Curcumin and depression

Posted on January 8, 2021  in Uncategorized

Patients taking antidepressants suffer from several side effects. In 63% of cases, there is anxiety, suicidal thoughts, insomnia, weight gain, and sexual disorders. Some patients do not respond to medication at all, and their number is 17%. 

The antidepressant effect of curcumin has been known for a long time. In a study on volunteers, it was found that there was no difference in the effects between curcumin and fluoxetine in the treatment of depression over 6 weeks. Curcumin has been shown to be beneficial in terms of no side effects. It is safe even in large doses – 8 grams per day. The curcumin- based drug is called BCM-95.

 The use of curcumin itself is limited by poor absorption in the gastrointestinal tract, rapid destruction in the intestines, and slow absorption into the bloodstream. But the restored mixture of curcumin – the BCM-95 preparation does not have such disadvantages.

Clinical trials on volunteers have established that the bioavailability of BCM-95 is 7 times higher than that of curcumin . The active ingredient curcumin increases neurogenesis in the hippocampus , stimulates the synthesis of neurotrophic factor, and promotes the growth of new neurons. In addition, curcumin inhibits MAO-A and MAO-B monoamine oxidase isoenzymes , and affects the concentration of serotonin and dopamine in the brain.  

It also has anti-inflammatory effects, reduces the secretion of inflammatory markers of astrocytes , inhibits cyclooxygenase-2, nuclear factor-kappa B (NF-kappa B), nitric oxide synthetase ( iNOS ), interleukin-1.  

Curcumin- based drugs may become the mainstay in the treatment of depressive disorders.

Depression and atypical antipsychotics

Posted on January 4, 2021  in Uncategorized

Atypical antipsychotics are used in the treatment of the depressive phase of bipolar disorder. The use of classical antipsychotics is limited to a number of points. Patients with bipolar disorder after treatment with classical antipsychotics are at risk of developing extrapyramidal disorders and dyskinesia. Classical antipsychotics also cause depression, so atypical antipsychotics should be preferred. 

When studying the effect of olanzapine and quetiapine , a decrease in psychotic symptoms, good tolerance, and antidepressant effect were found. Monotherapy with olanzapine and its combination with fluoxetine are also effective . Moreover, the combined use of drugs was more effective than monotherapy . The time to depression for olanzapine was 57 days, and 32 days for combined therapy.  

Side effects when using drugs: drowsiness, weight gain, increased appetite, dry mouth.

Quentiapine monotherapy was well tolerated in the treatment of depression in patients with bipolar disorder . But the following side effects were observed: sedation , dry mouth, dizziness. Quentiapine also reduced anxiety.

A study by Doree JP et al. In patients with resistant depression showed that supplementation with quentiapine and lithium improved the condition of patients. Moreover, the antidepressant / quetiapine combination was found to be more effective than the antidepressant / lithium combination.

The antidepressant effect of risperidone has not received evidence, but it potentiated the effect of citalopram in resistant depression ( Rapaport MN et al ., 2004). Small doses of amisulpride also had antidepressant effects

Atypical antipsychotics affect not only the main symptoms of depressive disorders, but are effective against psychotic symptoms.

Depression and neuroplasticity

Neuroplasticity and Depressive Disorder

Depressive disorder is associated with decreased neuroplasticity and decreased concentration of glutamate , which is a neurotransmitter of arousal.

Some monoamines act on secondary messengers – mitogen- activated protein kinase , contribute to the normalization of neuroplasticity and glutamate content . Some drugs cause an increase in glutamate secretion, act on synapsogenesis, and improve mood (eg ketamine). But the effect is short-lived. 

Electroconvulsive therapy and antidepressants at the cellular level cause an increase in the expression of neuroprotective proteins – the neurotrophic factor BDNF, which promotes neuronal life and regulates synaptic connections.

In experiments on rats, electroconvulsive therapy and antidepressants increase the secretion of neurons in the dentate gyrus of the hippocampus and reduce the effects of the action of the hypothalamic-pituitary-adrenal axis in depression.

In post-traumatic stress disorder, antidepressants restore the limbic system and the hippocampus . 

But in Russian medicine, these changes are not taken into account by clinicians, like the content of glutamate and the processes of neuroplasticity in depression.

Prolonged stress reduces the volume of the hippocampus, the number of neurons, and leads to neuronal atrophy.

Molecular markers of depression

Depression is one of the not fully understood diseases. Its symptoms are:

  • weight loss;
  • weight gain;
  • insomnia;
  • psychomotor agitation;
  • feeling of worthlessness, guilt.

