Abstract
Ketamine followed by memantine for the treatment of major depression
Recent clinical studies indicate that N-methyl-D-aspartate antagonists such as ketamine [1] and memantine [2] might represent a treatment option for depressive disorders. However, the long-lasting therapeutic effects of ketamine have not been proven, and because it is an addictive psychomimetic drug it is not suited for continuous treatment [1]. In contrast, memantine produces minor side-effects and can be administered orally. Memantine does not produce psychomimetic side-effects in healthy volunteers and depressive patients when applied in clinical dosages [2]. Still, the antidepressive effects of memantine remain controversial. We report the first case of a patient suffering from major depressive disorder (MDD) treated successfully by a two-step therapeutic regimen consisting of two infusions of ketamine followed by oral administration of memantine.
A 47-year-old woman was admitted to University of Erlangen-Nürnberg Hospital due to severe depressive episode and had tried to commit suicide at least 10 times within the last 2 months at another hospital. All pharmacological treatment failed and even electroconvulsive treatment had elicited only partial improvement of affective symptoms, but had led to prolonged neuropsychological dysfunction. Therefore, we decided to treat the patient using an i.v. infusion of ketamine hydrochloride (Ketamine S, Abbott Laboratories, North Chicago, IL, USA) 0.5 mg kg−1 over a period of 40 min according to the protocol described by Zarate et al. [1]. After the first infusion the Beck Depression Inventory (BDI) score decreased to zero, but rapidly increased to the pre-therapeutical state on day 4 after infusion and remained stable. Similar results were observed for the 17-item Hamilton Depression Rating Scale (HDRS). Because of the lack of therapeutic options and the transient effect of ketamine, we started a second infusion 2 weeks later at the same dosage. This time, the BDI and HDRS normalized on day 1 and remained improved the following days. However, we could not observe any further improvement of the depressive symptoms. Trying to avoid repeated infusions of ketamine because of its addictive properties, we added 5 mg memantine to the medication per day. We increased the dosage to 15 mg day−1 over the following 4 weeks [3]. The major symptoms of depression disappeared as indicated by a stable BDI of 5 and a HDRS of 7. The patient could be discharged after 13 weeks with the following medication: memantine 15 mg day−1, duloxetine 90 mg day−1, olanzapine 15 mg day−1, lorazepam 1 mg day−1, venlafaxine 300 mg day−1, mirtazapine 90 mg day−1, and lamotrigine 200 mg day−1. The psychiatric status has remained stable over a period of 6 months.
Benzodiazepines and the treatment of anxiety disorders in patients with comorbid alcohol and/or drug abuse
Benzodiazepines were developed in the 1950s as a safer alternative to barbiturates. The first benzodiazepine, chlordiazepoxide, was introduced in 1961. After this a number of similar substances were released. Benzodiazepines are now among the most widely prescribed anxiolytic and hypnotic medications due to their effectiveness in relieving anxiety and insomnia [1], [2]. The prevalence of benzodiazepine use in population-based studies varies from 2% to 10% of the adult population. The use of benzodiazepines increases with age and is more common among women than men. Of the total users of benzodiazepines 15–30% are reported to be continuous users.
Anxiety disorders can cause profound individual distress. The significant impairment of quality of life, along with the chronicity of the condition, highlights the importance of long-term treatment of anxiety disorders. Benzodiazepines have a primary role in the treatment of panic disorder, generalized anxiety disorder, specific phobia, and social anxiety disorder in circumstances when immediate relief is of utmost importance or as-needed use is preferred [3–5]. The best data supporting longer term benzodiazepines use are in panic disorder, generalized anxiety disorder and social anxiety disorder. For some patients, long-term benzodiazepines (in low or high doses) are far more effective and better tolerated than selective serotonin re-uptake inhibitors (SSRIs).
SSRIs are generally the first choice for standing dose treatment because they lack risks of abuse and have less risk of physical dependence, and are easier to prescribe because they are not controlled substances. Some concerns have been raised that long-term benzodiazepines may cause increasing cognitive deficits. Nobody has been on SSRIs for 40 years yet, so we can only guess at the risks of this alternative.
Although it is preferable not to prescribe benzodiazepines or other sedative hypnotics as a first choice to treat psychiatric disorders in patients with a history of current alcohol or drug use disorders, this is not an absolute contraindication. Benzodiazepines are useful for detoxification from alcohol and from opioids, and patients with anxiety disorder or insomnia resistant to other treatments can often be treated safely along with careful monitoring for the emergence of signs of abuse or dependence.
