Posts Tagged antidepressants

[WEB PAGE] Identification and management of depression in people with epilepsy to save lives

Depression is the most common psychiatric comorbidity in people with epilepsy. Clinical studies have found that 20% to 30% of people with epilepsy have depression; the incidence may be as high as 50% to 55% in people visiting hospital epilepsy centers.

Untreated depression is associated with lower quality of life, poor treatment adherence, higher health care utilization and a risk for suicide up to 30 times higher than average.

Yet in most people with epilepsy, depression goes undetected. As an example, a Texas study conducted depression screening on 192 consecutive people visiting a high-volume epilepsy clinic. More than 1 in 4 people-;26%-;screened positive for depression and were subsequently diagnosed with depression. Of them, 65% had no previous history of the condition.

At the 33rd International Epilepsy Congress in Bangkok in June 2019, several sessions focused on psychiatric comorbidities in people with epilepsy and the crucial role of epileptologists in their identification and management.

Sometimes we think too much about the epileptology and not enough about comorbidities. There is individual clinician variation in this area. We must each recognize our own competency and know what we don’t know. Those are strongly influenced by our training, coworkers, culture, country and interests. But in the end, all clinicians must meet a minimum standard.”

Mike Kerr (UK), co-chair of a session on neuropsychiatric issues in epilepsy

This minimum standard was established by ILAE as part of its new epileptology curriculum. Domain 6 includes competencies and learning objectives about comorbidities, including the following:

6.1.1 Recognize psychiatric comorbidities, such as depression, anxiety, ADHD, psychosis and autism spectrum disorder

6.1.2 Appropriately manage or advise regarding psychiatric comorbidities

6.1.3 Adjust anti-seizure treatment as required by psychiatric comorbidities

However, the gap between knowledge and practice remains relatively wide. In a Bangkok session on psychological and psychiatric learning objectives in the ILAE curriculum, an informal survey found that most audience members did not conduct depression or suicidality screening in their clinics.

“Up to half of your patients will have depression and up to half will have anxiety,” said W. Curt LaFrance, Jr. (USA). “But almost no one in this session is using a depression screening tool.”

Generally, neurologists cite several reasons for not using screening tools or asking their patients about depression, including time constraints and the perception that screening is not their role. But physicians who manage the care of people with epilepsy are uniquely positioned to identify depression and initiate treatment that can improve quality of life and seizure control.

“It is part of our clinical responsibility as neurologists and epileptologists to take action in response to the high depression rates in people with epilepsy,” said Rosa Michaelis (Germany), co-chair of one of the sessions. “We should not expect other physicians to take over this task.”

Depression assessment: Individual variation

There’s no single “right” way for epileptologists to handle depression assessment and management, said Kerr. “Some people are multitaskers and will take on psychiatric management,” he said. “At the other end will be people who feel that none of it is their job. In the middle are the guiders, who keep epilepsy as a focus but also address the psychiatric issues.

Michaelis suggested that standardized screening is the most realistic strategy to increase detection rates. “We cannot rely on self-reported symptoms,” she said. Patients may not volunteer information about how they are feeling unless they are asked directly-;and even then, they may deny or downplay their symptoms, or physicians may misinterpret their complaints. Screening tools provide valuable information in only a few minutes; they also can be a gateway to conversations about depression and suicidality.

If the idea of establishing a formal screening program is overwhelming, Kerr suggested being alert to the possibility of depression in every patient and merely asking one question: “During the last month, have you felt down, depressed, or hopeless, or had little interest or pleasure in doing things?”

If the answer sounds at all like “Yes,” refer the patient to a mental health professional. Alternatively, he said, “If you feel competent in mental health assessment, consider using a validated measure” to get a better idea of the extent and severity of the patient’s issue.

For screening, Kerr and others in Bangkok recommended the Neurological Disorders and Depression Inventory in Epilepsy (NDDI-E), which is free for public use and available in more than a dozen languages. The NDDI-E consists of six short “feeling” statements:

  • Everything is a struggle
  • Nothing I do is right
  • Feel guilty
  • I’d be better off dead
  • Frustrated
  • Difficulty finding pleasure

For each statement, the person indicates how often they felt that way over the past two weeks. Points are given for each answer: always or often (4 points); sometimes (3); rarely (2); never (1).

A cutoff of 15 points is generally used to suggest depression, though cutoffs of 11 to 16 have been reported. According to Kerr, a cutoff score of 15 has 81% sensitivity and 90% specificity.

The Patient Health Questionnaire-9 (PHQ-9) or a shorter form, the PHQ-2, also can be administered.

The ILAE Commission on Psychiatry recommends annual screening, but many of the experts urged more frequent screening. They noted that because depression can be episodic, more frequent screening will better identify those patients in need of treatment. It also may improve patient-physician communication and trust.

Though the ILAE consensus statement does not include a recommendation for anxiety screening, Kerr urged clinicians to screen for anxiety as well. The NDDI-E screens for both depression and anxiety; Kerr also recommended the GAD-2 or the ET7, short questionnaires that have been tested in people with epilepsy. Patients with positive screens can be referred to a mental health specialist or assessed further.

“All clinicians should aim to identify depression and anxiety,” Kerr said. “To be a level-2 epileptologist by ILAE standards, you will have to know how to do this.”

Antidepressants: Myth and reality

Psychotherapy and medication are common treatments for depression. Though few studies have focused on the effectiveness of psychotherapy for depression specifically in people with epilepsy, dozens of trials and several meta-analyses support the use of cognitive behavioral therapy (CBT).

Some medical professionals may avoid prescribing antidepressants to people with epilepsy because they believe these drugs decrease the seizure threshold. There is little scientific basis for this, say experts.

A 2017 study followed adults with epilepsy six months before and after the initiation of antidepressant therapy with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norephinephrine reuptake inhibitors (SNRIs). Though the study was relatively small (N=84), the findings showed that antidepressants did not increase seizure frequency. In fact, among patients having more than one seizure per month at baseline, 27.5% went on to have less than 1 per month, and 48% had at least a 50% reduction in frequency. Of the patients, 73% had a therapeutic response to the antidepressant; changes in seizure frequency were independent of therapeutic response.

Pediatric screening

Janelle Wagner (USA) and Avani Modi (USA) addressed the issue of screening for depression and anxiety in the pediatric epilepsy population as it relates to two learning objectives in the ILAE curriculum:

  • 2.5.1 – Recognize when to refer patients for a higher level of care (as it relates to psychiatric comorbidities)
  • 2.9.1 – Provide counseling specific to children with epilepsy and their parents, according to the epilepsy types

Children with epilepsy are at higher risk than other children for depression, anxiety and attention deficit disorder, said Kette Valente (Brazil). Among children with epilepsy, 1 in 4 has depression, 1 in 4 has anxiety, and between 15% and 27% consider committing suicide.

A 2015 ILAE survey found that 55% of pediatric neurologists screened for these comorbidities, compared with only 7% in 2005. However, 50% of clinicians did not feel comfortable with their knowledge of anxiety, and only 40% said that screening for and managing comorbidities were priorities.

Depressive symptoms in children can look different than in adults, said Modi. Low self-esteem, cognitive symptoms, and negative thinking are common. Irritability and disruptive behavior also may be concerns, she said. “What may be seen as a conduct problem is actually depression.”

Valente, Wagner, and Modi described multiple screening instruments that take between 10 and 30 minutes to complete. Valente noted, however, that the instruments are often completed by parents, who do not always reflect their child’s behavior accurately.

The NDDI-E-Y, the pediatric version of the NDDI-E, had a sensitivity of 79% and a specificity of 92% in a 2016 validation study. Like the NDDI-E, the youth version can alert providers to suicidal ideation and provide a platform to discuss it.

Valente suggested screening children at their first visit, and then at certain time points:

  • Every 6 months
  • When seizures worsen
  • After medication changes
  • After any type of complaint about mood or behavior, whether it comes from the child or a parent or teacher

“Screening is not perfect, but it must be done,” she said. “There is no reason not to do it.”

Suicidality – what to do?

Jakob Christensen (Denmark) warned congress attendees that suicide risk overall is increasing worldwide, and that people with epilepsy have triple the risk of a suicide attempt and at least double the risk of death by suicide, compared with the general population. People with psychiatric comorbidities, and those recently diagnosed with epilepsy, are at even greater risk.

A recent meta-analysis found a prevalence of suicidal ideation of 23.2% among people with epilepsy-;more than 7 times the prevalence in the general population. The pooled event rate of completed suicide in the meta-analysis was 0.5%, more than 30 times higher than the global estimated suicide rate (0.016%).

Screening can reveal suicidal thoughts or plans; on the NDDI-E, this can be seen on item 4, “I’d be better off dead”. A score of 3 or 4 on this item has been shown to identify suicidality with 84% sensitivity and 91% specificity.

