Central nervous system-related safety and tolerability of add-on ketamine to standard of care treatment in treatment-resistant psychotic depression in patients with major depressive disorder and bipolar disorder.

Background: Psychotic treatment-resistant depression represents a complex and challenging form of mood disorder in clinical practice. Despite its severity, psychotic depression is frequently underdiagnosed and inadequately treated. Ketamine has demonstrated rapid and potent antidepressant effects in clinical studies, while exhibiting a favorable safety and tolerability profile. Although there is limited literature available on the use of ketamine in psychotic TRD, reports on its efficacy, safety, and tolerability profile are of great interest to clinicians. The aim of this study is to investigate the relationship between dissociative symptomatology and psychomimetic effects in inpatients with treatment-resistant major psychotic depression and treatment-resistant bipolar psychotic depression, who receive intravenous ketamine treatment alongside psychotropic medication, both during and after treatment. Materials and methods: A total of 36 patients diagnosed with treatment-resistant unipolar (17 patients) or bipolar (18 patients) depression with psychotic features were treated with eight intravenous infusions of 0.5 mg/kg ketamine twice a week over 4 weeks. Ketamine was given in addition to their standard of care treatment. The severity of depressive symptoms was evaluated using the MADRS, while dissociative and psychomimetic symptoms were assessed using the CADSS and BPRS, respectively. Results: There were no statistically significant changes observed in MADRS, CADSS, and BPRS scores within the study group during ketamine infusions. However, significant improvements in MADRS, CADSS, and BPRS scores were observed during ketamine infusions in both the unipolar and bipolar depression groups. Conclusion: This study provides support for the lack of exacerbation of psychotic symptoms in both unipolar and bipolar depression.

Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression.

Anhedonia constitutes one of the main symptoms of depressive episode. It correlates with suicidality and significantly effects the quality of patient's lives. Available treatments are not sufficient against this group of symptoms. Ketamine is a novel, rapid acting strategy for treatment resistant depression. Here we report the change in symptoms of anhedonia measured by Snaith-Hamilton Pleasure Scale as an effect of eight ketamine infusions as an add-on treatment in 42 patients with treatment resistant depression. We also determined the effect of this change on the severity of depressive symptoms measured by Inventory for Depression Symptomatology-Self Report 30-Item (IDS-SR 30). We have observed statistically significant decrease in the level of anhedonia during ketamine treatment. After adjusting for potential confounders we have found that significant reduction in Snaith-Hamilton Pleasure Scale (SHAPS) after each infusion and 1 week post treatment was observed only among patients who did not use benzodiazepines. The reduction in symptoms of anhedonia mediates the antidepressive effect of ketamine. The results need replication in a larger randomized placebo controlled trial.

Magnesium in Ketamine Administration in Treatment-Resistant Depression.

Relationship between depression and magnesium levels is reported. This observational study examined whether serum magnesium concentration change over time of ketamine treatment course, also whether association between magnesium concentrations and treatment response measured with Montgomery-Åsberg Depression Rating Scale (MADRS) score occurs. Moreover, interlink between changes in Young Mania Rating Scale (YMRS) score, somatic comorbidities, and magnesium concentration was studied. Inpatients with major depressive disorder or bipolar disorder were rated weekly by clinician using MADRS and YMRS. Magnesium levels assessments were carried out weekly, before start of ketamine treatment and then every second infusion and one week after last ketamine infusion. The concentration of Mg2+ ions differs depending on the measurement. The Mg2+ concentration in pre-measurement was significantly higher than in measurement after five infusions (p = 0.031) and after seven infusions (p = 0.003). No significant correlation was observed between changes in magnesium serum levels and MADRS or YMRS. The concentration of Mg2+ ion in course of the treatment was not associated with somatic comorbidities. The study supports data for role of magnesium in treatment-resistant depression, particularly related to ketamine treatment, but provides no clear evidence of straightforward association between magnesium serum concentration and treatment response or comorbidity.

