Treatment Of Drug-resistant Depression Research Articles

EE77 Cost-Effectiveness Analysis of Pharmacogenetic-Guided Treatment in Drug Resistant Depression

Drug side effects and ineffectiveness are a source of morbidity, significant disability, and mortality worldwide and increase the overall cost of care. Pharmacogenetics explore a patient’s risk for drug side effects and ineffectiveness and identify the most suitable medication. This research explores cost-effectiveness and potential budget impact on the National Organization for Healthcare Services in Greece (EOPYY), of the iDNA PGx-CNS, an in vitro diagnostic pharmacogenetics test for the treatment of Drug Resistant Depression (DRD).

Ketamine as a Novel Drug for Depression Treatment.

Depression is one of the most common mental disorders. Currently used antidepressants, acting on the monoaminergic system, are insufficient for depression treatment. In recent years, potential application of NMDA receptor modulators in the treatment of drug-resistant depression has gained attention. Administration of ketamine, being a non-competitive NMDA receptor antagonist, contributes to a faster remission of symptoms. The aim of this paper is to review current studies on the use of ketamine in the treatment of drug-resistant depression, compare results of various administration methods - intravenous, intranasal or oral, as well as compare its effectiveness with that of other antidepressants. Numerous studies show the drug is effective and well tolerated, particularly in patients with increased suicidal thoughts. However, there are concerns on increasing tolerance to the drug and the possibility of implementing a long-term treatment. Oral and intranasal forms of the drug are particularly promising due to their non-invasiveness and ability to self-administer. In March 2019, S-ketamine nasal spray was registered by the FDA for the treatment of drug-resistant depression.

The use of buprenorphine in the treatment of drug-resistant depression - an overview of the studies.

There is evidence that the endogenous opioid system in the brain plays an important role in mood regulation, and disturbances in its functioning may lead to the occurrence of depressive disorders. One of the drugs that affect the endogenous opioid system in the CNS is buprenorphine. The article is areview of the studies on the effectiveness of buprenorphine used as an augmentation of antidepressant treatment. The selection of articles was made by browsing the Medline and PubMed databases with the use of key words 'buprenorphine'and 'treatment of drug-resistant depression'. The analysis included thirty one studies. The results indicate that buprenorphine may be effective in drug-resistant depression in a similar manner as other augmentation strategies added to antidepressant treatment. Co-administration of buprenorphine and samidorphan may reduce the risk of addiction without losing the antidepressant effectiveness of buprenorphine. Further methodologically correct studies in this field are needed. In addition to being a partial agonist of the µ receptor, buprenorphine is also a potent antagonist of the kappa type opioid receptors. The antagonism of µ receptors alone does not cause antidepressant effects. Antagonism towards kappa receptors may cause antidepressant effects as well as reduce the severity of anhedonia. Depressed patients who do not respond to standard antidepressant treatment may have dysfunctions of the kappa receptor that are similar to opioid addicts.

Microglia modulation through external vagus nerve stimulation in a murine model of Alzheimer's disease.

Chronically activated microglia contribute to the development of neurodegenerative diseases such as Alzheimer's disease (AD) by the release of pro-inflammatory mediators that compromise neuronal function and structure. Modulating microglia functions could be instrumental to interfere with disease pathogenesis. Previous studies have shown anti-inflammatory effects of acetylcholine (ACh) or norepinephrine (NE), which mainly activates the β-receptors on microglial cells. Non-invasive vagus nerve stimulation (nVNS) is used in treatment of drug-resistant depression, which is a risk factor for developing AD. The vagus nerve projects to the brainstem's locus coeruleus from which noradrenergic fibers reach to the Nucleus Basalis of Meynert (NBM) and widely throughout the brain. Pilot studies showed first signs of cognitive-enhancing effects of nVNS in AD patients. In this study, the effects of nVNS on mouse microglia cell morphology were analyzed over a period of 280min by 2-photon laser scanning invivo microscopy. Total branch length, average branch order and number of branches, which are commonly used indicators for the microglial activation state were determined and compared between young and old wild-type and amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice. Overall, these experiments show strong morphological changes in microglia, from a neurodestructive to a neuroprotective phenotype, following a brief nVNS in aged animals, especially in APP/PS1 animals, whereas microglia from young animals were morphologically unaffected.