Christensen recommended asking every patient about suicidal thoughts. “It can be as simple as saying, ‘Do you ever feel like life isn’t worth living?’ he said. Asking the question will not increase the risk of suicidality, he said. “People who have these thoughts are actually quite happy to have you ask the question. They often don’t realize that suicidality can be associated with epilepsy.”

If NDDI-E results indicate suicidality, Milena Gandy (Australia) outlined next steps:

  • Ask the patient if they’ve thought about harming themselves in the past week. If they say yes, ask for details. Ask if they’ve ever tried to kill themselves and if so, how and when.
  • If you feel they may be in imminent danger of harming themselves, ask if they can guarantee their safety until you see them again.
  • If they ask for immediate help or can’t guarantee their safety, you can call a suicide hotline for them, refer them to the emergency room (or escort them there yourself), or refer them to a crisis service.
  • If they are not in immediate crisis, refer them for mental health support if they don’t already have it. If they do have it, talk with them about making an urgent appointment.

The clock is ticking

Screening and conversations do take time. And while all physicians are pressed for time, “We need to think creatively about how we can do what’s possible” with screening, said Markus Reuber (UK). For example, ensure that any patient information (brochures, videos, other handouts) includes mention of mood disorders and anxiety as common comorbidities.

Reuber also noted that some offices and centers have epilepsy nurses or community health advocates who can talk about mental health, and mental health services, with patients. Providers must find creative ways to make time for these issues, he said, as they are a crucial part of epilepsy treatment.

“We can draw on experiences from other health conditions,” said Modi. “In cancer care, chronic pain and heart disease, referring to a psychologist is common practice. Yet there are still some perceptions in neurological disorders that psychological care isn’t as important. But improving mental health can improve medical care.”

 

via Identification and management of depression in people with epilepsy to save lives

, , , , ,

Leave a comment

[ARTICLE] Pharmacological management of long-term aggression secondary to traumatic brain injuries

Abstract
Aggression is common after traumatic brain injuries (TBI) in acute and chronic settings. However, there is limited guidance regarding its assessment and effective management. Whilst a number of pharmacological options are available for long term treatment, the evidence base is not of an adequate strength to support a unified practice. This article will explore the currently available guidelines and recommendations for treating chronic aggression after TBIs and evaluate the evidence for its pharmacological management.


Introduction

Aggression is a long term neurobehavioural sequelae of TBIs with incidences quoted from 11.5-33.7%.1 In TBI patients, aggressive behaviour tends to be impulsive rather than premeditated and can manifest as episodic dyscontrol syndrome, disinhibition or exacerbated premorbid antisocial traits.2 The underlying mechanisms of aggression are complex allowing numerous and diverse interventions targeting various pathways.

In acute settings, Lombard and Zafonte (2005) describe non-pharmacological measures to manage aggression including environmental alterations and ensuring minimal or non-contact restraints. Screening for systemic causes, optimising pain control and patients’ sleep-wake cycle are also advocated. In the event of failed non-pharmacological treatment, Lombard and Zafonte (2005) recommend that medication choice should be tailored to individuals; with side effect profiles taken into consideration.3

For chronic aggression, psychological therapies are used as a first line with pharmacological interventions trialled in later stages.4 Psychological therapy options include cognitive behavioural therapy (CBT), behavioural management utilising operant learning theory and contingency management. However, a review by Alderman (2013) concluded that further evidence using scientific methods is needed to analyse these approaches.5  Comparatively, there is a diverse body of literature addressing long term pharmacological treatment although quality among studies are varied. This article will focus on the aetiology for chronic post TBI aggression, current management guidelines and the evidence for long term pharmacological interventions.

Aetiology

Post TBI aggression has been associated with lesions affecting the prefrontal cortex – particularly the orbitofrontal and ventromedial areas – causing a loss of behavioural regulation. Disruption to inhibitory pathways between the prefrontal cortex and limbic system also results in limbic kindling and inappropriate emotional responses to negative stimuli thus facilitating aggressive behaviour.2 Associated neurotransmitter abnormalities include low cortical serotonin and impaired gamma amino-butyric acid (GABA)/ glutamate levels.6 Altered catecholamine and cholinergic levels are associated with cognitive impairment2 thus distorting information processing and predisposing patients to aggression.6 In TBI patients, underlying anxiety, affective disorders, seizures and frontal lobe dysfunction also increase susceptibility.10

Differentials for aggression

When identifying a cause for chronic aggressive behaviour, a patient’s previous experiences, comorbid psychiatric conditions and alcohol and/or substance abuse must be established with a collateral history.2,7  McAllister (2008) highlights the importance of determining pre-injury behaviour in order to exclude the possibility of symptoms being an exaggeration of pre-injury personality traits.8 Additionally, psychosocial factors must be deduced to identify possible triggers.2,7

Clinicians must be aware that aggression can be a presenting feature of other psychiatric disorders. Depression has a prevalence of 18.5% to 61% in post-TBI patients  and is linked with aggression due to their shared association with frontal lobe lesions and serotonin level imbalance.9 Other differentials include manic disorders (which can involve a more marked aggressive component if secondary to TBIs), anxiety disorders and alcohol and/or substance abuse. Personality and behavioural disorders such as affective lability, behavioural disinhibition and acquired antisocial behaviour should also be considered.8

Management guidelines

The National Institute for Health and Care Excellence (NICE) refers to the Scottish Intercollegiate Guidelines Network (SIGN) for rehabilitating patients with acquired brain injuries (ABIs). Psychological treatments advocated by SIGN include CBT, contingency management procedures, music therapy and comprehensive neurobehavioural rehabilitation (CNR).10 Family involvement appears to be associated with better outcomes2 and is also recommended.10

Of the studies quoted by SIGN, CNR was found to cause a positive effect in ABI patients in one systematic review although inconsistent results were obtained for the other three methods. Regarding pharmacological treatment, SIGN advises propranolol and pindolol as first line options.10

Pharmacological treatment

The aberrant neurotransmitter changes in the cortex and limbic areas as a result of TBIs2 provide targets for pharmacological therapy (as summarised in Table 1). Theoretically, cortical behavioural regulation can be enhanced by serotonergic agents and antagonists of dopaminergic and noradrenergic neurotransmission. Limbic hyperactivity can be dampened by the use of gamma aminobutyric acid (GABA) agonists, glutamatergic antagonists and anticholinergics.6

Impaired behavioural regulation

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are indicated for their increase in dopamine and serotonin availability and the treatment of depression contributing to aggressive behaviour. In a trial conducted by Kant et al (1998), sertraline reduced aggression within one week of treatment although TBI severities were variable within the population.11 These results are mirrored in other trials presenting sertraline as a viable treatment option.12 Citalopram used in conjunction with carbamazepine successfully treated behavioural symptoms in a clinical trial of 22 patients conducted by Perino et al (2001)13 although the separate effects of both drugs are impossible to differentiate. A case study by Sloan et al (1992) found that fluoxetine improved emotional lability in one patient within a week.13

Tricyclic antidepressants have been shown to be useful for managing both post-traumatic and chronic aggression. Amitriptyline has reduced aggression with good tolerability despite its strong anticholinergic side effects in several studies and is suggested as the best option for treating behavioural disorders secondary to frontal lobe injuries without impairing cognition.13

Antipsychotics

There is a wide body of literature advocating antipsychotics for managing aggression due to their sedative effects.13 Nevertheless, the cognitive and extrapyramidal side effects of typical antipsychotics limit their value for chronic use. Comparatively, atypical antipsychotics have a milder side effect profile and are preferred although their cognitive impact in TBI patients is unclear.2 Furthermore, unlike older generations, atypical antipsychotics antagonise 5HT2 receptors and are therefore implicated in reduced aggression.9

Of the typical antipsychotics, chlorpromazine reduced explosiveness in one case study conducted by Sandel et al (1993). Various case studies also report haloperidol improving chronic agitation in TBI patients although significant side effects were encountered.13 Of the atypical antipsychotics the level of evidence is low. Quetiapine reduced aggression and irritability in seven patients in a trial conducted by Kim and Bijlani (2006).11 Olanzapine significantly reduced aggression within six months in a case study conducted by Umansky and Geller (2000). Clozapine was associated with varying levels of improvement in six case studies conducted by Michals et al (1993) however seizures were experienced in two patients.13

Overall, there is no reliable evidence advocating antipsychotic use for managing chronic post-TBI aggression. If antipsychotics are commenced for this purpose, it is suggested that their use is restricted to patients with psychosis.13

Beta blockers

Beta blockers are useful for cases where aggression is caused by underlying anxiety13 due to its inhibition of noradrenergic levels.9 A Cochrane review of four RCTs found that pindolol and propranolol reduced aggression within two to six weeks of starting treatment in ABI patients however no recommendations were made due to heterogeneity between samples, a small number of trials and small sample sizes.  The authors acknowledge that the trials involved high doses and so recommend caution when prescribing beta blockers for aggression.4

Methylphenidate

Methylphenidate is a psychostimulant indicated for its enhancement of dopamine and noradrenaline in the frontal lobe improving arousal and alertness.13 Mooney (1993) found in a single RCT that methylphenidate significantly improved anger scores in TBI patients.4 However other studies have yielded mixed results12,13 and no firm conclusion can be made.

