Antidepressant Augmentation: A Review of the Literature and a Review of the Pharmacoeconomic Considerations.

PURPOSE: Antidepressant augmentation strategies for treatment-resistant depression (TRD) are discussed here with an analysis of patient out-of-pocket costs for various medications. The choice of agent ranges from newer atypical antipsychotics (aripiprazole, brexpiprazole, quetiapine) to older agents including buspirone, liothyronine (T3), and lithium. We sought to better understand the differences among these agents to aid in clinical decision making. METHODS: We conducted a focused review of the support for each of the aforementioned agents in antidepressant augmentation. We then compared the approximate out-of-pocket cost for each medication during a typical augmentation trial using the typical prescription costs on ClinCalc.com derived from the Medical Expenditure Panel Survey. We calculated the cost to achieve response for one patient with TRD based on the number needed to treat (NNT). FINDINGS: We observed significant variance in cost to achieve response based on the NNT derived from our review of each of the medications. For example, the overall out-of-pocket cost for one patient to achieve response with aripiprazole (the costliest generic agent) could cover lithium prescriptions for 4 to 5 patients with TRD to achieve response. Although brexpiprazole was estimated separately because of its brand name cost, we estimated that 324 patients receiving lithium could achieve response for same cost of single patient receiving brexpiprazole. IMPLICATIONS: These findings suggest that among augmentation agents, there are differences in cost that may be highly important in clinical decision making. Other issues of medication monitoring may incur additional costs, and brand name medications offer significantly greater complexity and potential out-of-pocket costs to patients. The use of lithium as a first-line agent for TRD should be considered based on low cost, lowest NNT, and data in support of its efficacy.

Clinical repetitive transcranial magnetic stimulation for veterans with major depressive disorder.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is a relatively new treatment modality for patients with major depressive disorder (MDD). Numerous studies have demonstrated the efficacy of TMS for MDD in the general population. However, there is limited information regarding clinical outcomes among veterans receiving TMS for MDD. METHODS: The clinical outcome and characteristics of all veterans with MDD who were treated with TMS as outpatients at the James A. Haley Veterans' Hospital from October 2013 to December 2016 were assessed. RESULTS: Among 40 patients who received TMS, there was a significant improvement of depressive symptoms using the Quick Inventory of Depressive Symptomatology-Self-Report (45% response, 20% remission) and the Montgomery-Åsberg Depression Rating Scale (61.9% response, 42.9% remission). In addition to significant improvement in depressive symptoms, self-report of anxiety symptoms and function significantly improved. TMS was generally well tolerated, with only a small percentage of patients discontinuing treatment due to side effects. No seizures or persistent adverse effects were observed or reported. CONCLUSIONS: TMS is an effective and well-tolerated option for MDD in a veteran population with significant treatment resistance and multiple comorbidities.

Depressive Symptoms Before, During, and After Delirium: A Literature Review.

BACKGROUND: Delirium and depression are often thought of as mutually exclusive conditions. However, several studies cite depression as a risk factor for delirium whereas others note that patients with delirium often manifest depressive symptoms. Whether these depressive symptoms persist after delirium resolves remains unclear. OBJECTIVES: This article reviews published studies that have investigated the relationship between depression and delirium. METHODS: Literature searches on PubMed, CINAHL, Cochrane Library, and PsycInfo were conducted using search criteria "delirium" AND "depress⁎" as keywords or MeSH terms. RESULTS: Of 722 search results, 10 prospective cohort studies were identified for inclusion. These studies were categorized regarding the time of assessment for depressive symptoms. Included studies varied greatly (regarding their index population, their methods of assessment, and their timing of assessments). Of the studies, 3 involved patients undergoing hip fracture repair. They demonstrated more severe depressive symptoms both during delirium and after delirium ended. Conversely, the other studies did not find any statistically significant correlations between the 2 conditions. CONCLUSIONS: The literature suggests a correlation between depression and delirium in patients with hip fracture. Whether other specific populations have higher comorbidity is unclear. Unfortunately, studies varied widely in their methods, precluding a meta-analysis. Nonetheless, our review provides a foundation for future research.

