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Clinical Drug Monitoring & Medication Adherence
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Behavioral Health Considerations in Pain Management: The Initiation of Antidepressants and Antipsychotics

When initiating antipsychotics or antidepressants in a patient with a diagnosed mental health disorder, there are multiple considerations to be made. How to monitor medication and adverse effects to ensure treatment efficacy and prevent relapse.

The COVID-19 pandemic has influenced mental health in a way never seen before. The general public has shown increased levels of anxiety and depression and a decrease in overall well-being since the pandemic began.1,2 These increased rates may be attributed to the unknown, changes in daily life, and inability to interact socially with friends and family.

While COVID-19 has increased the incidence of mental health disorders, however, it has decreased access to behavioral and mental health treatments. The American Medical Association has encouraged providers to expand their services to include behavioral health in order to improve access for those suffering.3 With growing demand, it is imperative to address crucial considerations and clinical monitoring parameters for medications used to treat behavioral and mental health disorders, namely antidepressants and antipsychotics.

Another point to consider is that individuals presenting with a psychiatric condition have potentially trialed medications previously. It is essential to take a thorough medication history to determine maximum tolerated doses of medications, duration of treatment, and response. (Image: iStock)


Upon Initiation of Antidepressants and Antipsychotics

Patient History Taking

Before initiating any antidepressant or antipsychotic, it is essential to obtain a comprehensive history and examination of the patient to determine comorbid conditions, risk factors for developing adverse effects, and baseline presentation.4,5 A complete medical workup should be completed as certain conditions, such as hypo/hyperthyroidism, may appear similar to psychiatric disorders. One may consider obtaining a thyroid-stimulating hormone (TSH) and free T4, for example, before initiating therapy to rule out hypo/hyperthyroidism.

When obtaining a patient’s medical history, consider their use of alcohol, tobacco, and any recreational or illicit drug use. In individuals with alcohol use disorder (AUD), the use of duloxetine has been shown to increase alanine transaminase, aspartate transaminase, and alkaline phosphatase, indicating it may induce liver injury.6 Consider the use of selective serotonin reuptake inhibitors (SSRIs) or other agents in those with diagnosed AUD. Tobacco, on the other hand, is a potent inducer of CYP1A2. Numerous antipsychotics are metabolized via CYP1A2 and require dose adjustments in patients who smoke. Asenapine, clozapine, and olanzapine, for instance, are metabolized via CYP1A2 and may require higher doses to see an adequate effect.

Another point to consider is that individuals presenting with a psychiatric condition have potentially trialed medications previously. It is essential to take a thorough medication history to determine maximum tolerated doses of medications, duration of treatment, and response. Some medications may not have been optimized or discontinued too soon due to a lack of efficacy. Most antidepressants take 6 to 8 weeks to see the full effect. For antipsychotics, within the first few days, improvements can be seen in acute agitation, aggression, and increased motor agitation. Within the first 2 weeks, hallucinations, delusions, and disorganized thinking may respond. It may take 4 to 6 weeks to see the complete response of an antipsychotic. 

Providers should obtain a standardized rating scale before initiating any antidepressant or antipsychotic medications. Table I describes the standardized rating scales for a variety of psychiatric conditions. These scales can provide a clearer picture of the severity of the disease and its impact on the patient. Perform rating scales at both baseline and follow-up to discern a response to treatment.

View Table I full size


An expanding field of psychiatric care is the use of pharmacogenomics. While most major practice guidelines do not recommend routine pharmacogenomic testing, there are a few circumstances where it should be considered. For instance, patients who are unable to tolerate minimum doses of medications, who experience a repeated failure to respond to high doses, or who are at risk for nonadherence, may benefit from pharmacogenomic testing.7,8 If a patient previously underwent pharmacogenomic testing, the results can be used to drive treatment.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides guidelines, including 2D6 and 2C19 for tricyclic antidepressants (TCAs) and 2D6 and 2C19 for SSRIs, that address various genotypes and the implications of medications to guide prescribing.9 (See also, using  CYP2D6 genetic test results can be used to optimize opioid therapy.)

Safety Assessment

Before deciding the appropriate level of care for a patient, a safety assessment should be completed, most importantly, a suicide risk assessment. Two screening tools used in clinical practice include the Patient Health Questionnaire-9 (PHQ-9) and the Columbia Suicide Severity Rating Scale.10,11 Risk factors and protective factors noted in suicide are listed in Table II.12


Using both the rating scales, risk factors, and protective factors, the appropriate level of care can be discerned, as described in Table III.13 Of note, avoid prescribing TCAs to patients exhibiting suicidal behavior as these antidepressants are toxic at low doses. 