The immunomodulatory effect of ketamine in depression.

Major depression is one of the most frequent psychiatric conditions. Despite many available treatment methods, more than 30% of patients do not achieve remission, even after trying several antidepressants and augmentation strategies. S-enantiomer of ketamine, well-known anesthetic and analgesic, has been recently approved by Food and Drug Administration in the intranasal form as a new generation antidepressant. However, the mechanism in which ketamine reduces depressive symptoms in treatment-resistant depression patients is still not completely understood. There are several theories explaining how ketamine might reduce depressive symptoms, which have been described in detail; one of them is immunomodulatory effect of ketamine, according to the inflammatory theory of depression. In the review authors present and summarize studies showing ketamine effect on human immune system ex vivo and in vitro, including changes in cytokine levels, number, ratio and activity of various immune cell population and the correlation with clinical improvement in depressive symptoms. Most of the results confirm the anti-inflammatory effect of ketamine. There are only a few studies in the population of patients suffering from depression receiving ketamine, focused on correlation between immunological changes and clinical outcome of the therapy; further studies of that area are neccesary for understanding the immunomodulatory effect of ketamine in depression.

Magnesium and ketamine in the treatment of depression.

Depression affects over 121 million people annually worldwide. Relatively low remission rates among depressive patients enforce the search for new therapeutic solutions and an urgent need to develop faster-acting antidepressants with a different mechanism of action occurs. The pathomechanism of depression postulated by the monoamine hypothesis is limited. The results of abnormalities in glutamate and γ-aminobutyric acid (GABA) systems in the brains of people with mood disorders allowed to develop new theories regarding pathophysiology of these disorders. Glutamatergic transmission is influenced by magnesium and ketamine through glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonistic effects. Magnesium and ketamine have a common mechanism of action in the treatment of depression: an increase in GluN2B (NMDAR subunit) expression is related to the administration of both of the agents, as well as inhibition of phosphorylation of eEF2 (eukaryotic elongation factor 2) in cell culture and increase of the expression of BDNF in the hippocampus. Combination of ketamine and magnesium in a normal magnesium level presents a superadditive effect in depression treatment. Analysed substances affect the GABAergic system and have anti-inflammatory effects, which is correlated with their antidepressant effect. The synergistic interaction between the pharmacodynamic activity of magnesium and ketamine may be of particular importance for patients with mood disorders. Further research is needed to determine the relationship between magnesium levels and ketamine treatment response mainly in the attempt to establish if the magnesium supplementation can change ketamine treatment response time or present superadditive effect.

Efficacy of Ketamine in bipolar depression: focus on anhedonia.

Bipolar depression (BD) is among the most severe psychiatric disorders. A significant number of patients do not achieve an entirely symptom-free state and experience residual sub-syndromal depression. Most of the treatment options approved for bipolar depression give no rapid symptom improvement. Ketamine is an anaesthetic medication that acts as an antagonist of the NMDA receptor and has antidepressant potential. Due to its unique way of action, ketamine seems to be crucial for the treatment of anhedonia. This review paper aims to provide an overview of the efficacy of ketamine infusions in bipolar depression with a focus on anhedonia Literature suggests that intravenous ketamine 0.5 mg/kg over 40 min weekly could be useful in the treatment of bipolar depression with prominent anhedonia, but there is still a small number of studies that examine the efficacy of ketamine infusions in BD. In conclusion, ketamine should be considered as a valuable treatment option for patients with BD and anhedonia.

Role of copper in depression. Relationship with ketamine treatment.