Postviral Depression.

A previously healthy 68-year-old man rapidly developed a severe melancholic depression following influenza infection. There is an evolving understanding of the complex and possibly bidirectional relationship between depression and inflammation. We review the literature concerning this relationship in the context of viral infection and discuss possible implications for treatment.

Delirium Secondary to Lamotrigine Toxicity.

BACKGROUND: Lamotrigine is a phenyltriazine medication that has been approved by the United States Food and Drug Administration as monotherapy and as an adjunctive agent for the treatment of seizure disorder. It was later approved by the FDA for the treatment of bipolar disorder. Lamotrigine is generally well tolerated by patients, but some serious symptoms can occur during treatment. These severe side effects include rashes and multi-organ failure. Lamotrigine has also been associated with the development of mental status changes, frequently when used concurrently with other medications that may impact the metabolism of lamotrigine. OBJECTIVE: To present the case of a 65-year-old man being treated with lamotrigine and valproic acid who developed mental status changes after the addition of sertraline to his medication regimen, and to compare this case to existing cases reported in the literature. DISCUSSION: Our case adds to the existing literature by demonstrating that patients may experience adverse medication effects despite lamotrigine levels that are normally considered to be in the therapeutic range, highlighting the importance of clinical correlation when obtaining medication levels. CONCLUSION: Clinicians should use caution interpreting lamotrigine levels when working up delirium, as normal levels may not rule out the development of lamotrigine toxicity.

Impact of Comorbid PTSD on Outcome of Repetitive Transcranial Magnetic Stimulation (TMS) for Veterans With Depression.

OBJECTIVE: A recent randomized controlled trial of repetitive transcranial magnetic stimulation (TMS) for major depressive disorder (MDD) in veterans raised the question of whether comorbid posttraumatic stress disorder (PTSD) negatively impacted the outcome of TMS in veterans. To address this, a quality database was analyzed to compare outcomes of MDD treated with TMS in veterans with and without comorbid PTSD. METHODS: The clinical outcomes of all consecutive veterans with MDD treated with TMS at the James A. Haley Veterans' Hospital as outpatients from October 2013 through September 2018 were included. Patients were initially evaluated by an experienced psychiatrist, and the diagnosis of MDD was made by clinical evaluation per DSM-IV-TR/DSM-5 criteria. At the start of treatment, after every 5 treatments, and at the end of treatment, patients were assessed with self-report and clinician-rated scales of depression. All data were abstracted from an existing quality database. RESULTS: Among the 118 patients treated with TMS for depression, 55 (47%) had comorbid PTSD and 63 (53%) had no comorbid PTSD. Response and remission rates by score on the Montgomery-Asberg Depression Rating Scale were similar between patients with PTSD (52.5% and 40.9%, respectively) and without PTSD (53.8% and 35.6%, respectively). No seizures or persistent adverse effects were observed or reported in either group. CONCLUSIONS: Comorbid PTSD did not impact the outcome of TMS for depression in this sample of veterans. Future studies should include formal ratings of PTSD to determine if the severity of PTSD affects the outcome.

Nortriptyline Abuse: A Case Report and Review of the Literature.

The tricyclic antidepressants have long been a tool in the physician's armament for numerous indications, the most prominent of which being depression. Although their efficacy and side effects have been well documented, less known is their abuse. Prior literature has discussed this more for the tertiary amines such as amitriptyline, but currently, there are no documented cases of abuse with the secondary amine nortriptyline. This article reviews the prior literature in regard to tricyclic antidepressants and anticholinergics as substances of abuse, the proposed mechanisms of this, and susceptible populations, as well as a case review of a patient who admitted to using nortriptyline for its "buzz."

Bupropion Hydrochloride Sustained Release and Diurnal Enuresis: A Previously Unreported Adverse Effect.

Bupropion hydrochloride (HCl) is an antidepressant that has many different biological targets, acting as both a norepinephrine-dopamine reuptake inhibitor as well as a nicotinic antagonist. This second-generation antidepressant is available in 3 bioequivalent formulations: immediate release, sustained release, and extended release, allowing providers to customize a patient's regimen for maximum tolerability and compliance. Although bupropion HCl's safety and tolerability have been demonstrated through several clinical trials, there are still a number of adverse effects that have been reported in the literature. These include headache, agitation, tremor, and insomnia. There is also an increased risk of developing seizures during bupropion treatment. Although urinary symptoms were noted during the clinical trials, these are relatively rare adverse effects. Here we report the case of a 61-year-old man who developed diurnal enuresis during treatment with bupropion HCl sustained release. We will review the adverse effect burden associated with the use of bupropion and discuss the neuropharmacology of urinary symptoms associated with antidepressant treatment.

Improved Patient Outcomes and Reduced Wait Times: Transforming a VA Outpatient Substance Use Disorder Program.

Systematic evaluation and redesign of a substance use disorder treatment program resulted in elimination of wait times, same-day treatment, and increased pharmacotherapy for patients with alcohol and opioid use disorders.

One hertz versus ten hertz repetitive TMS treatment of PTSD: A randomized clinical trial.

The purpose of this trial was to test whether right prefrontal cortex 1 Hz versus 10 Hz rTMS provides a significantly greater improvement in PTSD symptoms and/or function. Veterans 18 to 50 years of age suffering from PTSD were randomized to right prefrontal 1 Hz rTMS [2400 pulses/session] versus right prefrontal 10 Hz rTMS [2400 pulses/session]. The treatments were performed 5 days a week for 6 weeks with a 3-week taper using the NeuroStar system. There were one month and three months post treatment follow-up evaluations. Forty-four participants were enrolled with 17 being randomized to 1 Hz rTMS and 18 to 10 Hz rTMS. Both groups had significant improvement in PTSD and depression scores from baseline to the end of acute treatment. The 10 Hz group but not the 1 Hz group demonstrated significant improvement in function. Although both groups demonstrated significant improvement in PTSD and depression symptoms, a significant advantage for either the 1 Hz or 10 Hz frequency group on any of the scales acquired was not demonstrated. Further work is required with larger samples sizes to test whether low or high frequency is superior or if individual differences would indicate the more effective frequency.

Poststroke Psychosis Reduction: A Case Report.

Strokes have been shown to result in psychiatric phenomena that can range from mood disorders to psychosis. Ablative neurosurgeries have been performed with the goal of reducing the burden of psychiatric symptoms following such cerebrovascular accidents. In this report, we review poststroke psychiatric manifestations, and then present the case of a woman with schizophrenia whose thought disorder improved following a hemorrhagic stroke. Not only did she require less medication, but her remaining symptoms were significantly less impairing than they had previously been. We then compare and contrast the effects of this stroke with ablative neurosurgery.

Serotonin syndrome associated with the use of escitalopram.

Escitalopram is the newest selective serotonin reuptake inhibitor (SSRI) available for use in the United States. It has been approved for the treatment of major depression and generalized anxiety disorder. It is the S-enantiomer of the SSRI citalopram and is highly serotonin specific as it has minimal effect on the reuptake of dopamine or norepinephrine. It is also a well-tolerated medication, with a side-effect profile comparable to the other SSRIs. While a number of side effects have been seen during escitalopram therapy, such as insomnia, nausea, and increased sweating, there are no reported cases of serotonin syndrome associated with escitalopram therapy to date. We present the case of a 24-year-old woman who developed serotonin syndrome after an increase in her escitalopram to 30 mg/day. We will review the diagnostic criteria of serotonin syndrome and the clinical scenarios in which serotonin syndrome can develop. We will also discuss the proposed treatments and role that polypharmacology may play in the development of this clinical entity.

Leukopenia Associated with Risperidone Treatment.

Risperidone is an atypical antipsychotic agent that was originally approved by the United States Food and Drug Adminstration for the treatment of schizophrenia. There are many side effects that are frequently associated with the use of risperidone. These include weight gain, anxiety, extra-pyramidal side effects, and elevated prolactin levels. More infrequently, the use of risperidone has been linked to leukopenia. We will now present the case of a 66-year-old gentleman who developed leukopenia after the initiation of risperidone to control agitation due to delirium. We will review the previous cases of leukopenia associated with risperidone, and will review possible risk factors for the development of leukopenia, based on the reported cases.

Hallucinations Associated with Topiramate Therapy: A Case Report and Review of the Literature.

BACKGROUND: Topiramate is a medication that is approved as both monotherapy and adjunctive treatment of seizure disorder in adults and adolescents. It is also approved for migraine prophylaxis. It has been associated with many side effects, including weight loss and the development of renal stones. It has also been associated with various central nervous system side effects such as dizziness, nervousness, parasthesias, and fatigue. Less commonly, it has been associated with the development of psychotic symptoms such as hallucinations. OBJECTIVE: To describe the relationship between the administration of topiramate and the development of hallucinations in this patient. METHODS: We will now present the case of a 32-year-old man who developed auditory hallucinations after initiating a relatively low dose of topiramate (25mg twice daily) for the treatment of chronic pain. We will review the prior cases of topiramate induced hallucinations, and discuss how these cases compare to the case we have described. We will review the treatment of these hallucinations. RESULTS: In this case, there was a close temporal relationship between the initiation of topiramate and the onset of auditory hallucinations. CONCLUSION: This case supports the previous reports describing the association between the use of topiramate and the developmenrt of hallucinations. Although the average daily topiramate dose associated with the development of hallucinations in previously reported cases was 150 mg in women and 181 mg in men, hallucinations can occur at lower doses (as low as 50 mg daily) as well.

Syndrome of inappropriate antidiuretic hormone associated with escitalopram therapy.

Escitalopram is the selective serotonin reuptake inhibitor (SSRI) most recently approved for use in the United States. It is structurally related to citalopram, but is felt to have a more tolerable side-effect profile than its parent compound. Side effects are not generally serious and include headache, diarrhea, and nausea. While hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) have been associated with treatment with other SSRIs, there has only been one case of escitalopram-induced SIADH reported in the literature to date. We now report another case of a patient who developed SIADH after being treated with escitalopram for 4 weeks. The patient's hyponatremia improved following the discontinuation of escitalopram. Clinicians should be aware of this uncommon but significant side effect of SSRIs and monitor high-risk patients for the development of SIADH.

The Use of Fluoxetine in a Patient With Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy is an acute coronary syndrome that is believed to be brought on by stress. Symptoms, which are similar to an acute myocardial infarction, include chest pain, shortness of breath, arrhythmias, and cardiogenic shock, and the electrocardiogram often shows ST and T wave changes. Left ventricular wall hypokinesis along with a significantly reduced ejection fraction are seen on echocardiogram. The great majority of these symptoms all occur in the absence of occlusive disease. Many cases have been reported in which the development of takotsubo cardiomyopathy was associated with serotonin norepinephrine reuptake inhibitors and tricyclic antidepressants. However, no cases of takotsubo cardiomyopathy have been reported involving selective serotonin reuptake inhibitors. This article presents the case of a 51-year-old woman receiving stable therapy with fluoxetine who developed takotsubo cardiomyopathy after an acute stress. We also discuss the clinical presentation of takotsubo cardiomyopathy, review possible causes, and discuss the treatment of depressive symptoms in patients who are at increased risk of developing this illness.