Tag Archive for: depression

Q&A: Pharmaceutical Specifications, Treatment Resistant Depression, and Intervention

PHARMACEUTICAL SPECIFICATIONS FOR DEPRESSION

Will SSRI and SNRI side effects go away with time?

SRIs and SNRIs are safer and better tolerated than other classes of antidepressants. Side effects are typically mild and they often go away after using the medication for a few days. Common side effects during the initiation of treatment that typically go away with time include gastrointestinal disturbance, headache, decreased appetite, and initial weight loss. Symptoms that sometimes go away with time include insomnia, vivid dreams, and emotional blunting. Other symptoms, if present, are likely to not resolve on their own which include sexual dysfunction (decreased libido or arousal, anorgasmia, and delayed ejaculation in men), restlessness/akasthisia, and weight gain. There is no consistent weight gain in short-term RCTs (4-12 weeks), but retrospective cohorts indicate they may cause modest gains of up to 1kg on average after 1 year.

What antidepressants are safe in liver disease?

Antidepressant drugs can cause drug-induced liver injury. Although data on antidepressant-induced liver injury are scarce, 0.5%−3% of patients treated with antidepressants may develop asymptomatic mild elevation of serum aminotransferase levels. All antidepressants can induce hepatotoxicity, especially in elderly patients and those with polypharmacy. Liver damage is in most cases idiosyncratic and unpredictable, and it is generally unrelated to drug dosage. The antidepressants associated with greater risks of hepatotoxicity are iproniazid, nefazodone, phenelzine, imipramine, amitriptyline, duloxetine, bupropion, trazodone, tianeptine, and agomelatine. The antidepressants that seem to have the least potential for hepatotoxicity are citalopram, escitalopram, paroxetine, and fluvoxamine.

What antidepressants are safe in kidney disease?

Comorbidity rates of depression in patients with renal disease are high, making the use of antidepressants in renal disease common. SSRIs are generally preferred in this population and medications should be started a low doses and titrated slowly. Among the SNRIs venlafaxine may be used, however the require dose adjustments and duloxetine should be avoided in severe renal impairment. Bupropion should be avoided in patients with chronic renal failure and on dialysis since the active metabolite (hydroxybupropion) is not dialyzable and plasma levels are increased in patients with even mild renal impairment thus increasing the risk for seizures and other adverse side effects. TCAs should be decreased by 50% in geriatric patients with moderate to severe renal dysfunction.

What other conditions are antidepressants used for?

The use of antidepressant medications are not limited to depressive disorders. There is evidence for a variety of indications. Some of these include:

  • Obsessive compulsive disorder: SSRIs (in high doses), TCAs (clomipramine)
  • Panic disorder: SSRIs, TCAs, MAOIs
  • Eating disorders: SSRIs (in high doses), TCAs
  • Social anxiety disorder (social phobia): SSRIs, SNRIs, MAOIs
  • Generalized anxiety disorder: SSRIs, SNRIs (venlafaxine), TCAs
  • Posttraumatic stress disorder: SSRIs
  • Irritable bowel syndrome: SSRIs, TCAs
  • Enuresis: TCAs (imipramine)
  • Neuropathic pain: TCAs (amitriptyline and nortriptyline), SNRIs
  • Chronic pain: SNRIs, TCAs
  • Fibromyalgia: SNRIs
  • Migraine headaches: TCAs (amitriptyline)
  • Smoking cessation: Bupropion
  • Premenstrual dysphoric disorder: SSRIs
  • Insomnia: Mirtazapine, trazodone, TCAs (doxepin)

TREATMENT RESISTANT DEPRESSION

What is the definition of treatment-resistant depression?

Treatment-resistant depression (TRD) is most commonly defined as a failure of treatment response or remission with two or more treatment attempts of adequate dose and duration. Unfortunately, there is not a clear consensus about this definition. Specifically, what is an adequate response? 50% reduction in symptoms? Complete resolution of symptoms? Also, what are the specifics regarding the adequacy of both dose and duration of treatment? 

