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) their adverse effects. For example, antipsychotics are designed to be dopamine-2 receptor blockers, but they also have an effect – an 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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