Diagnostic Overview
SSRDs include several distinct disorders:

1. Somatic Symptom Disorder (SSD)
   Characterized by one or more distressing somatic symptoms that are accompanied by excessive thoughts, feelings, or behaviors related to those symptoms. Importantly, the symptoms may or may not be medically explained. The focus is on the psychological response to the symptoms rather than the presence or absence of a medical explanation.
2. Illness Anxiety Disorder (IAD)
   Previously known as hypochondriasis, IAD involves preoccupation with having or acquiring a serious illness despite minimal or no somatic symptoms. Patients frequently misinterpret normal bodily sensations and engage in repeated health checks or avoidant behaviors.
3. Conversion Disorder (Functional Neurological Symptom Disorder)
   This condition involves neurological symptoms (e.g., paralysis, seizures, blindness) that are inconsistent with recognized medical conditions. Symptoms often emerge in the context of psychological stress or trauma.
4. Psychological Factors Affecting Other Medical Conditions
   This diagnosis applies when psychological or behavioral factors significantly affect the course, treatment, or outcome of a medical illness.
5. Factitious Disorder
   Involves intentional falsification of physical or psychological symptoms without obvious external incentives, distinguishing it from malingering.

Epidemiology and Clinical Features
SSRDs are common across healthcare settings. SSD affects approximately 5-7% of the general population, with a higher prevalence in women. IAD affects 1.3-10% of the population, with equal gender distribution. Conversion disorder is more frequently diagnosed in females and typically presents in adolescence or early adulthood.

Patients with SSRDs often have co-occurring psychiatric disorders such as depression or anxiety. Adverse childhood experiences, trauma, and chronic stress are significant risk factors. Additionally, these patients often have complex relationships with the healthcare system—frequent visits, diagnostic procedures, and a feeling of being misunderstood or invalidated are possible.

Challenges in Diagnosis
Diagnosing SSRDs requires careful differentiation from medical conditions, malingering, and other psychiatric disorders. The DSM-5-TR emphasizes the need to avoid over pathologizing patients with medically unexplained symptoms and instead focus on the degree of psychological distress and functional impairment.

Clinicians are best served to conduct comprehensive assessments that include medical, psychiatric, and psychosocial components. Collateral information from family and medical records is often helpful. Importantly, SSRDs are not diagnoses of exclusion but require positive identification of specific clinical features.

Best Practices in Treatment

1. Psychoeducation and Therapeutic Alliance
   Establishing a strong therapeutic alliance is foundational. Patients often feel invalidated by previous medical encounters, so clinicians must acknowledge their suffering without reinforcing somatic preoccupation. Psychoeducation should reframe the illness using a biopsychosocial model, emphasizing the truly felt nature of the symptoms while introducing the role of stress and emotional factors.
2. Cognitive Behavioral Therapy (CBT)
   CBT is the most evidence-based treatment for SSRDs. It targets beliefs and thoughts about illness and health, and avoidant or excessive health behaviors. CBT helps patients develop more accurate appraisals of bodily sensations and encourages gradual re-engagement in activities.
3. Mindfulness and Acceptance-Based Therapies
   Interventions such as mindfulness-based stress reduction (MBSR) and acceptance and commitment therapy (ACT) show promise by helping patients observe their symptoms non-judgmentally and reduce experiential avoidance. These approaches may be particularly helpful in patients with chronic pain or functional neurological symptoms.
4. Pharmacotherapy
   While no medications are FDA-approved specifically for SSRDs, selective serotonin reuptake inhibitors (SSRIs) may be helpful when comorbid depression or anxiety is present. SNRIs and tricyclic antidepressants have also shown utility in somatoform pain syndromes. For example, the SNRI Duloxetine has an FDA approval for chronic pain. However, polypharmacy and iatrogenic harm should be avoided.
5. Interdisciplinary Care and Coordination
   Patients benefit from collaborative care models involving primary care providers, psychiatrists, psychologists, physical therapists, and sometimes neurologists or pain specialists. Coordinated care prevents redundant testing and provides consistent messaging. Regular case conferences and shared treatment plans are key to success.
6. Limit Medical Investigations and Set Boundaries
   While it is essential to rule out medical conditions, repeated investigations reinforce illness behavior. Providers should adopt a “diagnostic closure” strategy, providing reassurance based on appropriate evaluation, and shift focus to functional recovery. Structured visits, time-limited appointments, and continuity with a single provider help reduce fragmentation.
7. Address Trauma and Comorbidities
   Because many patients have histories of trauma, integrating trauma-informed care is essential. Screening for PTSD, dissociation, and borderline personality disorder is often appropriate. Psychotherapy targeting trauma (e.g., EMDR, trauma-focused CBT) can reduce somatic symptom intensity.