Depression is one of the most common psychiatric issues with a proportion of adults with major depressive disorder who fail to achieve remission with index pharmacological treatment. There are unmet needs in ADT focus on non-monoaminergic agents. Accumulating evidence suggests that the N-Methyl-d-aspartate receptor (NMDAR) plays an important role in the neurobiology and treatment of major depressive disorder. The role of copper ions in pathogenesis and treatment of depression is not fully clarified, however interaction between copper and NMDAR is of prime importance. Release of copper ions inhibits NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor function thus protects neurons from glutamatergic excitotoxity. Abnormalities in glutamatergic transmission are the key of glutamate hypothesis of depression. Some authors revealed that NMDARs are also regulated by cellular prion protein (PrPC) and indicated that interactions of copper, glycine and NMDARs subunits are vital for the regulation of the receptor. As NMDAR antagonist ketamine is known to produce rapid antidepressive effect, observation of copper serum levels in patients treated with ketamine may provide important information about connections between NMDAR antagonistic agents and trace elements antagonistic to that receptor. It is necessary to carry out further studies related to copper and ketamine in depression treatment.

Antidepressants in epilepsy.

People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.

Benzodiazepines as adjunctive therapy in treatment refractory symptoms of schizophrenia.

Antipsychotics are a key intervention strategy in pharmacotherapy in schizophrenia. However, the benzodiazepines are often prescribed to control sleep disturbances, anxiety or hostile behaviour. There is some evidence supporting the combination therapy with antipsychotics and benzodiazepines providing beneficiary treatment effect to the psychosis in positive and negative symptom domains as well as catatonia or adverse reactions to antipsychotic drugs. In particular, in a population suffering from residual symptoms of schizophrenia, in particular anxiety, emotional flattening, being refractory to approved treatment strategies, benzodiazepines as add-on to antipsychotics seem to be an option. There is rationale for the therapeutic use for long-acting benzodiazepines as the treatment of option with limited literature indicating the use of chlordiazepoxide, and diazepam. The paper reviews the best clinical practice indications for benzodiazepines as the add-on treatment to antipsychotics in schizophrenia.

Decision-making in panic disorder. Preliminary report.

BACKGROUND: The impaired decision-making with high risk-aversive behavior and elevated impulsivity are reported as a trait feature in anxiety disorders including panic disorder (PD). It is hypothesised that PD patients exhibit difficulties in executive functions which can influence patients behavioural strategies e.g. problem solving, decision making, planning, impulse control. The aim of this study was to asses decision making process, risk-taking and impulsivity in PD patients as compared to healthy controls. MATERIAL AND METHODS: Twenty-one psychotropic drug-naive PD outpatients and 20 healthy subjects matched by age and sex were examined. Cognitive decision-making and risk-taking behaviour was measured with CGT (Cambridge Gambling Task) from CANTAB battery. The PD severity was assessed with Panic and Agoraphobia Scale (PAS). The level of anxiety and depression was assessed with HADS (Hospital Anxiety and Depression Scale). Impulsivity was evaluated with the Barratt Impulsiveness Scale, 11th version (BIS-11). RESULTS: There were no statistically significant differences on CGT in PD patients as compared to healthy control. However, having observed more closely, there are some differences between patients and healthy control. PD patients with higher anxiety level in HADS exhibited lower percentages of risky decisions comparing to PD with lower anxiety in HADS. PD patients with higher depression level in HADS demonstrated slowed decision-making when compared to PD patients with low level of depression in HADS. Total impulsivity and its attentional and motor dimensions were significantly higher in panic disorder patients versus healthy controls. CONCLUSION: There were no statistically significant differences with regard to CGT assessed decision-making between drug-naive PD patients and healthy controls. The PD patients with higher HADS-D depression level demonstrated slowed decision-making as compared to PD patients with low level of depression.

Benzodiazepines in combination with antipsychotic drugs for schizophrenia: GABA-ergic targeted therapy.