Amantadine

Amantadine increases dopamine availability and acts on glutamatergic pathways. An advantage of its use is its non-sedating qualities however there is contradicting evidence for its efficacy.13 An RCT conducted by Schneider (1999) found no significant improvement4 however the trial was limited by a small sample size and large heterogeneity. Interestingly, studies of a lower level of evidence demonstrate favourable results.13 Due to this variability, its efficacy is still in question.

Buspirone

Buspirone – a serotonergic agonist licensed for treating anxiety13 – has also reduced aggression in several case studies2,12,14 warranting further research. Its side effects are amenable for use in TBIs although one disadvantage is its delayed onset.13

Hyperactive limbic drive

Anticonvulsants

The mood stabilising effects of anticonvulsants are mediated through their enhancement of GABA transmission.2 Carbamazepine has been demonstrated in studies to be effective for managing acute and chronic post- TBI aggression.12,13 Its side effects include impaired balance, sedation13 and cognitive impairment particularly in brain injured patients2 due to their heightened sensitivity. In a trial conducted by Mattes (2005), Oxcarbazepine reduced impulsive aggression however the number of TBI participants in the sample was unclear. Nine of the 48 participants also dropped out due to adverse effects11 suggesting more research is needed into its tolerability in TBI patients. Valproate has also been demonstrated to effectively manage behavioural and affective disorders13 with a milder cognitive impact compared to carbamazepine.2 Regarding other anticonvulsants, the evidence is of a lower standard. Pachet et al (2003) found that lamotrigine reduced aggression with good tolerability in one case study.11 Topiramate has been demonstrated to effectively treat manic symptoms but due to its side effects of psychosis and cognitive impairment,2 may be inappropriate for TBI patients. Case reports reference lithium to reduce post – TBI agitation however it may be unsuitable as a first line option due to its neurotoxicity.13

Benzodiazepines

Benzodiazepines are indicated for their anticonvulsive, anti-anxiety and sedative qualities facilitated by stimulation of the GABA receptor.13 There is limited literature on their chronic use in TBI patients due to their side effects of agitation, cognitive impairment and tolerance2 thus they are recommended to be more appropriate for cases of acute agitation or anxiety.11

Conclusion

There are many challenges in assessing and managing chronic aggression due to its complex aetiology. Previous literature presents a selection of pharmacological options however, their effect on TBI patients has not been confirmed resulting in limited guidance. The heterogeneity between samples also renders it impossible to predict treatment outcomes in the TBI population warranting the need for low doses, slow titration and frequent monitoring.13 A six-week trial period is advised by Fleminger et al (2006) to ascertain effects of treatment before trialling a new medication.4 Patient and family education regarding realistic treatment outcomes and side effects of treatments is also necessary to ensure treatment compliance.2 In future, a clarification of the underlying neurochemical changes is needed to identify further treatment targets. Additional larger scale RCTs are also needed to guide decision making and predict treatment outcomes. Table 2 offers a practical guide on medication choice in relation to aggressive behaviour in ABI.

References

  1. Tateno A, Jorge RE, Robinson RG. Clinical correlates of aggressive behaviour after traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2003;15(2):155-60.
  2. Kim E. Agitation, aggression and disinhibition syndromes after traumatic brain injury. NeuroRehabilitation 2002;17:297-310.
  3. Lombard LA, Zafonte RD. Agitation after traumatic brain injury: considerations and treatment options. Am J Phys Med Rehabil. 2005;84(10):797-812.
  4. Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev. 2006;18(4):CD003299.
  5. Alderman N, Knight C, Brooks J. Rehabilitation Approaches to the Management of Aggressive Behaviour Disorders after Acquired Brain Injury. Brain Impairment. 2013;14(1):5-20.
  6. Siever LJ. Neurobiology of Aggression and Violence. Am J Psychiatry. 2008;165(4):429-42.
  7. McAllister TW. Neurobehavioral sequelae of traumatic brain injury: evaluation and management. World Psychiatry. 2008;7(1):3-10.
  8. Schwarzbold M, Diaz A, Martins ET, Rufino A, Amante LN, Thais ME et al. Psychiatric disorders and traumatic brain injury. Neuropsychiatr Dis Treat. 2008;4(4):797-816.
  9. Coccaro EF, Siever LJ. Pathophysiology and treatment of aggression. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropsychopharmacology: The Fifth Generation of Progress. 5th ed. Pennsylvania: Lipincott, Williams & Wilkins; 2002:1709-23.
  10. Scottish Intercollegiate Guidelines Network. Brain injury rehabilitation in adults. Edinburgh: SIGN; 2013. 68 p. Report no.:130.
  11. Luauté J, Plantier D, Wiart L, Tell L, the SOFMER group. Care management of the agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and practice recommendations. Ann Phys Rehabil Med 2016;59(1):58-67.
  12. Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, Bruns J, et al. Guidelines for the Pharmacological Treatment of Neurobehavioral Sequelae of Traumatic Brain Injury. J Neurotrauma 2006;23(10):1468-501.
  13. Levy M, Berson A, Cook T, Bollegala N, Seto E, Tursanski S, et al. Treatment of agitation following traumatic brain injury: A review of the literature. NeuroRehabilitation 2005;20(4):279-306.
  14. Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury – a state-of-the-art review. J Rehabil Res Dev 2009;46(6):851-79.

Anum Bhatti is currently in her final year of training for her MBchB at Keele University. She is interested in pursuing psychiatry as a career choice.

 

Dr George El-Nimr, MBChB, MSc (Neuropsych), MRCPsych, MSc (Psych), MMedEd, is a Consultant Neuropsychiatrist and Academic Secretary of the Faculty of Neuropsychiatry at the Royal College of Psychiatrists.

 

Correspondence to: Dr El-Nimr, Consultant Neuropsychiatrist, Neuropsychiatry Services, Bennett Centre, Richmond Terrace, Shelton, Stoke-on-Trent ST1 4ND. Tel: 01782 441614
Conflict of interest statement: None declared
Provenance and peer review: Submitted and externally reviewed
Date first submitted: 18/4/18
Date submitted after peer review: 21/9/18
Acceptance date: 15/5/19
To cite: Bhatti A, El-Nimr G. 
ACNR 2019;18(4);15-17
Published online: 1/8/19

via Pharmacological management of long-term aggression secondary to traumatic brain injuries | ACNR | Online Neurology Journal

, , , , , , , , , , , ,

Leave a comment

[BLOG POST] Antidepressants During Pregnancy Dangerous for the Child?

Antidepressants During Pregnancy Bad for Child Health

Depression is sometimes described as a disease of modernity, as sharp changes in lifestyle during the last century or so have given rise to many chronic disorders including or linked to depression. Depression is a state of low mood: the person affected tends to lose interest in previously enjoyable activities. In severe cases, self-harm is also possible. Fortunately, there are many options available today to help treat this condition.

Research studies and statistics show that although pregnant women are less prone to major depression, they are more inclined to minor depressive episodes. The prevalence of depression can be anywhere between 8–16% among pregnant women. There are also higher chances that diagnosis of depression is overlooked in pregnant women.

The treatment of depression is quite challenging in pregnancy, as medical specialists have to weigh the benefits of treatment against the risks for the mother and the health of her unborn baby. Furthermore, the health professional has to take into consideration the risks and benefits of any such therapy to the long-term health of the child. New research seems to indicate that treatment of pregnant women with antidepressant drugs may increase the risk of autism, disturbances in motor function, and mental health problem in children. Some of these issues may become clear later in the life, thus studying this subject remains a challenge for researchers.

Why treat depression in pregnancy?

There is a widespread misconception that depression is not as threatening as other medical illnesses. Thus, treating depression is viewed as a matter of choice or even a luxury. Moreover, many patients that are on antidepressant drugs before pregnancy are in the remissive stage. Therefore, their doctors may think of discontinuing the therapy.

However, if a pregnant woman that is vulnerable to depression is not provided with antidepressant therapy, there is a higher risk of preterm birth, low birth weight, substance abuse in pregnancy (e.g., smoking and drinking alcohol), and a significantly higher risk of postpartum depression.

Research has shown that if antidepressants are discontinued for the period of the pregnancy, the relapse rate of major depression is as high as 60–70%. This can have severe consequences for the patient, family, and child. In addition, children born to mothers with untreated depression have higher levels of cortisol, which may have adverse impacts on their health.