The main symptom of depression is anhedonia – a loss of interest in pleasure, reward, cognitive impairment, a deficit in social cognition, and a slowdown in information processing.

Cognitive impairment cannot always be cured with pharmacological drugs. But, for example, fluoxetine enhances cognitive function to a greater extent than desipramine and amitriptyline. And SSRIs enhance memory, indirectly, by improving mood.  

Cognitive drugs may be new treatments for depression. Thus, donesepil helps to reduce the signs of depression, which has been proven by positive ratings of the depression scale. Experiments have shown that the enhancement of cholinergic and serotonergic transmission with drugs leads to a change in neuroplasticity , network synchrony between the amygdala and hippocampus.  

Depression is associated with chronic social damage and is reflected at the proteome level. This is confirmed by the action of fluoxetine, which affects the expression of many proteins.

Thus, the search for mediator, molecular markers of depression will reveal the pathogenesis of the disease and prescribe drugs not by trial and error, but based on objective criteria .

Brain changes in schizophrenia and depression

Patients with schizophrenia and depression have various structural changes in the brain. In schizophrenia, after the first episode of psychosis, the volume of gray matter in some areas of the brain changes after 2-3 years.

With depression, there is a decrease in the amount of gray matter in the middle temporal gyrus, left medial ventral prefrontal gyrus, dorsal medial prefrontal gyrus, left lingual gyrus of the brain.

 The pathology of the superior temporal gyrus leads to impaired perception of sensory information. This leads to a mood disorders of t mild to moderate in severity. Also, disturbances in the perception of sensory signals are associated with the development of psychotic syndromes, as well as emotional rejection, dullness, hallucinations.

The frontal lobe of the cerebral cortex is responsible for executive control. The pathology of this zone leads to a decrease in cognitive capabilities – attention, cognition, and behavioral disorders. The decrease in the amount of gray matter in patients with schizophrenia reflects the progression of the disease during the first 2 years after the first psychosis, and the decrease in the amount of white matter does not reflect the pathological changes in schizophrenia.

Pro-inflammatory cytokines in depression

Cytokines are protein molecules. Produced by cells of the thymus gland, immune system, spleen, blood. 90% of cytokines are secreted by B and T lymphocytes. Cytokines perform various functions in the human body, but their main task is to ensure interaction between cells. More than 200 cytokines have been discovered so far. According to the mechanism of action, they are divided into:

  • pro-inflammatory cytokines (interleukin 1,2, 6, 8, interferon);
  • anti-inflammatory cytokines (interleukin 4.10).

Cytokines are essential for the normal development and functioning of the brain. They affect neurotransmitters – serotonin, dopamine, GABA. The introduction of proinflammatory cytokines or the activation of immune cells activate the adaptive capabilities of humans against viruses and bacteria. Promote recovery from traumatic brain injury.

But the constant stimulation of proinflammatory cytokines leads to long-term changes in the level of neurotransmitters , which leads to mental disorders, including depression.

 The effect of cytokines on behavior is associated with the activation of inflammatory processes in the brain, which contributes to the imbalance of monoamines, glutamate, neuropeptides, and a decrease in the production of growth factor – a neurotrophic factor in the brain. In addition, pro-inflammatory cytokines are produced during obesity, childhood mental trauma, stress, poor sleep, which also causes depression.  

Evoked potentials and depression

Evoked potential studies (auditory, cognitive, visual, sympathetic) show changes in the electrical activity of the brain in response to certain stimuli. The amplitude of the evoked potentials is small and ranges from tenths of a microvolt to several microvolts.

When interpreting survey data, methods are used that are independent of the reporting point. Analysis of field strength, dipole signal curves is preferred. Time division into different components is used to isolate a single peak in the signal curve. Evoked potentials from stimulation with simple stimuli are usually investigated.

 In psychiatric practice, stimuli are compared with the cognitive assessment of the signal, the degree of concentration of attention.

By modality, evoked potentials are divided into:

  • auditory;
  • somatosensory;
  • visual;
  • olfactory.

Auditory evoked potentials P50 appear in 50 msec . after clicking. The auditory cortex of the temporal lobe is responsible for the reaction.

Auditory evoked potential N-100 is induced in the superior temporal gyrus and is modulated by attention.

Auditory P300 evoked potentials arise in response to frequent stimuli. The patient must calculate these stimuli at the push of a button. Signals are divided into: P300a and P300b. P300a is a reflection of orientation response, P300b is associated with attention and cognitive ability. The temporal and parietal lobes are responsible for its occurrence. With depression, a change in the shape and amplitude of N100-P200 is observed and reflects serotonergic activity and the intensity of serotonin metabolism.