While using benzodiazepines in current or recent alcohol/drug users may be best left for addiction psychiatrists, most patients with a distant history can be safely treated in the general psychiatric practice provided that patients are (i) advised of the risk of combining sedative–hypnotic medications with alcohol and other drugs of abuse; (ii) warned about diversion; (iii) given safer medications (more selective agonists such as zolpidem or medications with slower onset of action and longer duration of effect such as oxazepam or clonazepam); and (iv) monitored for adverse effects (e.g. excessive sedation) and for any indications of inappropriate use (e.g. dose escalation, use to achieve euphoria). Red flags for misuse or diversion include demands for a particular (usually fast-acting) medication, repeated lost prescriptions, discordant pill count, and excessive preoccupation with securing medication supply. In summary, benzodiazepines can be used for the treatment of anxiety disorders comorbid with alcohol and/or drug abuse.
‘Moans, stones, groans, bones and psychiatric overtones’: lithium-induced hyperparathyroidism
Lithium is the mainstay of treatment in the acute and maintenance phases of bipolar affective disorder. It is an effective augmentation strategy in treatment-resistant depression and has anti-suicidal effects. But Lithium has significant metabolic and endocrine adverse effects. With regards to the endocrine effects, hypothyroidism is the best recognized. Another important side-effect is lithium-induced hyperparathyroidism leading to hypercalcaemia, which has a range of psychological and potentially serious physical manifestations.
We provide a short description of two cases of lithium-induced hyperparathyroidism after long-term lithium use that have been managed at Wyong Psychiatric Emergency Care Centre, Wyong Hospital. In the first case a 46-year-old woman who had been stable on lithium for 10 years with one previous hypomanic episode was being investigated for renal cysts when her corrected calcium levels were found to be raised (2.63 mmol L−1; normal range = 2.10–2.60 mmol L−1). Further investigations indicated raised parathyroid hormone (PTH) at 13 pmol L−1 (1.6–6.9 pmol L−1) and increased urinary calcium excretion, which confirmed the diagnosis of primary hyperparathyroidism. A renal ultrasound indicated small calculi.
Her lithium was gradually ceased without any deterioration in the mental state. This normalized the calcium level but her PTH remains elevated at 9.7 pmol L−1. Lamotrigine was considered as an alternative because she had predominant depressive episodes.
In the second case a 72-year-old woman who had been stable on lithium for 15 years was incidentally found to have elevated corrected calcium (2.77 mmol L−1) by the endocrinologist. PTH was found to be elevated at 13.7 pmol L−1. There were no secondary effects of the hyperparathyroidism in the form of reduced bone density or renal calculi. The lithium was gradually reduced. She presented to Wyong Psychiatric Emergency Care Centre, Wyong Hospital with features of mania and interspersed episodes of confusion 6 weeks after the cessation of lithium. The patient was commenced on valproate. Her corrected calcium level normalized with a moderate reduction in PTH levels albeit above normal.
Approximately 10–15% of lithium-treated patients become hypercalcaemic with laboratory evidence and symptoms of hyperparathyroidism [1]. Classically the symptoms of hyperparathyroidism are described by the rhyme: ‘moans’ (not feeling well), ‘stones’ (renal calculi), ‘groans’ (abdominal pain, constipation and gastric reflux), ‘bones’ (osteoporosis and bone pain) and ‘psychiatric overtones’ (fatigue, lethargy, depression and memory problems and confusion). The psychiatric presentation can mimic a worsening of depression or mania. In the event of a breakthrough depression or mania in patients on lithium therapy one should consider the differential of hyperparathyroidism prompting investigations for serum calcium and PTH level in addition to lithium levels, and other endocrine and metabolic parameters. Lithium-induced parathyroid dysfunction can also present with weakness, fatigue, delirium, hypertension, and arrhythmias (bradycardia, short QT interval, asystole), which requires immediate treatment. Investigations include serum corrected calcium, PTH levels, serum magnesium and phosphate, urea and electrolytes. Lithium-induced primary hyperparathyroidism shows a raised calcium and raised PTH. Low calcium should alert one to the possibility of secondary hyperparathyroidism usually due to lithium-induced nephrotoxicity. Bone scan, parathyroid scan, renal ultrasound and electrocardiogram should be done to rule out secondary effects of hyperparathyroidism.
The exact mechanism of lithium-induced hyperparathyroidism is not known. It is postulated that lithium blocks the influx of calcium into various cells. It also raises the threshold of the calcium-sensing receptor thereby affecting the feedback loop that controls parathyroid secretion. Indirectly it acts by inhibiting the action of glycogen synthase kinase 3b (GSK-3b), which in turn has an inhibitory action on PTH. Thus it releases the brake to speed up production of PTH [2]. Lithium can also cause morphological changes in the gland, leading to parathyroid hyperplasia and adenoma formation [3], which can cause persistent hyperparathyroidism despite lithium cessation.