Risks of antidepressants

As already mentioned, the use of antidepressants in pregnancy is a complicated issue due to possible dangers. Below are some of the common problems associated with the use of antidepressants during pregnancy.

Persistent pulmonary hypertension

This is a failure of lungs blood vessels to dilate in a child post-birth. Thus, a new-born may have breathing difficulties, a deficit of oxygen in the blood, leading to intubation. In many cases, outcomes may be fatal. This condition is also found to be related to maternal smoking, diabetes, and sepsis. Though the risk of persistent pulmonary hypertension in new-born increases up to six times with the use of antidepressants, at the same time there is a consensus among the medical community that non-use of antidepressants may be even more harmful.

Withdrawal symptoms

This is also called “poor neonatal adaptation.” These symptoms are common when a mother has been exposed to antidepressants during the third trimester of pregnancy. Some of the symptoms characteristic of this syndrome include difficulties in breathing, unstable body temperature, hypo- or hypertonia, irritability, constant crying, and seizures. Therefore, some specialists recommend tapering the dose of antidepressants in the third trimester.

Motor development

By motor development, we mean child’s ability to move around and handle the environment. There are clinical studies that indicate that the use of antidepressants during pregnancy may slow the motor development. A child may start walking later than other kids, or may have other problems related to movements.

Autism spectrum disorders

This is a neurodevelopmental disorder of children. Studies seem to show the modest increase in the risk of autism if a mother is exposed to antidepressants during the first trimester.  However, no link has been found if such treatment has been given before the pregnancy, nor much relationship has been demonstrated if the therapy was initiated in a later phase of pregnancy. Thus, researchers caution that decision of prescribing antidepressants should be taken on a case by case basis by analysing the risks and potential benefits for maternal and child health.

Psychiatric disorders

In one of the large-scale studies, scientists analysed the data of almost one million births, and they found that the use of antidepressants in pregnancy was related to higher risk of developing psychiatric disorders later in life. Nonetheless, at the same time, researchers cautioned against jumping to the quick conclusions because it is a well-known fact that mental disorders have relation to genetics. It means that women prescribed antidepressants during the pregnancy have higher chances of passing to children the genes that may result in psychiatric diseases later in life.

Although antidepressants may increase the risk of specific disorders in the new-born babies or may even have a negative impact later in the life, it does not mean that antidepressants should not be taken during the pregnancy. It is essential that women should not feel guilty about taking such drugs. The medical specialists must be aware of the risks and weigh them against the benefits before they prescribe antidepressants to pregnant women.

References

Casper, R.C., Fleisher, B.E., Lee-Ancajas, J.C., Gilles, A., Gaylor, E., DeBattista, A., Hoyme, H.E., 2003. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J. Pediatr. 142, 402–408. doi:10.1067/mpd.2003.139

Croen, L.A., Grether, J.K., Yoshida, C.K., Odouli, R., Hendrick, V., 2011. Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders. Arch. Gen. Psychiatry 68, 1104–1112. doi:10.1001/archgenpsychiatry.2011.73

Ko, J.Y., Farr, S.L., Dietz, P.M., Robbins, C.L., 2012. Depression and Treatment Among U.S. Pregnant and Nonpregnant Women of Reproductive Age, 2005–2009. J. Womens Health 2002 21, 830–836. doi:10.1089/jwh.2011.3466

Payne, J.L., Meltzer-Brody, S., 2009. Antidepressant Use During Pregnancy: Current Controversies and Treatment Strategies. Clin. Obstet. Gynecol. 52, 469–482. doi:10.1097/GRF.0b013e3181b52e20

Image via xusenru/Pixabay.

via Antidepressants During Pregnancy Dangerous for the Child? | Brain Blogger

,

Leave a comment

[WEB PAGE] Faster-acting antidepressants may soon be a reality

Understanding where antidepressants act is the key to improving their function.

 

Using cutting-edge techniques, researchers have investigated the mechanism by which common antidepressants work, finally pinning down the specific receptors responsible for their action. The findings might pave the way to designing improved, faster-acting antidepressants.

Depression is characterized by persistent low mood and feelings of hopelessness, and it is one of the most common mental disorders in the United States. In 2014, there were an estimated 15.7 million U.S. adults who experienced at least one major depressive episode, representing around 6.7 percent of the country’s adults.

Treatments for depression generally include talking therapies in conjunction with medication. The class of drugs most commonly prescribed is selective serotonin reuptake inhibitors (SSRIs), and these include brands such as Prozac and Zoloft.

SSRIs can help some people with depression, but they are not perfect; not everyone responds well to them, and side effects including nausea, insomnia, agitation, and erectile dysfunction can be unpleasant.

Also, SSRIs can take some time to kick in; although some people might feel some benefit within hours or even minutes, most people do not feel the full antidepressant effect until they have been taking the drugs for weeks or even months.

How do SSRIs work?

In the brain, messages are sent between neurons by releasing neurotransmitters into a gap between the cells, or the synapse. Serotonin is one such neurotransmitter. It is released from the first neuron and binds to receptors on the second neuron.

Normally, once serotonin has been released into the synapse and relayed its message, the majority is reabsorbed into the first nerve cell for reuse at a later date. SSRIs prevent serotonin from being reabsorbed. In this way, they ensure that serotonin hangs around in the synapse for a longer time, exerting more of an effect.

Although SSRIs have been known to medical science since the 1950s, their exact mechanism is not understood. This is because there are at least 1,000 types of neuron that can be influenced by a surge in serotonin, and some of these neurons may be excited, while others might be inhibited.

The mixed response is because there are 14 subtypes of serotonin receptor throughout the body and any single nerve could have a cocktail of receptor types. Teasing out which receptor subtype is playing the most significant role has proven challenging.

The role of the dentate gyrus

A group of scientists from Rockefeller University in New York City, NY, recently set out to take a closer look at the action of SSRIs on a particular type of nerve cell. The team was headed up by Lucian Medrihan and Yotam Sagi, both research associates in the Laboratory of Molecular and Cellular Neuroscience, and Paul Greengard, Nobel laureate.

Their findings were recently published in the journal Neuron.

Many different types of synapses throughout the brain use serotonin as their neurotransmitter. An issue of major importance has been to identify where in the myriad of neurons the antidepressants initiate their pharmacological action.”

Paul Greengard

The team concentrated on a group of cells in the dentate gyrus (DG). According to the authors, they chose the DG because previous work has established that “SSRI treatment promotes a variety of synaptic, cellular, and network adaptations in the DG.”

Specifically, the team investigated cholecystokinin (CCK)-expressing neurons within the DG. These neurons were of interest because they are heavily influenced by neurotransmitter systems that are associated with mood disorders, such as depression.

Finding the right receptor

Using a technique called translating ribosome affinity purification, the team were able to identify the serotonin receptors on CCK cells. Sage explains, “We were able to show that one type of receptor, called 5-HT2A, is important for SSRIs’ long-term effect, while the other, 5-HT1B, mediates the initiation of their effect.

The next step in the study involved efforts to mimic SSRIs’ effects by manipulating CCK neurons in mice. They used chemogenetics to switch nerve cells on or off and implanted tiny electrodes inside the mouse brains.

The findings were clear. When the CCK neurons were inhibited, the pathways important for the mediation of SSRI responses lit up. In other words, the scientists had recreated a Prozac-like effect without using the drug.

To back up these findings, the team used behavioral experiments in a pool and observed swimming patterns. Again, silencing the CCK neurons created behavior that was similar to that displayed by the mice that had been given SSRIs: they swam for longer with increased vigor.

According to the researchers, understanding the importance of the DG and the specific cells important for treating depression will help to design faster-acting, more effective antidepressants with fewer side effects.

The work was carried out using techniques that would have been impossible just 5 years ago, and the studies that follow are likely to improve our understanding even further.

Source: Faster-acting antidepressants may soon be a reality

, , , , , , , ,

Leave a comment

[WEB SITE] Electric Brain Stimulation No Better Than Meds For Depression: Study

Wednesday, June 28, 2017

HealthDay news imageWEDNESDAY, June 28, 2017 (HealthDay News) — For people who battle depression and can’t find relief, stimulating the brain with electric impulses may help. But a new study by Brazilian researchers says it’s still no better than antidepressant medication.

In a trial that pitted transcranial, direct-current stimulation (tDCS) against the antidepressant escitalopram (Lexapro), researchers found that lessening of depression was about the same for either treatment.

“We found that antidepressants are better than tDCS and should be the treatment of choice,” said lead researcher Dr. Andre Brunoni. He’s director of the Service of Interdisciplinary Neuromodulation at the University of Sao Paulo.

“In circumstances that antidepressant drugs cannot be used, tDCS can be considered, as it was more effective than placebo,” he said.