Antipsychotics are a key intervention strategy in pharmacotherapy of schizophrenia. However, benzodiazepines are often prescribed to control sleep disturbances, anxiety or behavioural disinhibition. There is clinical evidence for the beneficial effect of the combined treatment of antipsychotics and benzodiazepines resulting in more favorable treatment outcome in schizophrenia with regard to positive and negative symptoms. This clinical phenomenon seems to be associated with the GABA-ergic activit ythat is believed to be disrupted in the schizophrenia and direct benzodiazepines effect on GABA-A receptors. In the brain there are both excitatory and inhibitory neurotransmitters which cooperate between themselves maintaining the proper functioning of the brain. GABA neurons carry inhibitory signals that help keep brain activity at optimal levels of operation, Glutamate, on the other hand, carry excitatory signals. As the interplay between these two exists they keep the dopamine levels in the average levels. The disruption of GABA-ergic transmission in schizophrenia may induce alternations in dopaminergic neurotransmission providing no inhibitory effect to the central glutamate activity, resulting in the rise of the dopamine levels being associated with psychosis precipitation. Benzodiazepines are believed to reduce presynaptic dopamine release at the mesolimbic level and delay postsynaptic adaptation of dopaminergic neurons to antipsychotics potentiating the action of antipsychotics in resistant schizophrenia. Benzodiazepines also act on mesocortical regions where antipsychotics are less effective and where there is a particular sensitivity to stress. This association is particularly useful in resistant patients or in patients with severe anxiety with or without intolerance to antipsychotics. Improvement concerns anxious symptoms but also positive symptoms (hallucinations, delirium and dissociative syndrome) and negative (social withdrawal, affect flattening). As the available studies are limited there is some clinical evidence that the use of antipsychotic drugs with addition of benzodiazepines can provide better general outcome in ill patients than antipsychotics administration alone.

Lithium therapeutic dose monitoring in human saliva.

BACKGROUND: Lithium carbonate is valuable and effective agent in the treatment and prophylaxis of mood disorders, particularly bipolar disorder (BD). Due to its narrow therapeutic range, frequent serum lithium estimation is necessary. To avoid the discomfort of frequent venipuncture, a non-invasive method for serum lithium concentration is needed. An alternative method of determining lithium level could be saliva or urine. Literature data regarding the reliability of saliva lithium levels is not conclusive. MATERIAL AND METHODS: The aim of this study is to provide an overview of possibility to replace blood serum with saliva look through research in that field. RESULTS: Some authors conclude that there is constant ratio between serum and saliva lithium level and they suggest that saliva can replace serum for estimation lithium level. Other revealed that saliva/serum lithium ratio is constant individually, so saliva/serum lithium ratio should be estimated individually. Finally there are studies excluding the possibility of replacement serum with saliva. CONCLUSIONS: There is little number of studies on saliva clinical use in lithium level monitoring. Further studies should base on current data including methods of obtaining saliva and its biochemical analysis, collecting samples in a specific time frame from the last dosage of lithium, as well as inter-subject or intra-subject measurements.

Immediate and delayed visual memory and recognition in patients with panic disorders.

BACKGROUND: In Panic Disorder (PD) both somatic and cognitive symptoms occur. Cognitive functions which may be involved with anxiety and maladaptive cognition such as e.g. attention, memory and perception might be decreased. MATERIAL AND METHODS: Within the preliminary studies eleven patients diagnosed with panic disorder (DSM-IV-TR), and nine healthy controls were studied. The severity of disorder was measured by the Panic and Agoraphobia Scale. To assess working memory Delayed Match to Sample (DMS) with CANTAB (Cambridge Neuropsychological Test Automated Battery) was used. RESULTS: Percent of correct answers was significantly different in both groups in delayed visual memory and recognition test. In the control group results were higher (M=92.22) than in the experimental group (86.06). CONCLUSIONS: PD is associated with impaired performance on a DMS task that requires the stable maintenance of representations in working memory.

Impulsivity in panic disorder: neuropsychological correlates.