While not a consensus, the most commonly used definition in research studies regarding response are the following :

  • No response: Improvement <25 percent.
  • Partial response: Improvement 25 to 49 percent.
  • Response: Improvement ≥50 percent but less than the threshold for remission.
  • Remission: Rating scale scores within the normal range.

What are augmentation options if antidepressant medications fail to show an adequate response?

Some patients may not achieve an adequate treatment response after a full trial of SSRI or SNRI at therapeutic doses. If there is no response then switching to another medication in the same class or a different class should be considered. If there is some response than maximizing dose or augmentation strategies should be considered. There are a number of medications that have been trialed for treatment resistant depression. We will list some of the more common augmentation strategies below:

  • Buproprion: included in the STAR*D trial and typically well-tolerated from a side effect perspective. Can also help with SSRI induced sexual side effects, smoking cessation, and weight loss.
  • Mirtazapine: effective antidepressant and improves appetite and sleep. Be aware of weight gain and sedation.
  • Lithium: well supported in the literature and is recommended by the NICE guidelines.
  • Second-generation antipsychotics (SGAs): particularly aripiprazole, quetiapine, olanzapine, and risperidone (2nd choice) have shown to be effective.
  • Buspirone: supported by STAR*D trial. High doses are usually required and poorly tolerated due to dizziness at high doses.
  • Lamotrigine: reasonably well researched and possibly the best tolerated augmentation strategy. Appropriate dosing is unclear and requires slow titration due to risk of Steven Johnson’s Syndrome.
  • T3 (Triiodothyronine): augmentation has some research support but also has negative studies.
  • TCAs or MAOIs can be used as augmentation or to replace the primary antidepressant (SSRI/SNRI). Often considered later in the treatment algorithm due to significant side effects, food restrictions, and higher lethality in overdose.

INTERVENTION TECHNIQUES FOR TREATMENT RESISTANT DEPRESSION

What interventional techniques are available for treatment resistant depression?

Electroconvulsive Therapy (ECT)

  • Formerly known as shock therapy.
  • Involves a brief electrical stimulation (generalized seizure) of the brain while the patient is under general anesthesia.
  • Most effective and rapid treatment in severe depression, psychotic depression, depression with catatonia, and treatment refractory depression.
  • There are no absolute contraindications to ECT, however several relative contraindications exist including recent myocardial infarction or stroke, increased intracranial pressure, retinal detachment, and unstable dentition.
  • Standard practice in the U.S. is to give treatments three times per week.
  • Most symptoms improve substantially in 6-12 treatments, however there is no absolute standard number of treatments.
  • Certain medications that affect the seizure threshold should be held prior to ECT including benzodiazepines, valproate, lamotrigine, gabapentin, carbamezapine, and lithium.
  • ECT can cause acute confusion, anterograde and retrograde amnesia. These are typically the most feared side effects from patients. Many patients do experience some adverse cognitive effects, however objecting indicates that impairment is generally short lived (weeks). ECT does not appear to be associated with an increased risk of dementia.

Transcranial Magnetic Stimulation (TMS)

  • Machine that produces weak repetitive electric currents in the brain tissue by rapidly changing magnetic fields.
  • Numerous small-scale studies have demonstrated efficacy in the treatment of major depression; however, studies show less efficacy than for ECT.
  • TMS works by passing a weak alternating electrical current through a metal coil placed against the scalp. This produces rapidly changing magnetic fields. These magnetic signals pass through the skull and induce electric currents that depolarize neurons in a specific area of the surface of the cortex and associated neural circuits. The mechanism of antidepressant effects is not completely understood.
  • FDA approved for major depressive disorder, migraine headaches, and obsessive-compulsive disorder. There is also growing evidence for anxiety disorders and PTSD.
  • Treatment typically occurs every weekday for 4 to 6 six weeks or a total of 20-30 treatments. Each session lasts around 30-40 minutes.
  • Relative contraindications of TMS include implanted metallic hardware or electrical devices and unstable general medical disorders. Patients with epilepsy or increased risks of seizures can be considered for low frequency TMS if benefits outweigh the risks.