The researchers used the Hamilton Depression Rating Scale. This test has a score range of zero to 52, with higher scores indicating more depression.

People who received brain stimulation lowered their depression score by 9 points. Those taking Lexapro had depression scores drop by 11 points. Patients receiving placebo experienced a drop of 6 points in their depression score, the researchers found.

“tDCS has been increasingly used as an off-label treatment by physicians,” Brunoni said. “Our study revealed that it cannot be recommended as a first-line therapy yet and should be investigated further.”

The report was published June 29 in the New England Journal of Medicine.

Dr. Sarah Lisanby is director of the Division of Translational Research at the U.S. National Institute of Mental Health. “When you consider if this treatment adds anything to the ways we have to treat depression, you want to know that a new treatment is better than or at least as good as what’s available today,” she said.

“But this study failed to show that tDCS was better than medication,” said Lisanby, who wrote an accompanying journal editorial.

Lisanby pointed out that unapproved tDCS units are being sold on the internet. She cautioned that trying brain stimulation at home to relieve depression or enhance brain function is risky business, because side effects can include mania.

“There are people who are doing do-it-yourself tDCS,” she said. “People are trying to find ways to treat depression, but it’s important for them to know that tDCS is experimental and not proven to be as effective or more effective than antidepressant medications.”

To get a better idea of how well brain stimulation worked for depression, Brunoni and colleagues randomly assigned 245 patients suffering from depression to one of four groups. One group had brain stimulation plus a placebo pill, another had fake brain stimulation plus Lexapro. The third group had brain stimulation plus Lexapro, and the final group had fake brain stimulation plus a placebo.

Brain stimulation involved wearing sponge-covered electrodes on the head. The treatment was given for 15 consecutive days at 30 minutes each, then once a week for seven weeks.

Lexapro was taken daily for three weeks, after which the daily dose was increased from 10 milligrams (mg) to 20 mg for the next seven weeks.

After 10 weeks, patients receiving brain stimulation fared no better than those taking Lexapro. Patients receiving brain stimulation, however, suffered from more side effects, the researchers found.

Specifically, patients receiving brain stimulation had higher rates of skin redness, ringing in the ears and nervousness than those receiving fake brain stimulation.

In addition, two patients receiving brain stimulation developed new cases of mania. That condition can include elevated mood, inflated self-esteem, decreased need for sleep, racing thoughts, difficulty maintaining attention and excessive involvement in pleasurable activities.

Patients taking Lexapro reported more frequent sleepiness and constipation.

Brunoni, however, is not ready to write off brain stimulation as a treatment for depression based on this study.

“We did not test, in this study, the combined effects of tDCS with other techniques, such as cognitive behavior therapy and other antidepressant drugs,” he said.

“Previous findings from our group showed that tDCS increases the efficacy of antidepressant drugs, however, it should not be used alone, and its use must be supervised by physicians due to the side effects,” Brunoni said.

Lisanby said the tDCS dose in the study may be in question. She said it may have to be adjusted to each individual patient in terms of how strong the electrical stimulation should be. The treatment length also needs to be individualized, as does what part of the brain it should be directed toward.

Also, “we need larger studies to give us the definitive answer about whether tDCS is better than the treatments we have today,” Lisanby said.

SOURCES: Andre Brunoni, M.D., Ph.D., director, Service of Interdisciplinary Neuromodulation, University of Sao Paulo, Brazil; Sarah Lisanby, M.D., director, Division of Translational Research, U.S. National Institute of Mental Health; June 29, 2017, New England Journal of Medicine

Source: Electric Brain Stimulation No Better Than Meds For Depression: Study: MedlinePlus Health News

, , ,

Leave a comment

[BLOG POST] UCLA offers transcranial magnetic stimulation to treat patients with depression

Download PDF Copy

Americans spend billions of dollars each year on antidepressants, but the National Institutes of Health estimates that those medications work for only 60 percent to 70 percent of people who take them. In addition, the number of people with depression has increased 18 percent since 2005, according to the World Health Organization, which this year launched a global campaign encouraging people to seek treatment.

The Semel Institute for Neuroscience and Human Behavior at UCLA is one of a handful of hospitals and clinics nationwide that offer a treatment that works in a fundamentally different way than drugs. The technique, transcranial magnetic stimulation, beams targeted magnetic pulses deep inside patients’ brains — an approach that has been likened to rewiring a computer.

TMS has been approved by the FDA for treating depression that doesn’t respond to medications, and UCLA researchers say it has been underused. But new equipment being rolled out this summer promises to make the treatment available to more people.

“We are actually changing how the brain circuits are arranged, how they talk to each other,” said Dr. Ian Cook, director of the UCLA Depression Research and Clinic Program. “The brain is an amazingly changeable organ. In fact, every time people learn something new, there are physical changes in the brain structure that can be detected.”

Nathalie DeGravel, 48, of Los Angeles had tried multiple medications and different types of therapy, not to mention many therapists, for her depression before she heard about magnetic stimulation. She discussed it with her psychiatrist earlier this year, and he readily referred her to UCLA.

Within a few weeks, she noticed relief from the back pain she had been experiencing; shortly thereafter, her depression began to subside. DeGravel says she can now react more “wisely” to life’s daily struggles, feels more resilient and is able to do much more around the house. She even updated her resume to start looking for a job for the first time in years.

During TMS therapy, the patient sits in a reclining chair, much like one used in a dentist’s office, and a technician places a magnetic stimulator against the patient’s head in a predetermined location, based on calibrations from brain imaging.

The stimulator sends a series of magnetic pulses into the brain. People who have undergone the treatment commonly report the sensation is like having someone tapping their head, and because of the clicking sound it makes, patients often wear earphones or earplugs during a session.

TMS therapy normally takes 30 minutes to an hour, and people typically receive the treatment several days a week for six weeks. But the newest generation of equipment could make treatments less time-consuming.

“There are new TMS devices recently approved by the FDA that will allow patients to achieve the benefits of the treatment in a much shorter period of time,” said Dr. Andrew Leuchter, director of the Semel Institute’s TMS clinical and research service. “For some patients, we will have the ability to decrease the length of a treatment session from 37.5 minutes down to 3 minutes, and to complete a whole course of TMS in two weeks.”

Leuchter said some studies have shown that TMS is even better than medication for the treatment of chronic depression. The approach, he says, is underutilized. “We are used to thinking of psychiatric treatments mostly in terms of either talk therapies, psychotherapy or medications,” Leuchter said. “TMS is a revolutionary kind of treatment.”

Bob Holmes of Los Angeles is one of the 16 million Americans who report having a major depressive episode each year, and he has suffered from depression his entire life. He calls the TMS treatment he received at UCLA Health a lifesaver.

“What this did was sort of reawaken everything, and it provided that kind of jolt to get my brain to start to work again normally,” he said.

Doctors are also exploring whether the treatment could also be used for a variety of other conditions including schizophrenia, epilepsy, Parkinson’s disease and chronic pain.

“We’re still just beginning to scratch the surface of what this treatment might be able to do for patients with a variety of illnesses,” Leuchter said. “It’s completely noninvasive and is usually very well tolerated.”

Source: UCLA offers transcranial magnetic stimulation to treat patients with depression

, , , ,

Leave a comment

[ARTICLE] Pharmacological interventions for traumatic brain injury – Full Text 

Psychostimulants, antidepressants, and other agents may speed the recovery of patients suffering from the functional deficits that follow an insult to the brain.

Traumatic brain injury is common in North America and has dramatic and wide-ranging effects on survivors’ quality of life. Those who survive traumatic brain injury may experience anxiety, agitation, memory impairments, and behavioral changes. When managing the immediate and long-term consequences of such injuries, clinicians have many pharmacological options, including psychostimulants, antidepressants, antiparkinsonian agents, and anticonvulsants. These and other agents can play a role in managing the neuropsychiatric, neurocognitive, and neurobehavioral sequelae of injury to the brain.

Traumatic brain injury (TBI) is commonly defined as an insult to the brain from an external force that causes temporary or permanent impairment in functional, psychosocial, or physical abilities.1 It is a significant cause of morbidity and mortality, and the leading cause of death and disability among young adults.

Common causes of TBI include motor vehicle accidents, falls, sports injuries, and violence,[1] and it is recog­nized increasingly in war zone injury.[2] In the US, approximately 2 million people will sustain a TBI each year, one-quarter of whom will require hospitalization, leading to a conservative estimate of direct and indirect costs of $50 billion to $100 billion annually.[3]

With advances in the management of head trauma, an increasing number of patients are surviving with residual neurological impairments. A National Institute of Health panel estimates that 2.5 to 6.5 million Americans currently live with TBI-related disabilities.[4]

The effective treatment of TBI requires input from multiple disciplines and professions starting at the time of injury and continuing through the rehabilitation phase.