Conclusion
Somatic Symptom and Related Disorders are complex conditions that straddle the boundary between psychiatry and medicine. When properly diagnosed and treated using evidence-based, multidisciplinary approaches, many patients experience significant improvements in functioning and quality of life. Mental health providers play a critical role in destigmatizing these conditions, guiding collaborative care, and helping patients shift from symptom preoccupation to adaptive functioning.

AUTHOR:

Shawn Singh Sidhu, MD, DFAPA, DFAACAP

Co-Medical Director, Vista Hill Foundation

Vista Hill Native American SmartCare Program

Psychotropic drug-related weight gain can lead to non-initiation, discontinuation, or dissatisfaction with treatment. Moreover, it contributes to obesity, which is linked to an increased risk of sleep apnea, type 2 diabetes, dyslipidemia, nonalcoholic fatty liver disease, and cardiovascular disease. Therefore, healthcare providers must be aware of the differential risks associated with psychotropic medications in order to evaluate these risks against the potential therapeutic benefits.

ANTIDEPRESSANTS

The risk of weight gain varies significantly across different antidepressants. Those associated with a high risk of weight gain include:

• Amitriptyline
• Citalopram
• Clomipramine
• Fluvoxamine
• Mirtazapine
• Nortriptyline
• Paroxetine
• Phenelzine

Moderate-risk antidepressants include:

• Desipramine
• Duloxetine
• Escitalopram
• Sertraline
• Venlafaxine

Low-risk antidepressants include:

• Agomelatine
• Desvenlafaxine
• Gepirone
• Levomilnacipran
• Moclobemide
• Selegiline
• Tranylcypromine
• Vilazodone
• Vortioxetine

Antidepressants with a neutral or weight-loss effect include:

• Bupropion
• Dextromethorphan-bupropion
• Esketamine
• Fluoxetine
• Zuranolone

Antidepressants are thought to stimulate appetite and caloric intake due to their effects on cholinergic, histaminergic (H1), and serotonergic receptors.

          ANTIPSYCHOTICS

Antipsychotics, particularly second-generation antipsychotics, are strongly associated with weight gain. The medications most likely to cause significant weight gain include:

• Clozapine
• Olanzapine

Moderate-risk antipsychotics include:

• Chlorpromazine
• Olanzapine/samidorphan
• Paliperidone
• Quetiapine
• Risperidone

Low-risk antipsychotics include:

• Amisulpride
• Aripiprazole
• Asenapine
• Brexpiprazole
• Cariprazine
• Haloperidol
• Iloperidone
• Ziprasidone

Antipsychotics with a neutral risk for weight gain include:

• Lumateperone
• Lurasidone

Risk factors for weight gain with antipsychotics include younger age, early stages of illness, antipsychotic-naïve status, lower pretreatment weight, and weight gain soon after starting treatment. Weight gain is dose-dependent with certain antipsychotics, such as olanzapine, and tends to increase with longer exposure. It is thought to result from a combination of factors, including high affinity and antagonism at histamine (H1), alpha-1 adrenergic, and 5-HT2C receptors; the absence of specific genetic variants (i.e., 5-HT2C receptor variant); and interactions between central dopamine and insulin signaling.