Intranasal Ketamine

  • Ketamine is technically considered a dissociative anesthetic, however has been discovered to be helpful in treatment resistant depression. It is an NMDA glutamate antagonist and also affects brain growth factors and opioid receptors, suggesting a possible mechanism for its antidepressant properties.
  • Unlike many of our treatment options (antidepressant medications, psychotherapy, TMS) esketamine nasal spray has the unique benefit of a rapid onset of action to reduce suicidality or other serious acute symptoms of depression.
  • The recommended frequency of intranasal esketamine for acute suicidal ideation or behavior in adults with unipolar major depression is twice weekly for four weeks. After four weeks of treatment with esketamine, its benefit should be evaluated to determine the need for ongoing treatment.
  • Side effects may include increased blood pressure, perceptual disturbances, or dissociative / out of body experiences.

Vagus Nerve Stimulation (VNS)

  • Surgical treatment involving the implantation of a medical device that sends electrical impulses to the brain via the vagus nerve.
  • Has been used for epilepsy since 1997 and for refractory major depression since 2005.

Deep Brain Stimulation (DBS)

  • Surgical treatment involving the implantation of a medical device that sends electrical impulses to specific parts of the brain.
  • Originally used in treatment refractory neurologic conditions such as Parkinson’s disease, dystonia, and tremor.
  • Now used in treatment refractory major depression.

REFERENCES

1. Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry. 2018;75(4):336–346. doi:10.1001/jamapsychiatry.2017.4602

2. National Institute for Health and Care Excellence. (2009). Depression in adults: recognition and management. Retrieved from https://www.nice.org.uk/guidance/cg90/chapter/Recommendations

3. Cuijpers, P., Andersson, G., Donker, T., & van Straten, A. (2011). Psychological treatment of depression: results of a series of meta-analyses. Nordic journal of psychiatry, 65(6), 354–364. https://doi.org/10.3109/08039488.2011.596570

4. Blumenthal SR, Castro VM, Clements CC, et al. An Electronic Health Records Study of Long-Term Weight Gain Following Antidepressant Use. JAMA Psychiatry. 2014;71(8):889–896. doi:10.1001/jamapsychiatry.2014.414

5. Voican, C. S., Corruble, E., Naveau., and Perlemuter, G. (2014). Antidepressant-Induced Liver Injury: A Review for Clinicians. The American Journal of Psychiatry. https://doi.org/10.1176/appi.ajp.2013.13050709

6. Ward, S. W., Reach, W. J., &amp; Thomas, C. (2016). When to adjust the dosing of psychotropics in patients with renal impairment. Current Psychiatry, 15(8), 60–66.

7. Puckett, J. A., Beach, S. R., &amp; Taylor, J. B. (2020). Pocket psychiatry. Wolters Kluwer.

8. Gaynes BN, Asher G, Gartlehner G, Hoffman V, Green J, Boland J, Lux L, Weber RP, Randolph C, Bann C, Coker-Schwimmer E, Viswanathan M, Lohr KN. Definition of Treatment-Resistant Depression in the Medicare Population. Technology Assessment Program. Project ID: PSYT0816. (Prepared by RTI–UNC Evidence-Based Practice Center under Contract No. HHSA290201500011I_HHSA29032006T). Rockville, MD: Agency for Healthcare Research and Quality. February 2018. http://www.ahrq.gov/clinic/epcix.htm.

9. Taylor, D., Barnes, T. R. E., Young, A. H. (2018). Depression. The Maudsley Prescribing Guidelines in Psychiatry (13th ed., pp. 208–212). Wiley Blackwell.

10. Williams, N. R., Taylor, J. J., Kerns, S., Short, E. B., Kantor, E. M., & George, M. S. (2014). Interventional psychiatry: why now?. The Journal of clinical psychiatry, 75(8), 895–897. https://doi.org/10.4088/JCP.13l08745

11. United States Food and Drug Administration approved labelling. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s004lbl.pdf (Accessed on August 10, 2020).

Q&A: Defining Depression and Treatment Options

What is depression?