BACKGROUND: Impulsivity plays a prominent role in numerous psychopathological states and poses an important clinical dilemma. However, different aspects of impulsivity are related to mood disorders, addictions, personality disorders, eating disorders, the relationship between anxiety and impulsivity is controversial and not well explored. The impact of anxiety on cognitive functioning is less explored than in other disorders (e.g. depression). The findings on cognitive functioning and impulsivity in anxiety disorders are inconsistent and are most likely due to methodological differences between the studies. MATERIAL AND METHODS: Eleven patients diagnosed with panic disorder (DSM-IV-TR) and nine healthy volunteers were enrolled to the study. Both groups did not differ significantly in terms of age, gender and educational level. The experimental group comprised of psychotropic drug naïve patients. The severity of PD was measured with Panic and Agoraphobia Scale. Impulsiveness was evaluated with the Barratt Impulsiveness Scale - 11th version (BIS-11). To asses cognitive functions CANTAB (Cambridge Neuropsychological Test Automated Battery) was used and Paired Associate Learning (PAL) test was chosen for episodic memory evaluation. RESULTS: Mean BIS-11 scores observed in the group of psychotropic drug naïve patients with panic disorder were 71.36 (SD 7.31). Mean BIS-scores recorded in the control group were 60.77 (SD 9.57). The correlation between impulsivity and PAL results in the experimental group was found at the level r=0.708723; p<0.05. The respective value for the controls was r=0.200839; p<0.05. CONCLUSIONS: Impulsivity in the experimental group was higher than adjusted average for the control group. Our findings indicate also the correlation between impulsivity and cognitive deficits in panic disorder in psychotropic drug naïve patients.

Cognitive correlates in panic disorder as related to impulsivity - preliminary report.

BACKGROUND: Impulsivity is the neurophysiologically based inability to confirm behaviour to its context or consequences. Overimpulsiveness characterizes many mental disorders and poses an important clinical dilemma. Although the relationship between mood disorders and impulsivity has been well studied the relationship between anxiety and impulsivity is controversial and not well explored. Some studies hypothesise that patients with the diagnosis of panic disorders are characterised by higher levels of impulsivity as a trait as compared to healthy individuals. The aim of this study was to assess cognitive correlates in panic disorder as related to impulsivity measures. MATERIAL AND METHODS: Within the preliminary studies four patients diagnosed with panic disorder (DSM-IV-TR) were studied. The severity measure was the Panic and Agoraphobia Scale. The experimental group comprised of psychotropic drug naive patients. Impulsiveness was evaluated with the Barrat Impulsiveness Scale - 11th version (BIS-11). To asses cognitive functions we used CANTAB (Cambridge Neuropsychological Test Automated Battery). RESULTS: BIS-11 scores observed in the group of psychotropic drug naive patients with panic disorder were higher than the adjusted average for the population and correlated with the number of mistakes in CANTAB (Spatial Working Memory Test); rs=0.949; p=0.0513. CONCLUSIONS: The preliminary findings indicate a correlation between impulsivity and cognitive deficits in panic disorder in psychotropic drug naive patients.

Mood disorders in epilepsy - diagnostic and methodological considerations.

BACKGROUND: Mood disorders are common in people with epilepsy (PWE) with prevalence rates ranging from 11% to 62%. The variation in epidemiological data results probably from the diversity of methodologies employed and selection of the populations across the studies. Moreover, the symptomathology of mood disorders in epilepsy is often atypical, intermittent and pleomorphic and fails to meet DSM-IV-TR categories. Several studies suggested the existence of distinct interictal dysphoric disorder (IDD) in patients with epilepsy. The majority of research studies in mood disorders in epilepsy were based on screening instruments in the diagnosis of mood disorders in PWE. However, the results in validity and reliability in detecting major depression in epilepsy using self-report inventories of mood symptoms is vague. The aim of this study was to review studies on mood disorders in epilepsy with particular focus on diagnostic methods. SUBJECTS AND METHODS: The focus of this Review was on patient studies on mood disorders in epilepsy (2000-2012). We searched PubMed using the following search terms (effective date: 20th May 2012): (epilepsy (Title/Abstract) OR seizure (Title/Abstract)) AND depression (Title/Abstract) OR Dysthymia OR mania OR bipolar disorder OR affective disorder OR Interictal Dysphoric Disorder OR AND (humans (MeSH Terms) AND English (lang) AND (2000/01/01(PDAT): 2012/04/31(PDAT)). RESULTS: Depression is the most frequent comorbid psychiatric disorder in epilepsy. Recent studies pointed out that bipolar disorders are not rare in epilepsy. Most of the research in PWE did not rely on standardized psychiatric measures and only about 18% of studies were based on diagnostic psychiatric interviews (mainly MINI and SCID-I). Mood disorders in epilepsy excluding the ictal or periictal symptoms can be categorized using standardized measures. CONCLUSIONS: Common self-report depression measures may be used to screen for depression in clinical settings. The use of screening instruments in epilepsy must be followed by structured psychiatric interviews designed to establish a DSM-IV-TR diagnoses. Standardized psychiatric interview procedures based on DSM criteria like SCID-I or MINI provide a comprehensive way to diagnose mood disorders in patients with epilepsy.