View Table III full size

In-Depth Prescribing Considerations for Antidepressants and Antipsychotics


The goals of treating major depressive disorder (MDD) and anxiety, which commonly present in patients with chronic pain, includes relieving signs and symptoms, minimizing disrupting effects on daily life, and preventing recurrence. The prevalence of pain is 5% to 85% and 16.5% to 28.8% respectively for MDD and anxiety.14,15 The goals of MDD and anxiety treatment are often achieved with a combination of both medication and therapy. While most antidepressants do not require baseline laboratory testing, it is best practice to consider possible underlying medical conditions that influence prescribing. Table IV highlights clinical pearls and renal/hepatic dose adjustments required for antidepressants.15,16

View Table IV full size

A few examples of considerations include patients with chronic pain, especially neuropathic pain; a serotonin-norepinephrine reuptake inhibitor (SNRI) or TCA may improve pain as well as underlying mood disorders. The underlying medical history and prior medication trials should determine which medication is prescribed.

Patients with underlying hyponatremia, for instance, should avoid SSRIs as these may worsen hyponatremia. SSRIs more commonly cause hyponatremia, although SNRIs may cause it as well, with the incidence varying widely from 0.5% to 32%. Those at the highest risk for developing SSRI-induced hyponatremia include older age and use with diuretics.17-20 Safer options for those with hyponatremia include either mirtazapine or TCAs.21-24 If a TCA is chosen, an electrocardiogram should be obtained at baseline to rule out any cardiovascular abnormalities as TCAs should be avoided in this population. SNRIs have evidence supporting their elevation of blood pressure, but SSRIs have shown no difference in blood pressure.25-28 If a patient has controlled blood pressure, it is appropriate to initiate an SNRI and continue to monitor blood pressure. 


In patients with schizophrenia, treatment goals include relieving the signs/symptoms that are bothering the patient, improving their ability to care for themselves, and preventing further acute episodes of schizophrenia. Prevalence of pain in patients with schizophrenia is thought to be around 47%.29 Treatment of schizophrenia requires the use of medications, most notably antipsychotics.

Before initiating an antipsychotic, however, it is crucial to obtain BMI, waist circumference, lipid panel, fasting blood glucose, and hemoglobin A1c as these medications may cause metabolic syndrome.30,31 Clozapine, olanzapine, and chlorpromazine have the highest risk of developing metabolic syndrome.32 An electrocardiogram (ECG) should be obtained at baseline as many antipsychotics can prolong the QTc. Chlorpromazine, iloperidone, haloperidol, thioridazine, quetiapine, and ziprasidone have a higher risk of prolonging the QTc versus other antipsychotics.33-49 Lastly, before initiating antipsychotics, the prescriber should obtain a liver panel due to the risk of transient increases in LFTs.50-54 Olanzapine, quetiapine, asenapine, and risperidone are those most commonly associated with elevated liver enzymes.50

Another treatment option for individuals with schizophrenia is long-acting injectable medications (LAIs). Previously, LAIs were only recommended to individuals who were non-adherent to oral antipsychotics. More recent recommendations state that LAIs should be discussed/offered as a first-line option or to those who are would prefer LAIs.55,56 While the literature is not clear about exactly when to recommend LAIs, it is essential to discuss with patients as a potential treatment option.

If clozapine is considered for a patient, it is required that the prescriber, pharmacist, and pharmacy are registered with the Clozapine REMS program. Clozapine has a risk of inducing agranulocytosis in about 1% of patients and neutropenia in about 3%.57,58 To mitigate the risk of agranulocytosis, a baseline CBC must be obtained. For patients without benign ethnic neutropenia, the ANC must be ≥1500 cells/µL, and for the with benign ethnic neutropenia, the ANC must be ≥1000 cells/µL.59

An overview of clinical pearls and renal/hepatic dose adjustments can be seen in Table V.17,60

View Table V full size


Patient Follow-Up and Clinical Monitoring

After initiation of pharmacotherapy, follow-up should occur at 4 to 6 weeks to assess treatment efficacy. At each follow-up, patients should be evaluated on their mental health disorder signs and symptoms to discern the effect of therapy. One way to determine response is through the standardized rating scales noted in Table I. These scales have cutoffs that can help assess response and remission.

Also consider the following regarding clinical drug monitoring and medication adherence:

  • If a patient is experiencing a complete response, continue the current dose and monitor for adverse effects.
  • If a patient is experiencing a partial response with no adverse effects, doses should be maximized first.
  • If the patient is still experiencing partial response despite the maximum tolerated dose, switching to another medication should be considered.
  • If a patient is not responding to the treatment, it should be considered if the patient has had adequate time to respond. If yes, consider if another medication may be warranted. If no, consider if a longer duration may be necessary.
  • If a patient is in remission, it is vital to continue the patient on the medication at that dose for an adequate time before the discussion of decreasing dose or discontinuing.

Noteworthy Considerations for Patients with Depression or Schizophrenia

  • In depression, if a patient has continued on treatment and responded well for the first 1 to 3 months, at months 4 to 9, these medications should be continued to minimize the risk of relapse. After month 9, discuss whether the patient is a candidate for continuing treatment life-long or tapering off of the medication.
  • In schizophrenia, patients should be treated lifelong with pharmacotherapy at adequate doses to minimize the risk of relapse.

Overall, at follow-up for any antidepressant or antipsychotic use, ask patients if they are experiencing any adverse effects since starting their medications. It has been shown that a leading cause for psychotropic non-adherence is adverse effects.61 By addressing adverse effects, it can determine the next steps in treatment and potential augmentation strategies. 

All patients on antipsychotics should have their BMI and waist circumference monthly for the first 3 months, at 5 months, and annually thereafter.30,31 Patients should have their hemoglobin A1c, fasting plasma glucose, and fasting lipid panel at 3 months then annually thereafter. If a patient shows signs/symptoms of developing metabolic syndrome, more frequent A1c and lipid panels may be warranted.30,31

Antidepressant and Antipsychotic Side Effects: What to Expect

This article only addresses common and notable side effects of antidepressants and antipsychotics. The next paper in this series will address side effect management and medication adherence in patients. 

Antidepressants and Side Effects

Antidepressants have numerous side effects, including bruxism, sexual dysfunction, and insomnia.62

Bruxism, which can occur during sleep or while awake, is most commonly associated with the use of venlafaxine, fluoxetine, and sertraline but may occur with other antidepressant use as well.62 In a cross-sectional study, the prevalence of sleep bruxism was 24.3% in the antidepressant group vs 15.3% in the placebo group.63 The mechanism of antidepressant-induced bruxism is not fully understood, but symptoms tend to appear within 3 to 4 weeks after initiation or dose titration.62

SSRIs have also been shown to cause sexual dysfunction in 40% to 65% of patients, but this effect is frequently not discussed,64 often due to discomfort about the patient and/or clinician. The highest incidence of sexual dysfunction has been found with paroxetine, fluvoxamine, sertraline, and fluoxetine.65 Sexual dysfunction has been found to correlate with dose; therefore, the lower the dose, the lower the risk.66 It is postulated that the sexual dysfunction is due to 5-HT2 agonism at the descending spinal cord synapse on sympathetic and parasympathetic neurons.66

Antipsychotics and Side Effects

Both first- and second-generation antipsychotics have numerous side effects. Some of the more notable effects include metabolic syndrome, extrapyramidal movements, hyperprolactinemia, and restless leg syndrome. 

Second-generation antipsychotics have the highest probability of causing metabolic syndrome, encompassing hyperlipidemia, diabetes, and weight gain. Clozapine and olanzapine have sown the greatest weight gain, increase in total cholesterol, LDL, and decrease in HDL. Antipsychotic-induced diabetes is likely mediated via weight gain and insulin resistance.67 Typically, patients can manage these side effects via diet and exercise, but some patients may require additional interventions. 

Extrapyramidal symptoms (EPS) are another adverse effect typically associated with first-generation antipsychotics. There are four types of EPS:

  • Pseudoparkinsonism
  • Acute dystonia
  • Akathisia
  • Tardive dyskinesia

Pseudoparkinsonism is likely to occur within 1 to 2 weeks after initiation of increasing doses of medications and is also more common in the elderly, women, or those taking high-potency medications. This effect is likely caused by an imbalance of dopamine and acetylcholine in the nigrostriatal pathway.

Acute dystonia is characterized by facial grimacing and spasms of the facial muscles, and typically occurs between 24 to 96 hours of initiation or dose change of first-generation antipsychotics. Those at increased risk include young individuals, males, those with a history of cocaine use, or use high potency/doses of medications.

Akathisia is often noted as feeling restless or unable to sit still and occurs most frequently within the first 2.5 months of treatment, most commonly experienced by middle-aged females.

Lastly, tardive dyskinesia (TD) is the involuntary movement of the face and limbs. This effect can occur after months to years of treatment with antipsychotics. Those at increased risk include non-white, elderly patients on high doses of medications. For TD, prevention is crucial because, in some cases, it may be irreversible. An Abnormal Involuntary Movement Scale or Dyskinesia Identification System Condensed User Scale should be completed on an annual basis to assess for tardive dyskinesia. 

Clinical Takeaways

Before initiating antipsychotics or antidepressants in a patient with a diagnosed mental health disorder, there are multiple considerations to be made. It is important to recognize the patient's unique symptoms and baseline characteristics to drive medication choice. (Download these FAQs on medication adherence for your patients)

Once the medication has been initiated, clinicians need to monitor for adverse effects and efficacy of treatment at regular intervals. Even once a patient has stabilized, continued monitoring and assessment can help to prevent relapse. 



This work is the sole opinion of the authors and does not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies mentioned or specific drugs discussed. It was not prepared as part of official government duties.



Last updated on: May 26, 2021
Continue Reading:
Lessons Learned from the COVID Pandemic: Monitoring Mental Health as Part of Pain Management
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