Everyone experiences a range of emotions that typically vary based on events and circumstances. Normally feelings of disappointment, sadness, and grief ebb and flow. By contrast, depression tends to feel heavy and constant. People who are depressed are less likely to be feel happy, have good days, be cheered, comforted, or consoled. Clinically, a major depressive episode is characterized by at least two weeks of depressed mood or a loss of interest in enjoyable activities. It also includes a number of other symptoms which may include difficulties with sleep, feelings of worthlessness or guilt, fatigue, difficulty concentrating, appetite changes, or recurrent thoughts of death or suicide.

Can depression be associated with suicide? What are other risk factors for suicide?

According to the Centers for Disease Control and Prevention (CDC) in 2018, suicide was the 10th leading cause of death overall in the United States, claiming the lives of over 48,000 people. It is the 14th leading cause of death globally. Individuals dealing with depression are at a higher risk of suicide than other individuals. Some studies estimate this risk to be 20-30 times higher than the non-depressed population. Other risk factors for suicide include past history of suicide attempt, history of self-directed violence, family history of suicide, having a psychiatric disorder, lack of social supports, history of childhood abuse, substance use, homelessness, access to firearms, and more.

What is the difference between depression and bereavement?

Grief or bereavement is the powerful emotional response that occurs following the death of a loved one or other difficult losses in life. Stages of bereavement may include denial and isolation, anger, bargaining, sadness, and acceptance. The majority of survivors heal over time and their symptoms of grief gradually improve as they resume their routines and activities. They are able to function in their life. Complicated grief occurs when grief responses are considered excessive and depression may occur if individuals do not progress through the normal healing process and have continued symptoms and dysfunction and prolonged feelings of sadness and hopelessness.

What are first-line treatments for depression based on severity?

Mild: Active monitoring, individual guided self‐help, exercise, cognitive behavioral therapy (CBT), or other psychotherapy protocols are preferred.2 Antidepressant medications are not recommended as a first‐line treatment in recent‐onset mild depression.

Moderate to severe: Antidepressants are recommended for the treatment of moderate to severe depression and for dysthymia (persistent depressive disorder).

What type of psychotherapy is best for depression?

Multiple meta-analyses show psychological therapies to be as effective as antidepressant medications for those with mild or moderate severity of depression. Studies also demonstrate the effectiveness of a number of different types of therapy in depression3. Effective therapies include:

•Cognitive behavior therapy (CBT): based on the idea that our thoughts (cognitions), behaviors, and emotions are all interrelated, so that if we change one then we change the rest.

Interpersonal psychotherapy (IPT): intervention that focuses on relieving symptoms by improving interpersonal functioning. A central idea in IPT is that psychological symptoms can be understood as a response to current difficulties in everyday relationships with other people.

•Psychodynamic psychotherapy: the psychological interpretation of mental and emotional processes. Rooted in traditional psychoanalysis, it draws from object relations, ego psychology, and self psychology. It was developed as a simpler, less-lengthy alternative to psychoanalysis.

•Problem-solving therapy (PST): brief intervention patients experiencing depression and distress related to inefficient problem-solving skills. The PST model instructs patients on problem identification, efficient problem-solving, and managing associated depressive symptoms.

Non-directive supportive therapy: relies on the therapeutic alliance to alleviate symptoms, improve self-esteem, restore relation to reality, regulate impulses and negative thinking, and reinforce the ability to cope with life stressors and challenges.

•Behavioral activation therapy: behavioral activation is a component of CBT but behavioral strategies can also be used alone. Behavioral activation is based on the theory that, as individuals become depressed, they tend to engage in increasing avoidance and isolation, which serves to maintain or worsen their symptoms

What are the first-line medication options for depressive disorders?

There are a number of available antidepressant classes that have evidence for the treatment of depression, anxiety, and other disorders. Each class of antidepressants have a unique mechanism but they all act to manipulate the levels of neurotransmitters in the brain that are responsible for modulating mood and emotions. Examples include serotonin, norepinephrine, and dopamine. Classes of antidepressants include: Selective serotonin reuptake inhibitors (SSRIs); Serotonin-norepinephrine reuptake inhibitors (SNRIs); Tricyclic antidepressants (TCAs) and Tetracyclic antidepressants; Monoamine oxidase inhibitors (MAOIs); and novel or atypical antidepressants.