Withdrawal of SSRI antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are used to treat depression. Withdrawal symptoms may occur after treatment with these drugs. It can start suddenly. It will manifest itself as symptoms of depression, anxiety. At the same time, patients believe that they are depressed again and ask to prescribe medications again.

Withdrawal syndrome depends on the half-life of the drug. The half-life is the time at which the active substance of the drug remains in the blood. Drugs with a short half-life require more frequent administration to maintain adequate drug concentration. If the drug has a long half-life, then it is stable in the blood for a long time and does not undergo changes in concentration. Fluoxetine has a long half-life. Therefore, after stopping its intake, its concentration in the blood decreases slowly. Other antidepressants in the SSRI group have a shortened half-life, so when you stop taking the drug, the patient experiences withdrawal.

In general, long-term use of SSRIs affects the biochemical processes in the brain. The number of serotonin receptors decreases, since the SSRI causes an increased secretion of serotonin – a serotonin burst. At the same time, the number of serotonin receptors in the brain decreases to prevent increased stimulation of brain neurons. After the end of treatment, the receptors become smaller and there is a decrease in serotonin activity.

20% of patients using cipralex , zoloft , paxil experience withdrawal symptoms after depression treatment. Withdrawal symptoms can last from one to seven weeks, and those who have been using SSRIs for many years have long-term withdrawal symptoms. Therefore, in order to avoid withdrawal syndrome, the dose of SSRIs is reduced slowly. If the drug has been used for less than 8 weeks, dose reduction should be carried out within one to two weeks. If the medication was taken for more than 6-8 months, then a dose reduction is required within 6-8 weeks.

Treatment of depression with SSRI drugs should be carried out while monitoring the concentration of the drug in the blood, and when deciding on drug withdrawal, one should also rely on objective criteria.

Optogenetic stimulation and treatment of depression

In recent years, the science of optogenetics , a field of neurobiology , has been developing . Optical and genetic methods are used to study neural connections, neuronal excitation, and the activity of neural networks. A number of microbial opsin proteins are used :

  • ChR2 ( Channelrhodopsins );
  •  VChR1;
  •  galorhodopsin ( Halorhodopsin ); 
  • arherhodopsin ( Archaerhodopsin ) 

Proteins can be injected into neurons and act as ion channels that open or close when exposed to light. When exposed to 470 nm light, Channelrhodopsin-2 transmits Na + into neurons. Using the properties of opsins allows you to improve the method of deep brain stimulation ( Deep Brain Stimulation .   

Selective activation and inactivation of the fibers of the brain substance is a more modern method of treating Parkinson’s disease, cluster headaches. But the technology requires surgical intervention – electrode implantation , but stimulation occurs contactlessly, under the influence of photoactivation . The study of the effects of deep brain stimulation using opsins has just begun. But there is already evidence of the antidepressant effects of optogenetic stimulation of the prefrontal medial cerebral cortex. Devices based on this principle of operation are portable and can be used by the patient at any time of the day. 

Electroconvulsive therapy and treatment of depression

Electroconvulsive therapy has a proven mechanism of action. When using it, the level of norepinephrine and other catecholamines in the hippocampus, frontal cortex, and basal ganglia increases. Dopamine secretion is increased in the striatum.

The indications for the appointment of electroconvulsive therapy (ECT) are:

  • depression in the context of bipolar disorder and paroxysmal schizophrenia; 
  • resistant depressive states.

There are emergency and routine indications for ECT. Emergency indications include:

  • depression with strong motor response and physical exhaustion;
  •  depression with thoughts of sinfulness and suicidal intentions;
  • stuporous depression with longing and refusal to eat;
  • depression with motor retardation, self-blame;
  • depression with Kotard’s delusions (nihilistic statements).

Emergency indications for ECT include:

  • depression with hypochondriacal delirium;
  • depression with paranoid elements.

Before ECT, it is necessary to determine the somatic and neurological status. The patient is examined for a general analysis of blood, urine, EGC, blood biochemical parameters. Consultations are carried out: therapist, ophthalmologist, neuropathologist, gynecologist. X-rays of the spine are taken. 

Contraindications for ECT are: 

  • fevers of an inflammatory nature;
  • heart defects;
  • arrhythmias;
  • aortic aneurysm;
  • tuberculosis;
  • bronchial asthma;
  • osteoporosis;
  • osteomyelitis;
  • ulcerative bleeding;
  • organic lesions of the brain;
  • glaucoma.

Electroconvulsive treatment of depression is carried out using anesthesia, muscle relaxants, atropine, which reduces the risk of complications. And it is a necessary procedure in the treatment of drug-resistant depression.