The efficacy of Cognitive-Behavioural Therapy (CBT) as related to sleep quality and hyperarousal level in the treatment of primary insomnia.

BACKGROUND: Primary insomnia (PI) is a common sleep disorder affecting diurnal functioning. It may contribute to the development of several comorbidities such as major depression or arterial hypertension. It affects about 7% of the adult population. Pharmacotherapy remains the most common treatment for insomnia. However, many studies suggest CBT may be a supreme therapeutic approach resulting in a better long-term outcome. The aim of the study was to determine the efficacy of a CBT-protocol in the treatment of PI by means of sleep onset latency and the number of awakenings during night parameters along with sleep quality and the level of psychophysiological hyperarousal. The secondary outcomes were focused on CBT efficacy as determined by the predisposition to insomnia as related to higher vulnerability to stress (measured with FIRST) MATERIAL AND METHODS: Twenty-six individuals from a tertiary reference sleep disorders outpatients' clinic (22 women; mean age 41.4; 4 men; mean age 42.5) with primary insomnia (DSM-IV-TR) were included in the study. The exclusion covered other primary sleep disorders, secondary insomnia (psychiatric illness, unstable somatic illness, shift work), substance abuse/dependence, high results in HADS-M scale (score above 11). The participants were scored with HADS-M, Ford Insomnia Response to Stress Test (FIRST) at the beginning of the study. The Athens Insomnia Scale (AIS), Hyperarousal Scale, Leeds Sleep Questionnaire (LSEQ) were applied at the beginning, at the end and three months after the end of the study. The participants were also examined by 7 days actigraphic records before and after treatment. During the course of the treatment patients completed a Sleep Diary (SD). The CBT program employed was based on the Perlis protocol. Standard individual sessions of 50 minutes were provided on a weekly basis for 8-10 weeks by a board certified CBT therapist. After 3 months a follow-up session was scheduled. RESULTS: The significant improvement as related to the CBT treatment was present in the measures of sleep onset latency (67.2 vs. 23.4 min.; p<0.000), numbers of awakenings during night (2 vs. 0.4; p<0.000) and sleep efficiency (77.3 vs. 91%; p<0.000) - data from SD, quality of falling asleep (3.2 vs. 6; p<0.000), quality of sleep (3.3 vs. 5.8; p<0.000) and quality of morning awakening (3.2 vs. 6; p<0.000) - data from LSEQ. The improvement reached the significance level in the measure of psychophysiological arousal (52.3 vs. 42.4; p<0.000) and AIS (15.7vs. 6.8; p<0.000). No significant differences were identified between actigraphic records (light/dark ratio) before and after CBT. FIRST scores allocating patients to high and low stress vulnerability groups were non-contributory to the observed treatment efficacy. CONCLUSION: CBT is an effective treatment in primary insomnia. No relationship between CBT efficacy and predisposition to insomnia as determined by higher vulnerability to stress was identified.