The use of MR-less MNI based neuronavigation for 10 Hz rTMS depression therapy: electrophysiological and clinical implications

Repetitive transcranial magnetic stimulation (rTMS) is a popular and effective treatment for drug resistant depression. However, there is considerable variability in clinical outcomes, in previous studies and between patients. Because of high requirements for the use of fMRI based neuronavigation, many practitioners of rTMS still choose to use a standard 5 cm rule for rTMS coil placement which leads to large variations in which brain regions are being stimulated. We decided to test the possibilities of a MNI based MR‑less neuronavigation system in rTMS depression treatment, by comparing the physiological effects and clinical outcomes of 3 distinct stimulation targets. Forty‑six patients (thirty‑three female, thirteen male) from the Republican Vilnius psychiatric hospital, all with drug resistant depressive disorder, participated in the study. All patients received high frequency (10 Hz) stimulation for 10 to 15 daily rTMS sessions. However, before the treatment they were randomly sorted into 3 groups according to stimulation target in MNI map: Group 1 received rTMS at point ‑40; 48; 35; Group 2 received rTMS at point ‑46; 45; 38; Group 3 received rTMS at point ‑38; 44; 26. Electroencephalography (EEG) recordings and clinical tests were obtained the day before the rTMS course and after the last session. There were some notable differences in physiological changes between the groups, with the largest EEG band spectral power increases found in Group 1 patients and the lowest in Group 2 patients. There was a significantly larger decrease of the Hamilton Depression Rating Scale (HAM-D) scores in the Group 3 (66.94%) compared to Group 1 (57.52%) and Group 2 (56.02%). This suggests it is possible to achieve higher clinical efficacy and less physiological impact on the brain when using different targets in a neuronavigated MNI based MR‑less rTMS system.

The Effect of Electroconvulsive Therapy On Cognitive Functions in Treatment-resistant Depression

Introduction Electroconvulsive therapy (ECT) is the most effective treatment for drug-resistant depression. However, long-term effects of such therapy on cognitive functions have not been adequately studied. Aims The aim of the study was to estimate short-term and long-term effects of ECT on cognitive functions in patients with drug-resistant depression. Methods Thirty seven patients were included (10 male, 27 female), aged 34-75 years. Cognitive assessments were performed before, immediately after completion of 6-12 sessions of the ECT, and 3 months thereafter, using Benton Visual Retention Test, Digit Span of the Wechsler Adult Intelligence Scale (WAIS), the Rey Auditory Verbal Learning Test (RAVLT), Color Reading Interference (Stroop test), Verbal fluency test, Trail Making Test (TMT) and the Rey-Osterrieth Complex Figure Test (ROCF). Results Immediately after ECT, a significant worsening was noted in memory (most elements of RAVLT) and in verbal fluency. However, 3 months after ECT, the indices of both RAVLT and verbal fluency significantly improved compared to baseline, and also, these of Benton and ROCF were significantly better than before ECT. The results of Digit Span (WAIS), Stroop and TMT were not affected by the treatment. Conclusions The results suggest that the negative effects of ECT on cognitive functions are transient. After three months, the indices of memory, verbal fluency as well as Benton and ROCF were significantly better than those before the treatment. Therefore, in addition to antidepressant effect in drug-resistant depression, electroconvulsive therapy, in a long-term perspective, may also exert a favorable influence on some cognitive functions.

Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine, serotonin and noradrenaline in the rat frontal cortex

BackgroundSeveral clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors, in the treatment of drug resistant depression. The aim of our study was to understand the mechanism of the clinical efficacy of a combination of fluoxetine (FLU) and risperidone (RIS) in drug-resistant depression.We studied the effect of FLU and RIS, given separately or jointly on the extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex. MethodsAnimals were given single intraperitoneal injections of RIS at a doses of 0.1 or 1mg/kg and FLU at a dose of 10mg/kg. The release of DA, 5-HT and NAin the rat frontal cortex was investigated using microdialysis in freely moving animals. The extracellular level of DA, 5-HT and NA was assayed by HPLC with coulochemical detection. ResultsRIS (0.1 and 1mg/kg) and FLU (10mg/kg) increased the extracellular level of cortical DA, 5-HT and NA. Co-treatment of both drugs was more effective in increasing DA release than administration of each of the drugs alone at doses of RIS 1mg/kg and FLU 10mg/kg. Co-treatment of FLU and RIS 0.1mg/kg was more potent than FLU alone, while the effect of joint injection of FLU and RIS 1mg/kg was stronger than RIS 1mg/kg alone on 5-HT release. The combination of FLU with both doses of RIS was not effective in increasing NA release as compared to drugs given alone. ConclusionsOur data indicate that the effect of the combined administration of RIS and FLU on DA and 5-HT release in the rat frontal cortex may be of crucial importance to the pharmacotherapy of drug resistant depression.