All antidepressant classes have similar treatment response rates in treating major depression but vary in their mechanism of action, safety, and side effect profiles. SSRIs and SNRIs are the most commonly prescribed antidepressants and are considered first-line treatment due to several distinct advantages:

  • Low side effect profile, most of which resolve with time
  • No food restrictions (unlike MAOIs)
  • Much safer in overdose (unlike TCAs and MAOIs)

Practice Question:

A 47-year-old patient comes in discussing feelings of tiredness, decreased appetite, intense periods of irritation, lack of enjoyment in activities they once enjoyed, interpersonal relationship issues, and suicidal ideation. Which FDA-approved pharmaceutical treatment is the first-line treatment for a patient experiencing these symptoms?

A Escitalopram

B Risperidone

C Clozapine

D Fluvoxamine

E Imipramine

Answer: A

Explanation: In older adults suffering from depression, the first line of treatment are SSRIs, such as escitalopram (choice A). Fluvoxamine (choice D) is an SSRI that is only approved for OCD. If the patient had come forward with symptoms for schizophrenia, then an antipsychotic medication, such as clozapine (choice C), would be a good medication to consider prescribing. Risperdal (choice B) is an antipsychotic that is more useful in cases of aggression. Other antidepressants, such as monoamine oxidase inhibitors and tricyclic medications (choice E), are very effective in treating depressive disorders, but these medications are not amongst the group of medications that should be used as a first-line treatment option.

REFERENCES

1. Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry. 2018;75(4):336–346. doi:10.1001/jamapsychiatry.2017.4602

2. National Institute for Health and Care Excellence. (2009). Depression in adults: recognition and management. Retrieved from https://www.nice.org.uk/guidance/cg90/chapter/Recommendations

3. Cuijpers, P., Andersson, G., Donker, T., & van Straten, A. (2011). Psychological treatment of depression: results of a series of meta-analyses. Nordic journal of psychiatry, 65(6), 354–364. https://doi.org/10.3109/08039488.2011.596570

4. Blumenthal SR, Castro VM, Clements CC, et al. An Electronic Health Records Study of Long-Term Weight Gain Following Antidepressant Use. JAMA Psychiatry. 2014;71(8):889–896. doi:10.1001/jamapsychiatry.2014.414

5. Voican, C. S., Corruble, E., Naveau., and Perlemuter, G. (2014). Antidepressant-Induced Liver Injury: A Review for Clinicians. The American Journal of Psychiatry. https://doi.org/10.1176/appi.ajp.2013.13050709

6. Ward, S. W., Reach, W. J., &amp; Thomas, C. (2016). When to adjust the dosing of psychotropics in patients with renal impairment. Current Psychiatry, 15(8), 60–66.

7. Puckett, J. A., Beach, S. R., &amp; Taylor, J. B. (2020). Pocket psychiatry. Wolters Kluwer.

8. Gaynes BN, Asher G, Gartlehner G, Hoffman V, Green J, Boland J, Lux L, Weber RP, Randolph C, Bann C, Coker-Schwimmer E, Viswanathan M, Lohr KN. Definition of Treatment-Resistant Depression in the Medicare Population. Technology Assessment Program. Project ID: PSYT0816. (Prepared by RTI–UNC Evidence-Based Practice Center under Contract No. HHSA290201500011I_HHSA29032006T). Rockville, MD: Agency for Healthcare Research and Quality. February 2018. http://www.ahrq.gov/clinic/epcix.htm.

9. Taylor, D., Barnes, T. R. E., Young, A. H. (2018). Depression. The Maudsley Prescribing Guidelines in Psychiatry (13th ed., pp. 208–212). Wiley Blackwell.

10. Williams, N. R., Taylor, J. J., Kerns, S., Short, E. B., Kantor, E. M., & George, M. S. (2014). Interventional psychiatry: why now?. The Journal of clinical psychiatry, 75(8), 895–897. https://doi.org/10.4088/JCP.13l08745

11. United States Food and Drug Administration approved labelling. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s004lbl.pdf (Accessed on August 10, 2020).