There are no evidence-based monitoring or treatment strategies for lithium-induced hyperparathyroidism. The National Institute of Clinical Excellence guidelines (UK) and the Royal Australian and New Zealand College of Psychiatrists guidelines for bipolar disorder do not specifically mention the monitoring of calcium levels with lithium therapy [4], [5]. Some recommend that serum calcium level should be checked before commencing treatment with lithium and 6 monthly thereafter [6]. Any patient who is known to be hypercalcaemic or to have hyperparathyroidism prior to initiation of mood stabilizer therapy should not receive lithium. Patients who develop lithium-induced parathyroid dysfunction should be switched to an alternate mood stabilizer [2].
In most cases the hyperparathyroidism will resolve with cessation of lithium but in some cases surgical intervention is required, that is, parathyroidectomy [7]. There are no data on the duration or the probability of resolution. Patients who require continued lithium treatment due to the complexity of their psychiatric illness may need parathyroidectomy. The decision to continue lithium therapy in the presence of hypercalcaemia should be individualized [7]. Close liaison with an endocrinologist or physician is advisable.
Currently guidelines recommend 6 monthly monitoring of renal and thyroid functions. We believe that specific monitoring of calcium levels need to be incorporated in the existing guidelines to alert the clinician to this common and potentially serious complication of lithium treatment.
www.DoctorsHealth.com.au
‘Every female doctor of my age who I know well is taking antidepressants.’ This statement, by a young medical specialist I treated, is a concerning indicator of the effects of a medical career on the best and brightest of our population. There is no reason to believe male doctors fare any better. The suicide rate of female general practitioners is higher than that of their peers in other professions. Various medical specialties are known to have very high suicide rates.
www.DoctorsHealth.com.au is a voluntary service to the medical profession that I have initiated as a simple reference source for doctors and their families. It is designed to give doctors all around Australia information on psychiatrists and other professionals in their geographic area who are willing to treat them. Any other resources are welcome to advertise on the site, at no cost.
I am asking for any psychiatrists who are willing to treat colleagues to contact me, with a view to their contact details being provided on the site. For those who so wish, I will indicate that there are psychiatrists available, but contact details will be provided on a confidential basis only.
The distress and stigma of psychiatric illness can be minimized if our medical colleagues have an effective anonymous way of seeking help. I trust readers will be able to help. My email address is davidhorgan@email.com
Very limited role of psychiatry in late termination
At the conclusion of an excellent review of the role of psychiatry in late termination, Morris and Orr suggest that ‘it is timely for psychiatrists to consider their position on the discipline's involvement in the process’ [1]. They are right. If psychiatrists do not determine their position it is possible that legislators will do it for them. Without clear guidance from the profession, future law makers may mandate psychiatric review for any woman seeking a late termination of pregnancy. We believe that psychiatrists should have no routine role in the procedure.
Psychiatry often finds itself heavily involved in issues that are ethically controversial: the duty to warn, euthanasia and psychosurgery, for example. Such involvement is justified when the areas concerned are either a part of psychiatry or when a psychiatrist's skill and knowledge base will contribute to better understanding of the issues. The fact that an issue is ethically challenging is, by itself, however, not reason enough for psychiatry's involvement. Psychiatrists are not ethicists; but the frequent overlap of psychiatric and ethical interest occasionally leads to role confusion.
Termination of pregnancy remains a hot ethical topic, late termination even more so. However, as Morris and Orr ably illustrate, the psychiatric aspects of late termination are not prominent. In comparison, say, to requests for euthanasia where comorbid depression is common, there is no reason to believe that psychiatric illnesses might frequently complicate a patient's decision to undergo late termination [2]. As a routine, determining the validity of consent to late termination should be no harder than it is for any other procedure. While psychiatrists may be able to weigh the psychological risk factors and hypothesize about a patient's ability to cope, they do not routinely do this for all potentially distressing medical procedures.
There is no argument for the routine involvement of psychiatrists in late termination. Psychiatrists should be involved when there is concern that the patient is suffering from a psychiatric condition. They might be particularly useful if it is thought that the condition might be interfering with the capacity to consent or when it is thought that the procedure may significantly worsen the woman's mental state.
Psychiatry's role in late termination is, therefore, no different from its role in any termination of pregnancy and little different from its role in the rest of obstetrics and gynaecology.