Lithium and Anticonvulsants. Among anticonvulsants, valproic acid carries the highest risk for weight gain. Lithium can also lead to weight gain, though the risk is generally considered lower than thought previously. Anticonvulsants with a low risk of weight gain include carbamazepine, gabapentin, oxcarbazepine, and pregabalin, while lamotrigine and topiramate have the lowest risk.

Preventing and managing psychotropic drug-related weight gain involves several strategies. These include encouraging lifestyle and behavioral modifications, prioritizing medications with a lower risk of weight gain, and adhering to metabolic monitoring guidelines. Additionally, providers can consider medications to promote weight gain.

For both adults and youth, metformin can be prescribed to prevent or treat weight gain related to antipsychotics. There is also some preliminary evidence suggesting that glucagon-like peptide-1 (GLP-1) agonists may help manage psychotropic-drug related weight gain, perhaps even more effectively than metformin; however, further research is needed.

References

Mansuri Z, Makani R, Trivedi C, et a. The role of metformin in treatment of weight gain associated with atypical antipsychotic treatment in children and adolescents: A systematic review and meta-analysis of randomized controlled trials. Frontiers in Psychiatry. 2022;13. doi:10.3389/fpsyt.2022.933570

McIntyre RS, Kwan ATH, Rosenblat JD, Teopiz KM, Mansur RB. Psychotropic Drug–Related Weight Gain and Its Treatment. American Journal of Psychiatry. 2024;181(1):26-38. doi:10.1176/appi.ajp.20230922

Sepúlveda-Lizcano L, Arenas-Villamizar VV, Jaimes-Duarte EB, et al. Metabolic Adverse Effects of Psychotropic Drug Therapy: A Systematic Review. European journal of investigation in health, psychology and education. 2023;13(8):1505-1520. doi:10.3390/ejihpe13080110

AUTHOR:

Dr. Kristen Kim, MD

Child, Adolescent and Adult Psychiatrist

Vista Hill Foundation

A child who appears to be oppositional or aggressive may be reacting to internal anxiety—anxiety he may, depending on his age, not be able to articulate effectively, or not even fully recognize that he’s feeling. Anxiety is based on the body’s physiological response to a threat in the environment, as a response to maximize the body’s ability to either face danger or escape danger. Some children show their anxiety by becoming quiet, shrinking away from situations that make them anxious, and having trouble separating from their parents. These symptoms of anxiety are easy to detect for most providers.

However, the above symptoms are not the only way that anxiety manifests itself. Other children react with an overwhelming need to break out of an uncomfortable situation, which can be misinterpreted as anger or opposition. What people on the outside see is intense anger that is out of proportion to the situation, property destruction, elopement and aggression. In this way, anxiety can be a great masquerader.

Anxiety can present in the school setting as disruptive behavior. A child might find the academic work hard or become frustrated if he can’t do it perfectly. A child might have a hard time taking feedback or criticism from the teacher or peers. A child might be overwhelmed with the noise level in the classroom or a crowded lunch area

When a child presents with disruptive behavior, it is important to ask screening questions in other mental health areas as well, including depression, anxiety, obsessive compulsive disorder and autism. Examples of screening questions for anxiety include: Does your child worry excessively about everyday activities? Does your child have exaggerated or irrational fears?  If any of these screening questions are positive, consider asking more detailed questions or obtaining screening questionnaires (for example the GAD7 or SCARED) to elicit more details. Referral for a more thorough diagnostic evaluation with a psychologist could be helpful as well in cases that are diagnostically confusing.