Despite the prevalence and cost of TBI-related disabilities there is a paucity of literature reviewing modern approaches to pharmacotherapy. There is, however, growing evidence that medications may speed recovery by enhancing some neurological functions without impact­ing others.

Pharmacotherapy is in­creasingly being used in both the subacute (less than 1 month post-TBI) and chronic (more than 1 month post-TBI) phases.

Disabilities arising from TBI that have a direct impact on functioning and rehabilitative potential can be broadly classified into four main categories: decreased level of consciousness (LOC), and neuropsychiatric, neurocognitive, and neurobehavioral sequelae.5-8 Decreased level of consciousness refers to a diverse range of clinical states including coma, vegetative states, akinetic mutism, and locked-in states.

Neuropsychiatric symp­toms may present as mood disorders, posttraumatic stress disorder, and personality changes characterized by disinhibition and egocentricity. Neurocognitive injuries vary, but most frequently involve impaired attention, memory, and executive functioning.

Neurobehavioral deficits distinct from neuropsychiatric sequelae may take the form of irritability, hyperexcitability, nervousness, disinhibition, poor impulse control, restlessness, and aggression, with aggression and agitation seen in as many as 30% of brain-injured patients.[5-8]

Depending on the location of in­jury, damage can occur to a variety of neurotransmitter networks critical to cognitive processes. Investigation has focused on the loss of dopaminergic neurons that regulate executive functioning, as well as deficits in norepinephrine and acetylcholine, which limit attention—a critical function for effective rehabilitation.[9]

Fortunately, a number of pharmacological interventions show promise in helping patients cope with these losses and deficits.

Although insufficient evidence exists to establish guidelines for optimal pharmocotherapy, medications may be used to support recovery. Examples are shown in the accompanying Table, which summarizes the pharmacological approaches discussed in more detail below.

When problematic TBI symptoms are identified, clinicians can use this information to determine pharmacological options and integrate them with nonpharmacological options such as physical therapy, occupational therapy, physiatry, and the patient’s support network.

Planning a pharmacological intervention strategy
The decision to use pharmacological intervention should be the result of multidisciplinary collaboration and made with the patient or his or her substitute decision maker. Goals of therapy should be clarified, and outcomes and adverse events should be reliably tracked, particularly so medications that are ineffective or cause adverse events can be discontinued and unnecessary polypharmacy can be avoided.

Selecting the most appropriate agent requires careful analysis of the neurological disabilities present, the nature of the underlying lesion, and the time elapsed since the injury.

Psychostimulants
Psychostimulants such as methylpheni­date are most commonly used to treat attention deficit hyperactivity disorder (ADHD), a condition that involves problems with executive functioning and can be characterized as similar to brain injury both in terms of symptoms and neurotransmitter aberrations.[10]

Although the complete mechanism of action of methylphenidate remains unknown, this agent is thought to bind dopamine transporters, thereby blocking reuptake and increasing extracellular dopamine levels, particularly in the frontal cortex.[11] It is also thought to increase norepinephrine and serotonin levels.

In the majority of studies, methylphenidate has been administered  twice daily, either at a fixed dose of 10 to 15 mg or at a dose of 0.3 mg/kg.[12-15]

In the acute phase after a TBI, methylphenidate-treated patients dem­onstrated better attention, concentration, and performance on motor memory tasks at 1 month, but these benefits did not persist at 3 months. Thus, it has been suggested that while methyl­phenidate may shorten recovery time, it does not change morbidity.[12]

In the chronic phase after a TBI, patients have reported improvements in mood, work performance, and alertness, with more limited evidence suggesting an improvement of fluency and selective attention.

The impact of methylphenidate on chronic attention is more ambiguous: one study suggests improvement in long-term processing speed and attention to tasks but not increased sustained attention or decreased susceptibility to distraction.[12]

Two separate studies have suggested methylphenidate is effective in the treatment of agitation and sei­zures,[16,17] while another demonstrated no neurobehavioral benefit.[18]

Despite the accumulation of controlled clinical trials, there is no consensus on the use of stimulants in treating TBI-induced impairments in arousal and motor activity.

It should be noted that one recent review concluded “at present there is insufficient evidence to support routine use of methylphenidate or other amphetamines to promote recovery from TBI,”[19] while another review noted that at least 10 clinical trials have demonstrated a role for methylpheni­date in both adult and pediatric brain injury patients suffering from neurocognitive deficits, particularly in attention, memory, cognitive processing, and speech.[20]

Methylphenidate has a quick onset of action and relatively benign side effect profile, and we believe it to be useful in both the acute and chronic phase of TBI.

Antidepressants
Despite potentially severe consequenc­es, post-TBI psychiatric sequelae are underdiagnosed and undertreated. Fortunately, current evidence suggests that antidepressants can be used to manage both neuropsychiatric and additional neurological deficits persisting from brain injury.

Selective serotonin reuptake inhi­bitors (SSRIs) have been found useful in treating behavioral syndromes in TBI patients, particularly in the subacute stages of recovery[21] but also in chronic settings.

The majority of studies suggest that SSRIs improve neurobehavioral, neurocognitive, and neuropsychiatric deficits, specifically agitation, depression, psychomotor retardation, and recent memory loss; however, most data originates from nonrandomized trials.

Sertraline administered at an average dose of 100 mg daily for 8 weeks has been found to be beneficial for agitation, depressed mood, and deficits in psychomotor speed and recent memory; shorter treatment durations have demonstrated no benefit.[21]

Similarly, 60 mg daily of fluoxetine for 3 months was shown to be effective in the treatment of obsessive-compulsive disorder caused by brain injury.[22] Finally, paroxetine or citalopram, at a dose of 10 to 40 mg daily, was shown by another study to be equally effective in the treatment of pathological crying.[23] None of the re­viewed studies addressed neurocognitive deficits.

The highest concentration of serotonergic and adrenergic fibres is located near the frontal lobes, the most common site of traumatic contusion.[24]

Consequently, these fibres are commonly injured in TBI, suggesting that newer antidepressants with effects on both norepinephrine and serotonin, such as mirtazapine and venlafaxine, may also be effective in the treatment of TBI sequelae; however, clinical data with these agents in TBI is lacking.

Similarly, bupropion increases both dopamine and norepinephrine levels and is a weak inhibitor of serotonin reuptake. At 150 mg daily, this agent has been useful in treating restlessness.[25]

Antiparkinsonian drugs
The antiparkinsonian drugs amantadine, bromocriptine, and levodopa combined with carbidopa (e.g., Sine­met) have varied mechanisms of action, but all ultimately serve to increase dopamine levels in the brain.

Amantadine acts presynaptically to enhance dopamine release or inhibit its reuptake, and can act postsynaptically to increase the number, or alter the configuration of, dopamine re­ceptors.[26] It is also a noncompetitive NMDA receptor antagonist and may provide protection against possible glutamate-mediated excitotoxicity in the context of TBI.[27]

Bromocriptine is a dopamine receptor agonist affecting primarily D2 receptors and to a lesser extent D1 receptors.[28] The use of levodopa and carbidopa in combination directly increases dopamine levels: levodopa becomes dopamine once de­carboxylated, while carbidopa inhibits L-amino decarboxylase, allowing levodopa to reach the central nervous system.[28]

Multiple studies of amantadine at a dose of 100 to 300 mg daily have suggested its effectiveness in both the acute and chronic care phases after TBI, particularly in diffuse, frontal, or right-sided brain injury.

Currently, the evidence suggests neurocognitive or neurobehavioral deficits, particularly cognition difficulties and agitation, are primary indications for amantadine use.[26,29,30]

Amantadine-treated patients demonstrated improvements in motivation; decreased level of apathy; increased attention, concentration, and alertness; improved executive functioning; decreased processing time; reduced agitation, distractibility, fatigue, aggression, and anxiety.

In addition, patients treated with amantadine demonstrated changes in outcome LOC, specifically improved arousal and LOC as measured by the Glasgow Coma Scale. Interestingly, one study also suggested decreased mortality.[31] To date, no study has shown an improvement in memory.

Three case reports using 5 to 45 mg of bromocriptine daily,[32] and one study using a combination of 100 mg of bromocriptine with 100 mg of ephedrine,[33] showed improvement in akinetic mutism, while another study using 5 mg of bromocriptine combined with sensory stimulation led to improvements in patients with vegetative or minimal consciousness.[34]

The evidence is similarly limited for levidopa and carbidopa medications where nonrandomized studies suggest that they might be useful in the chronic phase of TBI with diffuse injury and persistent vegetative state.[35]

Combining agents has also been tried in one study that found improvements in neuropsychiatric deficits with the daily administration of 25 mg/200 mg of levodopa/carbidopa three times daily, 250 mg of amantadine, and 5 mg of bromocriptine twice daily.[36]

Anticonvulsants
Anticonvulsants have been used with varying results for treating symptoms of TBI. Valproic acid, for example, enhances inhibitory control mediated by the neurotransmitter GABA, thereby promoting general central nervous system stabilization, but findings thus far have been mixed.