Lithium therapy - the effectiveness of the medicine, side symptoms, complications and their influence on the quality of the life in affective diseases

Lithium is a medicine of the first choice in the preventive treatment of bipolar affective disorder. It is also used to enhance the treatment of drug resistant depression. How excatly this element acts is not yet fully understood. Lithium influences the transportation of sodium via cellular membranes (sodium-potassium ATPase dependant), has an inhibitory influence on the second transmitter system (connected with phosphatidylinositol), thus probably acting as a stabiliser of inter cellular processes. Lithium does not associate with plasmatic proteins and is almost entirely excreted by kidneys. The side effects of the medicine are linked to its influence on the central nervous system and on the renal transportation of electrolytes as well as the narrow therapeutic index of the medicine, which can cause intoxication if the recommended doses are not when medical recommendations are not observed. The undesirable effects are more intensive when the level of lithium in the blood plasma increases. Among the most common side effects are stomachaches, nausea, diarrhoea, lack of appetite, polydipsia, polyuria, shaking hands, headaches, sleepiness or deterioration of memory. Complications during lithium therapy listed in lite

Induction of kf-1 after repeated electroconvulsive treatment and chronic antidepressant treatment in rat frontal cortex and hippocampus.

It has been proposed that signaling pathways involved in adaptive neural plasticity are long-term targets for the action of electroconvulsive treatment (ECT), which is widely used in the treatment of drug-resistant depression. We have previously performed EST analysis to identify some molecular machinery responsible for antidepressant effect. One of the cDNA fragments identified as antidepressant related genes/ESTs was identified as kf-1 which has a RING-H2 finger motif at the carboxy-terminus. In the present study, we have demonstrated the induction of kf-1 in rat frontal cortex and hippocampus not only after chronic antidepressant treatment, but also after a single and repeated ECT. RING finger proteins are proposed to play some important roles in the ubiquitin-proteasome system. In conclusion, the current investigation has identified kf-1 as a novel molecular target for antidepressants and ECT.

Treatment of drug resistant depression: J.K. Rybakowski. Department of Psychiatry, University of Medical Sciences, Poznań, Poland

Depression is drug-resistant, if the severity of the symptoms has not decreased to half of the starting situation, despite appropriately conducted treatment with two antidepressants belonging to two different pharmacological categories. The incidence of drug-resistant depression in Finland is approximately 1%, and it is being treated too passively, whereby the number of disability pensions is rising. Current treatments include combinations of antidepressants, additional drugs for depression, psychotherapy, electrotherapy and serial magnetic stimulation. Ketamine infusions are also an effective, yet still experimental form of treatment.

Applications de la stimulation magnétique corticale

In the last decade, a new electrophysiological tool has become available since the development of painless magnetic stimulators able to activate the primary motor cortex and the motor roots in conscious man. Therefore, it became possible to measure the conduction time within fast-conducting central motor pathways by substracting from the total latency of muscle responses elicited by cortical stimuli the conduction time in peripheral nerves. This technique proved sensitive enough to illustrate early abnormalities of central motor conduction in various neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, cervical spondylotic myelopathy, degenerative ataxias or hereditary spastic paraplegias. When recorded early after stroke, motor evoked potentials are also a valuable tool to predict functional outcome. They can also illustrate subtle pathophysiological disturbances in diseases where there is no direct involvement of central motor pathways such as Parkinson's disease, dystonia or epilepsy. Magnetic cortical stimulation also offers unique opportunities to explore intracerebral inhibitory and excitatory circuits and mechanisms of brain plasticity. The recent development of rapid rate stimulators also enables functional studies of non-motor cerebral regions such as visual or frontal cortices. Moreover, rapid rate stimulation seems useful in the treatment of drug-resistant depression but the safety of this procedure, particularly with regard to the production of seizures or kindling, remains to be fully documented.

Long-term enhancement of entorhinal-dentate evoked potentials following `modified' ECS in the rat

Electroconvulsive therapy (ECT) is widely used as a treatment for drug-resistant depression. The animal analogue of ECT is electroconvulsive shock (ECS) seizures. We have recently shown that repeated ECS seizures cause a long-lasting, perhaps permanent, enhancement in entorhinal-dentate evoked potentials in the rat. Our study, however, involved `unmodified' ECS, whereas in clinical practice ECT is now usually given in its `modified' form (with near-threshold currents, a short-acting barbiturate, muscle relaxant and oxygen). We have therefore repeated our experiments using modified ECS. Entorhinal-dentate evoked potentials were measured in Long–Evans rats before and after: (1) eight modified ECS seizures; or (2) eight sham modified ECS trials. Despite the use of the modified procedure, a significant and long-lasting enhancement in population spike amplitude was seen in the ECS group. We conclude that the modified procedure does not protect rats against the long-lasting enhancement of evoked potentials. Similar changes may be occurring in the brains of patients subjected to modified ECT.