This distinction is important to make sure a child has the right diagnosis, because it impacts treatment. The therapy approach for anxiety is different than the therapy approach for disruptive behavior disorders. Psychotropic medication, if being considered, would be different as well for these diagnoses. The SSRIs would be first line medication treatment for anxiety which the stimulants or non-stimulants like the alpha agonists (guanfacine and clonidine) or atomoxetine would be first line medication treatment for ADHD and other disruptive behavior disorders. If one is considering medication treatment for behavioral dysregulation that can be seen with anxiety, the alpha agonists can be helpful specifically for that. The stimulants can actually make the anxiety worse in these clinical situations.

In summary, it is important to ask what might be underlying the externalizing behavioral problems, because you might uncover anxiety masquerading as a disruptive behavior disorder. As always, SmartCare BHCS Parent Line 858-956-5900 is available to help families find appropriate resources and SmartCare Provider Line 858-880-6405 is available to providers to help with diagnostic clarification and medication treatment questions.

References:

https://childmind.org/article/how-anxiety-leads-to-disruptive-behavior/

Beyond Behaviors by Mona Delahooke PhD: https://monadelahooke.com/beyond-behaviors/

AUTHOR:

Charmi Patel Rao MD, DFAACAP

Co-Medical Director, Vista Hill Foundation

Health Science Clinical Professor, UCSD Department of Psychiatry

President, San Diego Academy of Child and Adolescent Psychiatry

This medication treatment algorithm outlines evidence-based pharmacological interventions for adolescent depression, incorporating safety considerations, efficacy, and potential adverse effects. The algorithm can serve as a guide and should be individualized based on clinical judgment, patient preferences, and specific clinical circumstances. Regular monitoring and reassessment are essential throughout the treatment process.

Step 1: Initial Assessment

• Comprehensive Evaluation: Conduct a thorough assessment, including psychiatric history, symptom severity, medical history, family history, and suicidality risk. Consider differential diagnosis and co-morbidities.
• Psychotherapy: Initiate or continue evidence-based psychotherapy, such as cognitive-behavioral therapy (CBT) or interpersonal therapy (IPT). Inform psychotherapist of planned psychopharmacologic treatment and maintain ongoing collaborative dialogue as warranted
• Education and Informed Consent: Educate the patient and their family about the potential benefits, risks, and side effects of medication treatment. Obtain informed consent.

Step 2: First-Line Pharmacotherapy

• Selective Serotonin Reuptake Inhibitors (SSRIs):
  • Fluoxetine: Start with a low dose (10 mg/day) and titrate gradually to therapeutic range (20-60 mg/day).
  • Escitalopram: Initiate at 5-10 mg/day, titrate up to 10-20 mg/day.
  • Sertraline: Begin with 25-50 mg/day, titrate up to 50-200 mg/day.
• Monitoring:
  • Close monitoring for therapeutic response and adverse effects, especially during the first 4-6 weeks and following future dose increases, if instituted.
  • Assess for emergence or worsening of suicidal ideation, agitation, or behavioral activation.

Step 3: Treatment Response Assessment

• Response Evaluation: Evaluate response to SSRI treatment after 4-6 weeks.
• Adjustment: If partial response or inadequate response, consider:
  • Increasing SSRI dose, gradually at q 2-4 week intervals.
  • Switching to another SSRI.
  • Adding psychotherapy or non-pharmacological interventions.

Step 4: Second-Line Pharmacotherapy

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):
  • Venlafaxine: Initiate at 37.5 mg/day, titrate up to 75-225 mg/day.
  • Duloxetine: Start with 30 mg/day, titrate up to 60-120 mg/day.
  • Bupropion: Consider in cases with atypical depression symptoms or when SSRIs or SNRIs are ineffective or not tolerated. Begin with 75 mg/day, titrate up to 150-300 mg/day.
• Monitoring:
  • Continuously monitor for therapeutic response and adverse effects.
  • Assess for potential drug interactions, especially with other psychotropic medications.

Step 5: Consultation and Collaboration

• Collaboration: Maintain open communication with the patient, their family, and involved healthcare professionals throughout treatment.
• Consultation: Consider consultation with a child and adolescent psychiatrist for complex cases, treatment-resistant depression, or significant comorbidities.