Investigations utilizing 600 to 2250 mg of valproic acid daily (resulting in serum levels of 40 to 100 µg/mL), have demonstrated positive neurocognitive effects, in­cluding improved recent memory and problem-solving, as well as ameliorating neuropsychiatric and neuro­behavioral symptoms such as depression, mania, destructive and aggressive behavior, restlessness, disinhibition, impulsivity, lability, and alertness.[37-41]

Conversely, one control­led trial found valproic acid negatively impacted decision-making speed, and another suggested an increased mortality rate with valproic acid use.[37-41]

Other agents
Modafinil is a vigilance-promoting drug commonly used to treat narcolepsy and idiopathic hypersomnia, illnesses that can present with symptoms similar to those seen in TBI: excessive daytime sleepiness, inattention, and decreased ability to perform social activities.

The precise mechanism of action remains unknown, although it is believed that modafinil can inhibit GABA or increase glutamate levels in the nondopaminergic anterior hypothalamus, hippocampus, and amygdale.[42,43]

Two studies that investigated the role of modafinil in chronic TBI showed an improvement in neurocognitive deficits, specifically memory and attention, as well as improving daytime somnolence at doses between 100 and 400 mg.[44,45]

Four randomized control trials examining the use of beta-blockers, specifically propranolol and pindolol, have demonstrated beneficial effects on neurobehavioral symptoms of ag­gression and agitation in both the chronic and subacute phase. This class of drugs deserves further attention for the management of both neuropsychiatric and neurobehavioral sequelae of TBI.[46]

Neuroleptics are being used in­creasingly in the setting of delirium, and one might consider using them in an attempt to allow the brain to recalibrate neurotransmitter levels. However, it should be noted that there is some evidence that dopamine blockade may negatively affect recovery.[47,48]

There are also a number of animal studies examining drugs that have the potential to adversely affect brain recovery following TBI. These studies typically use a stroke model, so generalizing to TBI may not be possible.

Nevertheless, the evidence currently does not support the use of neuro­leptics, benzodiazepines, phen­y­toin, prazosin, trazodone, and similar agents because of their potential adverse effect on recovery, presumably through the impacts they have on neurotransmitters such as dopamine, norepinephrine, or GABA.[49-51]

Preliminary evidence suggests cho­linesterase inhibitors such as don­epezil may improve long-term cognitive outcomes, particularly in domains such as memory and attention when administered early, and further in­vestigation with these agents is also warranted.[52,53]

Finally, antiandrogenic medications, such as estrogen and medroxyprogesterone, may have a role to play in reducing inappropriate sexual be­havior in patients with TBI. In a case study and one small trial, these drugs demonstrated effectiveness.[54]

Summary
The nature of TBI sequelae, whether psychiatric, cognitive, or behavioral, is poorly understood. Likewise, the use of pharmacological interventions to improve symptoms, function, and outcome is still under development.

There are, however, a number of agents that inspire optimism. When treating neurological deficits medically, there is evidence to support the tailored use of these agents for particular TBI clinical scenarios. The timing and nature of symptoms, along with wheth­er agents are administered in the acute or chronic phase after TBI, are all relevant factors for determining proper use.

With insufficient evidence to establish guidelines for optimal treatment, care must be taken when choosing pharmacological interventions for TBI.

If the decision is made to use medications to promote TBI recovery or treat its attendant disabilities, clinicians should thoroughly document the goals of pharmacotherapy and closely monitor for side effects. Future studies will undoubtedly add to the clinician’s armamentarium for the care of TBI patients.

Competing interests
None declared.


ReferencesTop

1. Bruns J Jr, Hauser WA. The epidemiology of traumatic brain injury: A review. Epilepsia 2003;44:2-10.
2. Okie S. Traumatic brain injury in the war zone. N Engl J Med 2005;352:2043-2047.
3. Thurman DJ, Alverson C, Dunn KA, et al. Traumatic brain injury in the United States: A public health perspective. J Head Trauma Rehabil 14 1999;14:602-615.
4. Woo BH, Nesathurai S (eds). The rehabilitation of patients with traumatic brain injury. Malden, MA: Blackwell Science; 2000:5-12.
5. Bricolo A. Prolonged posttraumatic coma, In: Vinken PJ, Bruyn GW (eds). Handbook of clinical neurology Amsterdam: Elsevier; 1976:699-755.
6. O’Dell MW, Riggs RV. Management of the minimally responsive patient. In: Horn LJ (ed). Medical rehabilitation of traumatic brain injury. Philadelphia: Hanley and Belfus; 1996:103-131.
7. Salmond CH, Sahakian BJ. Cognitive outcome in traumatic brain injury survivors. Curr Opin Crit Care 2005;11:111-116.
8. Hellawell DJ, Taylor RT, Pentland B. Cognitive and psychosocial outcome following moderate or severe traumatic brain injury. Brain Inj 1999;13:489-504.
9. Arciniegas DB, The cholinergic hypothesis of cognitive impairment caused by traumatic brain injury. Curr Psychiatry Rep 2003;5:391-399.
10. Evans RW, Gualtieri CT. Psychostimulant pharmacology in traumatic brain injury. J Head Trauma Rehabil 1987;2:29-33.
11. Challman T, Lipsky J. Methylphenidate: Its pharmacology and uses. Mayo Clin Proc 2000;75:711-721.
12. Whyte J, Hart T, Schuster K, et al. Effects of methylphenidate on attentional function after traumatic brain injury. Am J Phys Med Rehabil 1997;76:440-450.
13. Kaelin C, Cifu D, Matthies B. Methyl­phenidate effect on attention deficit in the acutely brain-injured adult. Arch Phys Med Rehabil 1996;77:6-10.
14. Speech T, Rao S, Osmon D, et al. A double blind controlled study of methylphen­idate treatment in closed head injury. Brain Inj 1993;7:333-338.
15. Plenger P, Dixon E, Castillo R, et al. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: A preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil 1996;77:536-540.
16. Mooney G, Haas L. Effect of methyl­phen­i­date on brain injury-related anger. Arch Phys Med Rehabil 1993;74:153-160.
17. Wroblewski B, Leary J, Phelan A, et al. Methylphenidate and seizure frequency in brain injured patients with seizure disorders. J Clin Psychiatry 1992;53:86-89.
18. Evans R, Gualtieri T, Patterson D. Treatment of chronic closed head injury with psychostimulant drugs: A controlled case study and an appropriate evaluation procedure. J Nerv Ment Dis 1987;175:110.
19. Forsyth R, Jayamoni B. Noradrenergic agonists for acute traumatic brain injury. Cochrane Database Syst Rev 2003;(1):CD003984.
20. Siddall OM, Use of methylphedinate in traumatic brain injury. Ann Pharmacother 2005;39:1309-1313.
21. Meythaler J, Lawrence D, Devivo M, et al. Sertraline to improve arousal and alertness in severe traumatic brain injury secondary to motor vehicle crashes. Brain Inj 2000;15:321-331.
22. Stengler-Wenzke K, Muller U. Fluoxetine for OCD after brain injury. Am J Psychiatry 2002;159:872.
23. Muller U, Mural T, Bauer-Wittmund T, et al. Paroxetine versus citalopram treatment of pathological crying after brain injury. Brain Inj 1999;13:808-811.
24. De Marchi R, Bansal V, Hung A, et al. Review of awakening agents. Can J Neurol Sci 2005;32:4-17.
25. Teng C, Bhalerao S, Lee A, et al. The use of buproprion in the treatment of restlessness after a traumatic brain injury. Brain Inj 2001;15:463-467.
26. Schneider W, Drew-Cates J, Wong T, et al. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: An initial double-blind placebo-controlled study. Brain Injury 1999;13:863-872.
27. Kraus M, Maki P. The combined use of amantadine and l-dopa/carbidopa in the treatment of chronic brain injury. Brain Inj 1997;11:455-460.
28. Zafonte R, Lexell J, Cullen N. Possible applications for dopaminergic agents following traumatic brain injury: Part 1. J Head Trauma Rehabil 2000;15:1179-1182.
29. Meythaler J, Brunner R, Johnson A, et al. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: A pilot double-blind randomized trial. J Head Trauma Rehabil 2002;31:300-313.
30. Zafonte R, Watanabe T, Mann N. Amantadine: A potential treatment for the minimally conscious state. Brain Inj 1998;12:617-621.
31. Saniova B, Drobny M, Kneslova L, et al. The outcome of patients with severe head injuries treated with amantadine sulphate. J Neur Transm 2004;111:511-514.
32. Crismon M, Childs A, Wilcox R, et al. The effect of bromocriptine on speech dysfunction in patients with diffuse brain injury (akinetic mutism). Clin Neuropharmacol 1988;11:462-466.
33. Anderson B. Relief of akinetic mutism from obstructive hydrocephalus using bromocriptine and ephedrine. J Neurosurg 1992;76:152-155.
34. Passler M, Riggs R. Positive outcomes in traumatic brain injury-vegetative state: Patients treated with bromocriptine. Arch Phys Med Rehabil 2001;82:311-315.
35. Haig A, Ruess J. Recovery from vegetative state of six months’ duration associated with Sinemet (levodopa/carbidopa). Arch Phys Med Rehabil 1990;71:1081-1082.
36. Karli D, Burke D, Kim H, et al. Effects of dopaminergic combination therapy for frontal lobe dysfunction in traumatic brain injury rehabilitation. Brain Inj 1999;13:63-68.
37. Wroblewski B, Joseph A, Kupfer J, et al. Effectiveness of valproic acid on destructive and aggressive behaviours in pa­tients with acquired brain injury. Brain Inj 1997;11:37-47.
38. Massagli T. Neurobehavioral effects of phenytoin, carbamazepine, and valproic acid: Implications for use in traumatic brain injury. Arch Phys Med and Rehabil 1991;72:219-225.
39. Dikmen S, Machamer J, Winn H, et al. Neuropsychological effects of valproate in traumatic brain injury. Neurology 2000;54:895-902.
40. Chatham-Showalter P, Kimmel DN. Agitated symptom response to divalproex following acute brain injury. J Neuropsychiatry Clin Neurosci 2000;12:395-397.
41. Kim E, Humaran T. Divalproex in the management of neuropsychiatric complications of remote acquired brain injury. J Neuropsychiatry Clin Neurosci 2002;14:202-205.
42. Lin J, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos im­muno­cytochemistry in the cat. Proc Natl Acad Sci U S A 1996;93:14128-14133.
43. Ferraro L, Antonelli T, Tanganelli S. The vigilance promoting drug modafinil in­creases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: Prevention by local GABAA receptor blockade. Neuropsychopharmacology 1999;20:346-356.
44. Saletu B, Saletu M, Grunberger J, et al. Treatment of the alcoholic organic brain syndrome: Double-blind, placebo-controlled clinical, psychometric and electroencephalographic mapping studies with modafinil. Neuropsychobiology 1993;27:26-39.
45. Teitelman E. Off-label uses of modafinil. Am J Psychiatry 2001;158:1341.
46. Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev 2003;(1):CD003299.
47. Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol and experience interact to affect the rate of recovery after motor cortex injury. Science 1982;217:855-857.
48. Goldstein LB. Common drugs may influence motor recovery after stroke. Neurology 1995;45:865-872.
49. Schallert T, Hernandez T, Barth T. Recovery of function after brain damage: Severe and chronic disruption by diaze­pam. Brain Res 1986;379:104-111.
50. Brailowsky S, Knight RT, Efron R. Phenytoin increases the severity of cortical hemiplegia in rats. Brain Res 1986;376:71-77.
51. Goldstein LB. Influence of common drugs and related factors on stroke outcome. Curr Opin Neurol 1997;10:52-57.
52. Zhang L, Plotkin RC, Wang G, et al. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil 2004;85:1050-1055.
53. Walker W, Seel R, Gibellato M, et al. The effects of donepezil on traumatic brain injury acute rehabilitation outcomes. Brain Inj 2004;18:739-750.
54. Levy M, Berson A, Cook T, et al. Treatment of agitation following traumatic brain injury: A review of the literature. NeuroRehabilitation 2005;20:279-306.