Step 6: Continuation and Maintenance

• Continuation Phase: Once remission is achieved, continue the effective medication at the same dose for at least 6-12 months to prevent relapse.
• Maintenance Phase: For recurrent depression or chronic conditions, consider long-term maintenance treatment with medication and/or psychotherapy.

Safety Considerations:

• Suicidality Risk: Monitor closely for emergence or worsening of suicidal ideation, especially during the initial weeks of treatment.
• Serotonin Syndrome: Educate about symptoms and signs, especially if combining SSRIs or SNRIs with other serotonergic medications.
• Drug Interactions: Be cautious with concomitant use of other medications metabolized by cytochrome P450 enzymes. Avoid monoamine oxidase inhibitors (MAOIs).
• Monitoring Parameters: Regularly assess for efficacy, adverse effects, vital signs, and growth parameters in adolescents.

Author:

Shawn Singh Sidhu, M.D., DFAPA, DFAACAP

​Medical Co-Director, Vista Hill Foundation

References:

• American Academy of Child and Adolescent Psychiatry (AACAP). (2019). Practice parameter for the assessment and treatment of children and adolescents with depressive disorders.
• Cheung, A. H., & Emslie, G. J. (2015). Treatment-resistant depression in adolescents. Pediatric Drugs, 17(6), 383-392.
• National Institute for Health and Care Excellence (NICE). (2019). Depression in children and young people: identification and management (Clinical guideline [CG) 28).
• Zhou, X., Hetrick, S. E., Cuijpers, P., Qin, B., Barth, J., Whittington, C. J., … & Xie, P. (2015). Comparative efficacy and acceptability of psychotherapies for depression in children and adolescents: A systematic review and network meta-analysis. World Psychiatry, 14(2), 207-222.
• Baldwin, D. S., & Montgomery, S. A. (2005). Serotonin selective reuptake inhibitors. Journal of Psychopharmacology, 19(2_suppl), 4-6.
• Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., … & Fava, M. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. The American Journal of Psychiatry, 163(11), 1905-1917.
• Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., … & Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, 391(10128), 1357-1366.
• Taylor, D., Paton, C., & Kapur, S. (2019). The Maudsley prescribing guidelines in psychiatry. John Wiley & Sons.
• Nutt, D. J. (2008). Relationship of neurotransmitters to the symptoms of major depressive disorder. The Journal of Clinical Psychiatry, 69, 4-7.

Fluoxetine and paroxetine are potent inhibitors of cytochrome CYP2D6. Here is a partial list of affected medications:

Psychotropic Medications          Other Medications

Atypical antipsychotics                    Tramadol (increased risk of seizures)

Typical antipsychotics                      Codeine-based pain medications

Tricyclic antidepressants                Dextromethorphan

Trazodone                                           Beta blockers

Benztropine                                        Diltiazem

Donepezil                                            Odansetron

Venlafaxine                                         Tamoxifen

Antiarrhythmic medications

With the drug interaction between fluoxetine and paroxetine and codeine-based pain medications, patients can experience reduced pain relief because the CYP2D6 inhibition will reduce conversion of codeine and related medications (hydrocodone, oxycodone) to the clinically effective metabolite (morphine, hydromorphone, oxymorphone).

Fluoxetine and fluvoxamine are potent inhibitors of cytochrome CYP2C19 (fluvoxamine more so than fluoxetine). Sertraline is a modest inhibitor of this enzyme. Here is a partial list of affected medications:

Psychotropic Medications            Other Medications

Tricyclic antidepressants                   Proton pump inhibitors (ex. Omeprazole)

Diazepam                                              Proguanil

Propranolol

Fluvoxamine is a fairly strong inhibitor of cytochrome CYP3A4. Here is a partial list of affected medications:

Psychotropic Medications            Other Medications

Benzodiazepines                                Calcium channel blockers

Carbamazepine                                   Proton pump inhibitors

Tricyclic antidepressants                   Fentanyl

Valproate                                              Statin medications

Nonbenzo hypnotics                          Loratadine

Mirtazapine                                          Antifungal medications

With the drug interaction between fluoxetine and paroxetine and codeine-based pain medications, patients can experience reduced pain relief because the CYP2D6 inhibition will reduce conversion of codeine and related medications (hydrocodone, oxycodone) to the clinically effective metabolite (morphine, hydromorphone, oxymorphone).

Fluoxetine and fluvoxamine are potent inhibitors of cytochrome CYP2C19 (fluvoxamine more so than fluoxetine). Sertraline is a modest inhibitor of this enzyme. Here is a partial list of affected medications:

Psychotropic Medications          Other Medications

Tricyclic antidepressants               Proton pump inhibitors (ex. Omeprazole)

Diazepam                                          Proguanil

Propranolol

Fluvoxamine is a fairly strong inhibitor of cytochrome CYP3A4. Here is a partial list of affected medications:

Psychotropic Medications           Other Medications

Benzodiazepines                                   Calcium channel blockers

Carbamazepine                                      Proton pump inhibitors

Tricyclic antidepressants                     Fentanyl

Valproate                                                Statin medications

Nonbenzo hypnotics                             Loratadine

Mirtazapine                                            Antifungal medications

Trazodone                                              Macrolide antibiotics

Hormone replacement

Fluvoxamine is a potent inhibitor of cytochrome CYP2C9, which can affect the following medications:

Psychotropic Medications            Other Medications

No significant interactions                 Glyburide/Glypizide

ARBs (ex. Losartan)

Warfarin

Phenytoin

Ibuprofen/Naproxen

Fluvoxamine is also a potent inhibitor of cytochrome CYP1A2, which can affect the following medications:

Psychotropic Medications            Other Medications

Some antipsychotic medications          Warfarin

Tricyclic antidepressants                       Acetaminophen

Mirtazapine                                               Methadone

It is also important to be aware of the risk of serotonin syndrome (increase heart rate, sweating, myoclonus, hyperthermia, and agitation) when combining certain medications with SSRIs because it can be life threatening. MAOIs are contraindicated with SSRIs for this and other reasons (the combination can also increase the risk of hypertensive crisis). Be cautious when combining SSRIs with Tramodol, Meperidine, St. John’s Wort (an herbal supplement used for mild depression), or dextromethorphan.

Some studies suggest that NSAIDs can reduce the efficacy of SSRI medications, although the overall data is inconclusive. However, the combination is also likely to lead to increased gastrointestinal side effects.

It is our hope that this discussion is helpful for providers in the primary care setting as they are prescribing SSRIs in conjunction with other medications for their patients.

References:

1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed 12/14/12.
2. Albers LJ, MD et al. Handbook of Psychiatric Drugs. 2008 Edition. University of California, Irvine.

Adequate Trial Length: These medications can take 4-6 weeks to see the full positive effect once reaching a therapeutic dose. It is important to discuss this with patients prior to starting the medication so they have a realistic expectation about how long it may take to feel relief from their symptoms. And it is important for the prescriber to wait the full 4 weeks at a therapeutic dose prior to changing the medication. Of course the dose can be optimized based on the patients’ response in the meantime.

“Starting Low and Going Slow”: Particularly when treating anxiety disorders and drug naïve patients, it is important to “start low and go slow” to avoid problematic side effects. This is particularly true when prescribing these medications to children and adolescents as well as older patients. Slow titration has been shown to decrease the risks for increased anxiety, increased agitation and akathisia (internal restlessness) in patients being treated with SSRIs. For example when using fluoxetine in these situations, the prescriber might consider starting at 10 mg per day for one week prior to increasing to 20 mg per day, and then waiting at 20 mg for one month to assess response.

Higher Therapeutic Dose for Anxiety Disorders: While it is important to “start low and go slow” when treating anxiety disorders, many anxious patients require a higher dose for full efficacy. Using the same example of fluoxetine, while a dose range of 20-40 mg per day is adequate for treating depression, doses in the 40-80 mg range are often needed to treat anxiety disorders effectively, particularly obsessive-compulsive disorder. In these cases, it can take 3-4 months to get to a full therapeutic dose and to see full relief from symptoms.

Discontinuation Syndrome: The SSRIs, particularly the ones with shorter half-lives like paroxetine, fluvoxamine, and sertraline, can have a discontinuation syndrome if they are stopped abruptly. While the discontinuation syndrome is not dangerous or life threatening, it can be very uncomfortable for patients. Symptoms include: gastrointestinal upset, sleep disturbance, flu-like symptoms and an electrical shock sensation. The best way to avoid it is to taper SSRIs that have a shorter half-life. Fluoxetine on the other hand does not necessarily require a taper because it has a very long half-life.

Serotonin Syndrome: Serotonin syndrome is a potentially life threatening drug reaction that occurs when the body is exposed to too much serotonin. It most commonly occurs when two medications that increase serotonin in the central nervous system are taken together. Aside from the SSRIs, other medications that can increase serotonin in the brain include the triptans (used for migraines), certain pain medications (including Tramadol and Demerol), the MAOIs, and dextromethorphan (cough medication). Drugs of abuse like LSD and ecstasy have also been associated with serotonin syndrome. The symptoms of serotonin syndrome include: agitation, restlessness, diarrhea, nausea, vomiting, increased heart rate, increased blood pressure, increased body temperature, hallucinations, loss of coordination, overactive reflexes, myoclonus, and tremor. It is important to discuss this risk with patients, especially if they are taking more than one medication that can increase serotonin levels, so that they can seek immediate medical attention if they exhibit these symptoms.

FDA Black Box Warning: In 2004, the FDA issued a black box warning for all antidepressants and mood stabilizer medications based on research that showed an increased rate of spontaneous reporting of suicidal thoughts in adolescents and young adults treated with SSRIs. The FDA is currently re-evaluating the black box warning but for now it is important to discuss it with young patients who are being treated with these medications. It is important to keep in mind that the rate of the side effect did not increase by much, from 2/1000 patients to 4/1000 patients. In addition while there was in increase in the rate of reporting suicidal thoughts there was not an increase in actual suicidal gestures, suicide attempts or completed suicides. Some hypotheses about why the increase in reporting is seen includes: patients who are being treated with medications have more contact with mental health and medical providers and therefore may be more comfortable disclosing their suicidal thoughts; patients may experience improvements in their energy levels prior to improvements in their mood; the suicidal thoughts might be related to the increase in activation seen in young patients with SSRI treatment; and that spontaneous reporting of already present suicidal thoughts is a sign that the patient’s depression is improving. It is also important to remind patients and their families that these medications overall decrease the rate of suicide. Therefore they are an important part of treatment, with close monitoring, which includes phone or in person contact within 1-2 weeks after starting medication or increasing the dose.

It is our hope that this discussion about the nuances of using the SSRIs and other antidepressant medications helps for more effective usage of these important medication treatments in the primary care setting. Please feel free to call PC2 for specific questions related to specific patients.

There are more complicated interactions between contraceptives and mood stabilizer medications, many of which are also used for epilepsy. Contraceptive medications can be affected by certain psychotropic medications. Carbamazepine, oxcarbazepine, and topiramate (mood stabilizers which induce the P450 3A4 pathway) can increase the metabolism of oral contraceptives (many of which are substrates of the P450 3A4 pathway), thereby reducing their effectiveness. This effect is also seen with vaginal contraceptive rings, because the hormones contained in these preparations are also metabolized by the liver. In these situations, the patient should either change her contraceptive method or change her mood stabilizer. Contraceptive alternatives include the birth control patch (which largely avoids liver metabolism) and barrier methods. Mood stabilizers like valproate and lamotrigine do not affect oral contraceptives, but lamotrigine clearance is increased with oral contraceptives that contain estrogen, thereby reducing the effectiveness of the medication. In patients who are taking a traditional mood stabilizer, including Lithium, highly effective contraception is important because these medications can have serious teratogenic effects if a patient accidently becomes pregnant. One option is a high-dose oral contraceptive, but because of the complexity of oral contraceptives and some traditional mood stabilizers as well as side effects of high-dose estrogen, it is important to consider non-hormonal approaches as a primary or adjunctive contraception. St. John’s Wort (an herbal supplement that many patients take for mild depression) can induce the P450 3A4 pathway, thereby inducing the metabolism of oral contraceptives, making them less effective.

There is some concern that progesterone-only pills and high-dose estrogen pills can lead to or worsen depression, although this has not been studied in a controlled fashion that clearly defines depression and addresses the confounding factor of natural fluctuations in mood symptom during various parts of the menstrual cycle. These hormones can increase the metabolism of serotonin in the brain, thereby lowering serotonin levels, which can contribute to depression. It is thought that low-dosed combined oral contraceptives have little risk for causing or worsening depression. However it is important to assess for changes in mood after a patient first starts contraception.

Here is a chart to summarize the interactions between BCP and psychotropic medications:

Currently, six types of SSRIs are available for prescribing in the U.S.: fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa), escitalopram (Lexapro). These drugs are subject to extensive oxidative metabolism in the liver. Because these antidepressants have a wide therapeutic index, inhibition or induction of their metabolism is unlikely to be of concern. However, SSRIs may cause a clinically relevant inhibition of CYP enzymes, and care must be exercised when an SSRI is being added to a multidrug regimen.

The potency of the SSRIs as inhibitors of the metabolism of the P450-P2-D6 varies and is reported in descending order of potency as paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine. Fluoxetine and paroxetine are more likely to cause P450 drug interactions than citalopram and sertraline, particularly in combination with medications metabolized by or inhibiting the cytochrome P450 2D6 isoenzyme (e.g., certain antidepressants, phenothiazines,antipsychotics type IC antiarrhythmics).

Drug interactions with clinical consequences usually involve combinations of an SSRI with other psychotropics, especially monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. The interaction between MAOIs and SSRIs is the most important drug interaction limiting SSRI use. MAOI’s are infrequently prescribed due to other options available and the high risk of interaction with other drugs.

Sertraline, citalopram and escitalopram have the lowest potential for drug interactions among the SSRIs, and are to be preferred in patients on other drugs for general medical conditions or if consideration is given to adding an SSRI to other psychotropic medication.

With the drug interaction between fluoxetine and paroxetine and codeine-based pain medications, patients can experience reduced pain relief because the CYP2D6 inhibition will reduce conversion of codeine and related medications to the clinically effective metabolite (morphine, hydromorphone, oxymorphone).

It is also important to be aware of the risk of serotonin syndrome (increase heart rate, sweating, myoclonus, hyperthermia, and agitation) when combining certain medications with SSRIs because it can be life threatening. MAOIs are contraindicated with SSRIs for this and other reasons (the combination can also increase the risk of hypertensive crisis). Be cautious when combining SSRIs with Tramodol, Meperidine, St. John’s Wort (an herbal supplement used for mild depression) or dextromethorphan.

Some studies suggest that NSAIDs can reduce the efficacy of SSRI medications, although the overall data is inconclusive.  This combination may lead to increased gastrointestinal side effects.

It is our hope that this discussion is helpful for providers in the primary care setting as they are prescribing SSRIs in conjuction with other medications for their patients.

References:

Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed 12/14/12.

Albers LJ, MD et al. Handbook of Psychiatric Drugs. 2008 Edition. University of California, Irvine.
https://www.uspharmacist.com/article/overview-of-drugdrug-interactions-with-ssris