Source: Pharmacological interventions for traumatic brain injury | BC Medical Journal

, , , , , , , , , ,

Leave a comment

[WEB SITE] The Secret Sadness of Pregnancy With Depression

At the beginning of spring in 2013, Mary Guest, a lively, accomplished 37-year-old woman, fell in love, became pregnant and married after a short courtship. At the time, Mary taught children with behavioral problems in Portland, Ore., where she grew up. Her supervisor said that he had rarely seen a teacher with Mary’s gift for intuiting students’ needs. “Mary was a powerful person,” he wrote to her mother, Kristin. “Around Mary, one felt compassion, drive, calmness and support.”

Mary had struggled with depression for much of her life. Starting in her 20s, she would sometimes say to Kristin that she just wanted to die. “She would always follow up by saying, ‘But you don’t need to worry, Mama,’ ” Kristin told me. “ ‘I don’t have a plan, and I don’t intend to do anything.’ ” In recent years, Mary and her mother went for a walk once a week, and Mary would describe the difficulties she was having. She was helped somewhat by therapy and by antidepressant and antianxiety medications, which blunted her symptoms.

Mary’s friends appreciated her wacky sense of humor and her engaging wit. Colleagues said that her moods never impinged on her work; in fact, few of them knew what she was dealing with. Yet for years Mary worried that she would never be in a stable relationship and experience love or a family of her own. She said plaintively to Kristin, “I think I would be a really good mother.”

Continue—>  The Secret Sadness of Pregnancy With Depression – NYTimes.com.

, ,

Leave a comment

[WEB SITE] Brain stimulation offers hope for depression, but don’t try it at home.

OPINION: Around 350 million people worldwide have depression. Antidepressant medications are often prescribed to treat the condition, alongside talking therapies and lifestyle changes such as regular exercise.

But a substantial proportion of people either don’t respond to antidepressants, or experience such significant side effects that they’d prefer not to take them.

In search of alternative solutions, researchers around the world, including our team, are investigating transcranial direct current stimulation (TDCS) as an alternative treatment for depression. But this isn’t something you can safely try at home.

Unlike electroconvulsive therapy, TDCS uses very mild electric current to stimulate the brain and has few side effects. The mechanics of TDCS are quite simple, involving a battery, two leads and the electrodes through which the current is passed.

The stimulation works by changing the activity of nerve cells in the brain. In depression, the left frontal areas of the brain are often less active than usual. TDCS stimulates this area to restore brain activity.

We’re still evaluating the effectiveness of TDCS, but so far studies have found that TDCS works better than a placebo (or simulated treatment) at reducing symptoms of depression.

When combined with the antidepressant medication sertraline (marketed as Zoloft in Australia), the combination TDCS-drug therapy works better than medication or TDCS alone.

Research has found that among people with depression, a course of TDCS can improve the brain’s “neuroplasticity”, which is the brain’s ability to learn and adapt to changes in the environment.

The therapy has a good safety profile – if administered by clinicians and researchers trained in stimulation technique and safety. Our research team has administered thousands of TDCS sessions without incident.

But this is not the case when TDCS is used in the “DIY” context, with DIY users trying to stimulate their own brains.

This phenomenon is often guided by online forums and websites dedicated to DIY TDCS. Users comment on their own experience and share tips on how TDCS can be used to treat their own depression. People with no medical training and limited understanding of TDCS self-treat their depression and advise others on treatment.

So, what can go wrong?

The most obvious concern is that poor technique and improper electrode placement could cause skin burns.

What’s more concerning is the ability for TDCS to produce lasting changes in brain functioning. Depending on how TDCS is given, these changes could be good or bad.

A DIY user could, for example, cause lasting impairment to their thinking and memory. For people with severe depression, incorrect application could worsen their condition or induce a hypomanic (manic) episode.

When it comes to medications, it’s important to get the right dose and dosing schedule. That’s why this role falls to qualified clinicians and researchers. The same goes for TDCS: current intensity, electrode size and position, and the duration and frequency of the stimulation determine the effects in the brain.

The relationship between dosing, intensity and position is highly complex. This isn’t a simple case of “the stronger the better”. Even researchers are yet to fully understand the effects of varying stimulation approaches and much more research is needed.

As with other forms of treatment, TDCS is not suitable for everyone. In clinical research trials, participants are screened for suitability to receive stimulation and their likelihood of responding to treatment. The stimulation is carefully controlled and the participants’ mood is carefully monitored during and after the course of treatment.

TDCS represents a promising future, where simple and cost-effective treatment for depression is possible, without drugs. Researchers worldwide are continuing to study this experimental treatment, which may one day become a conventional treatment for depression.

The acceptance and popularity of TDCS among the general community is encouraging. But TDCS is still experimental and isn’t safe to administer at home. DIY users are not trained in proper technique nor are they trained to identify, prevent or deal with unexpected outcomes.

If you’re interested in participating in our TDCS trials for depression, contact the research team at the Black Dog Institute for more information.

Kerrie-Anne Ho is a PhD candidate in non-invasive brain stimulation at UNSW.

Colleen Loo is a Professor of Psychiatry at UNSW.

This opinion piece was first published in The Conversation.

via Health News – Brain stimulation offers hope for depression, but don’t try it at home.

, , , , , , , , , , ,

Leave a comment

%d bloggers like this: