Objective: The purpose of this study was a retrospective study of the contingent of Impact of COVID-19 on the clinical picture and therapy of Bipolar I Disorder maniacal episode who were most infected with COVID-19. 
Materials and Methods: We study 150 patients Bipolar I Disorder who infected with COVID-19 impact on the clinical picture and therapy of the illness.  The investigation ware carried out in psychiatric hospital Ministry of Health of the Republic of Azerbaijan. The hospital has a capacity of 2000 beds. 
Results: patients with Bipolar I Disorder who infected with COVID-19 in these clinically observed following changes: the intensity of psychopathological symptoms increased, psychosomatic balancing occurs, that is, during the COVID-19 illness, Bipolar I Disorder symptoms fade into the background, practically prevalence maniacal faze become intensively. 
Conclusion: patients Bipolar I Disorder who infected with COVID-19 in these clinically observed shows psychotic maniacal faze become intensively. 

Current statistics on coronavirus as of 03, 2022;13:01 GMT, (worldwide)

Total infections 385,967,643 

Deaths: 5,721,171

Recovered 305,840,220

Current statistics on coronavirus as of 03, 2022;13:01 GMT, (Azerbaijan)

Population 10,284,189 thousand.       

Total infections 676,426

Total Deaths: 8,797

Recovered 633,994

COVID-19 Pandemic causes numerous mental disorders. In our early studies, we showed the mental disorders caused by the COVID-19 Pandemic [1-5].

We searched eight databases with search terms relating to COVID-19 and schizophrenia: 

MEDLINE

Pre MEDLINE

Cochrane Library

http://www.ema.europa.eu/ema/

https://scholar.google.com

https://www.rxlist.com/script/main/hp.asp

http://www.nejm.org

https://www.bmj.com

This would reflect the data of which mental disorder is most likely to have COVID-19 infection.  However, we did not find any data impact of COVID-19 on the clinical picture and therapy of Bipolar I Disorder.

Retrospective study 150 (all men) clinical record in psychiatric hospital, the Ministry of Health of the Republic of Azerbaijan.  The study was carried out from December 2020 to December 2021.The age of the patients ranged from 17 to 45 years. Most of the patients were 25-35 years old. The mental state of the patients with Bipolar I Disorder maniacal episode was the diagnosis was made using   DSM-5 [6, 7].

After recovery from COVID-19, the previous symptoms of Bipolar I Disorder maniacal episode returned. In patients with Bipolar I Disorder maniacal episode, not a single death was noted.

The results of the study are shown below. 

F30 Maniacal episode

All half-headings of this three-digit column should be used for one episode only. Hypomanic or manic episodes; if one or more affective episodes (depressive, hypomanic, manic, or mixed) have already occurred in the past, they should be coded as "biopolar affective disorder" (F31.-).

F30.1 Manic episode without psychotic symptoms

• Mood rises without adequate conditions.
• With a decrease in energy, speech flow and the need for sleep.
•  Normal social braking is disturbed, attention is unsustainable, high distraction and high self-esteem, overly optimistic and self-aggrandizing ideas are noticeable.
• In some manic episodes, the mood is more irritating and suspicious than elevated.

F30.2 Mania with psychotic symptoms

The following symptoms are added to the clinical picture described in sub-section F30.1: delirium (usually in the form of big ideas) or hallucinations (usually a voice addressed directly to the patient) or arousal, excessive physical activity, and the excitement of these ideas. leads to the fact that the individual becomes unfit for ordinary communication.

Mood swings with psychotic symptoms

The idea of ​​self-aggrandizement and self-aggrandizement can turn into delusion, and irritability and suspicion into delusion.

 Heavy physical activity and agitation can lead to aggression and violence.

 Illusions and hallucinations can be classified as congruent or non-congruent in affect.

Criteria for a manic episode

A. Overt, overtly abnormal, persistently elevated, expansive or irritable mood - mood, abnormal and constant increase in activity or energy. The symptoms last for more than 2 weeks, most of the day, and should be observed almost every day (if hospitalization is required, any period is sufficient).

B. Mood Disorders An increase in energy and activity is maintained by three of the following symptoms (or more, four if the mood is irritable), significantly different from normal behavior, and highly expressed:

1. Excessive self-esteem or greatness, grandeur, grandeur, grandeur.

2. Decreased need for sleep (feeling comfortable after 3 hours of sleep).

3. Putting pressure on others to talk, talk, or talk more than usual.

4. The flight of ideas or the collision of ideas in subjective practice.

5. Be different from what is reported or observed (ie easily distracted by unattractive or unrelated external stimuli).

6. Increased purposeful activity (social, work or school or sexuality) or psychomotor arousal (ie meaningless, aimless activity).

7. Excessive participation in activities that have abnormal, painful consequences (for example, buying unsafe, unpredictable spices, sarcastic, stupid, stupid investment in business, sexual misconduct, etc.).

C. Mood - the mood is so expressive that it leads to deterioration in the social or professional sphere, or the need for hospitalization to prevent harm to oneself or others, or the presence of a psychotic trait.

D. The episode does not relate to the physiological effects of medications (eg, drug abuse) or other medical conditions.

Note: Criteria A-D constitute a manic episode. Diagnosis of bipolar disorder I requires at least one lifelong manic episode.

Secondary prophylaxis of psychopharmacotherapy involves drugs that have the ability to prevent or alleviate the next affective phase and schizoaffective seizures. In the 60s of the XX century, the concept of secondary drug prevention began to be applied. Schou M. et all., & Baastrup PC, Schou M proposed the term "normothymic” that is, balancing the mood. The term refers to the bimodal effect of the drug, in other words, it prevents the inversion of the affective phase by keeping both poles stable [8, 9].

Classification of thymostabilizers

Currently, the following drugs of thymostabilizers include:

Salts of lithium (lithium carbonate, prolang preparations of lithium);

Antiepileptic drugs:

kabamazepine derivatives;

derivatives of valproic acid;

genetic antiepileptic drugs (lamotrigine, topiramate);

Calcium channel blockers (verapamil, nifedipine, diltiazem).

Lithium salts

The use of lithium salts for prophylactic purposes began in 1963. When taken for a long time in the late 60's, they clearly have a prophylactic effect on recurrent affective disorders. Lithium has been shown to have a stabilizing effect on mood. It is lithium that led to the emergence of a new class of independent psychotropic substances under the name of normothymics or thymostabilizers (thymoisoleptics - Delay J., Deniker P., 1961 nomenclature). According to modern data, lithium is indicated in the treatment of hypomanic and mild manic (psychopathologically more effective in classical mania) conditions.

Lithium has a positive effect in mild depression and mixed affective disorders (when depression has a manic phase). Lithium is not used in severe endogenous depression, reactive and neurotic depression. Because lithium does not have antidepressant properties. Sudden discontinuation of thymostabilizers soon leads to affective disorders. Due to this, their reception is gradually cut off.

Indications for determination of lithium salts:

Hereditary aggravation of the affective spectrum;

Low expression of negative symptoms;

Premorbid sinton personality;

Lack of "low-quality organic ground";

Classical biopolar disorder;

The predominance of manic episodes;

Lack of phase inversion;

When there is a daily rhythm;

In good remission.

Lithium salts

Lithium intake is limited due to the following factors.

Has a high frequency side effect:

Lithium tremor;

Dyspeptic disorders (nausea, vomiting, diarrhea);

Weight gain (mainly due to excessive fluid intake);

Renal dysfunction (polyuria, glomerulopathy, interstitial nephritis, renal failure causing secondary polydisia);

Cardiotoxic effects (hypokalemia);

Disorders of water-salt metabolism;

Seizures (this is why it should not be prescribed to patients with epilepsy);

Effects on thyroid function (exophthalmos, hyperthyroidism);

Lithium oxibate.

Tips: Manic state, psychomotor arousals of various origins. In addition to antimaniakal effect, it also has a pronounced travilizing effect.

Contraindications: See lithium kabonata, internal ventricular block, ulcers of the stomach and duodenum in the acute stage, cataracts.

Precautions: See lithium carbonate, the therapeutic amount of lithium in the blood is 0.4-0.8 mmol / l.

Side effects: See lithium carbonate. Side effects are less pronounced than lithium carbonate.

Dosage and Application: It is slowly injected intramuscularly into a vein in the form of a venous infusion. The average daily dose is 1600-4800 mg, in which case its level in the blood is 0.4-0.8 mmlo / l, which is enough to eliminate manic arousal.

Release form: 2 ml in 20% ampoule.

Lithium salts

Lithium intake is limited due to the following factors.

Complexity of control: the amount of lithium in the blood in the first month should be determined every week, in the second month every two weeks, and in 6 months every two months. If the patient's condition is stable during treatment with lithium, then it is prescribed 3-4 times a year.

A water-salt diet should be followed.

The small therapeutic interval makes it difficult to absorb lithium (the amount of lithium in the blood should be 0.6 - 1 mmol / l).

For prophylaxis, a minimum dose of lithium carbonate is prescribed. If after one week the dose does not reach 0.6 mmol / l, then the daily dose of lithium is increased and after 1 week its amount is checked again. Normally, the average daily dose of lithium carbonate should be 0.4-0.6 mmol / l.

Carbamazepine (carbamazepine)

Synonyms: kabamazepine, zeptol, carbapine, carzepin, mazepin, tegretol, timonil, finlepsin.

Has antiepileptic, analgesic, antidepressant and normothymic effects. Its antiepileptic effect is mainly associated with sodium-voltage sodium channels.

Tips: Partial seizures with or without generalized tonic-clonic seizures in the primary generalization. Bipolar affective disorder. Trigeminal neuralgia.

Contraindications: Atroventricular conduction disorders, bone marrow hematopoiesis, porphyria, as well as MAOI and lithium intake, abscesses, myoclonic seizures.

Side effects: Dose-related diplopia, dizziness, headache, nausea, drowsiness, neutropenia, hyponatremia, hypocalcemia, cardiac arrhythmias. Rash, agranulocytosis, aplastic anemia, hepatotoxicity, Stephen-Johnson syndrome, thrombocytopenia.

Carbamazepine has been used in the treatment of affective disorders since the 1980s. This is due to the fact that carbamazepine has antimicrobial and thymostabilizing properties. According to the hypothesis of  R. Post and J. Ballenger (1982), carbamazepine has a positive effect on affective disorders associated with inhibition of the "kindlina-process" in the amygdala and limbic systems. The prophylactic properties of carbamazepine appear fairly quickly. Stable remission is observed in 2-3 months of carbamazepine treatment. Carbamazepine is the drug of choice for affective, schizoaffective, and affective disorders in the form of rapidly changing continuum, when depressive symptoms predominate in the course of the disease. Side effects of carbamazepine usually appear at the beginning of treatment

Symptoms of most side effects: drowsiness, speech impediment, dizziness, diplopia, dyspeptic disorders. Rare side effects: thrombocytopenia, eosinophilia, tumors, weight gain, allergic reactions (or erythema), leukopenia, agrnolocytosis, aplastic anemia, etc. During treatment with carbamazepine, a clinical blood test should be performed every 3 months. Treatment with carbamazepine is usually prescribed in small doses in the evening, increasing to a maximum dose of 100 mg every 2-3 days and taken 3 times a day. Prolong form is prescribed in the morning and evening.

Oxacarbazepine (trilepta)

Oxacarbazepine is similar in chemical structure to carbamazepine. However, unlike the latter, it has little side effects.

Precautions: It should be used with caution in patients with impaired liver and kidney function, severe heart failure, allelic reactions, glaucoma, pregnancy, driving. It is necessary to control the picture of blood.

Reciprocal communication: It is a paniniductor of microsomal enzymes of the liver. Lowers plasma levels of clonozepam, lamotrigine, phenytoin, valproate, as well as oral contraceptives.

Doses and setting

In adults: 200 mg / day for 2 receptions, gradually increasing the dose to a maintenance level by increasing 200 mg per week - 600-1200 mg / day. The maximum dose is 1600 mg / day. Therapeutic concentration in the blood is 4-12 mcg / ml. The frequency of admission is 3 times a day. In children, 10-15 mg / kg is started, the maintenance dose is 10- Lamotrigine

Contraindications: Hepatic insufficiency, hypersensitivity, childhood (up to 2 years).

Side effects: Depending on the dose: drowsiness, diplopia, headaches, ataxia, tremor, nausea, rash, Stephen-Johnson syndrome. In general, it shows good tolerance in both monotherapy and adjunctive therapy.

Precautions: Skin rashes are observed in 5-10% of patients, so treatment should be started with small doses. Allergic reactions should be carefully monitored, blood picture, liver function is monitored.

Reciprocal communication: T1 / 2 decreases to 15 hours when co-administered with carbamazepine, phenytoin, phenobarbital, and extreme caution should be exercised as T1 / 2 increases to 50 hours in combination with valproate.

Doses and setting: In adults, during monotherapy, the initial dose is 25 mg / day, then gradually increased to a maintenance dose of 50 mg, 100-200 mg / day and taken twice. The dose should be increased gradually - once every 2-3 weeks. The dose of co-administered EEP varies significantly depending on the dose of lamotrigine when administered in combination with a drug that induces liver enzymes, and the maintenance dose is 300-400 mg / day and is taken twice. In children, the initial dose is 0.15 mg / kg, then gradually increased to 1-5 mg / kg.

Lamitrigine (Lamotrigine)

 Tips: It will be considered separately as an antiepileptic drug. Prevention of recurrent affective episodes (mainly depressive) in bipolar affective disorders in adults.

Contraindications, side effects, precautions See antiepileptic drugs.

Dosage and application: Inside: chew or dissolve in a small amount of water, or drink the pill completely with water.

Bipolar disorder: prophylactic treatment with lamotrigine is carried out gradually over a period of 6 weeks. After reaching the prophylactic dose of lamotrigine, if it is clinically manifested, the use of psychopharmacological drugs is stopped. The prophylactic dose can be changed according to the patient's condition. For patients taking drugs that reduce the activity of liver enzymes (eg, valproate), the starting dose of lamotrigine is 25 mg daily for 2 weeks, then 25 mg / day for 2 weeks. From the 5th week, gdoza is prescribed 50 mg once or 2 times a day. The average prophylactic dose is 100 mg / day once or twice a day.

The maximum dose is 200 mg / day. For patients taking drugs that increase the activity of liver enzymes (eg, carbamazepine and phenobarbital) (but not valproate), the starting dose of lamotrigine is 50 mg / day for 2 weeks, then 100 mg / day for 2 weeks. 200 mg / day from the 5th week. In the 6th week, the dose can be increased to 300 mg / day. The daily dose of Orat is 400 mg / day (2 doses) from the 7th week. The dose of lamitrijijn is doubled after discontinuation of drugs that reduce the activity of liver enzymes (eg valproate). When discontinuation of drugs that increase the activity of liver enzymes (eg, carbamazepine and phenobarbital), the dose of lamotrigine is gradually reduced over 3 weeks to the initial dose.

Topiramate (topframate)

Synonyms: topomax, topepsil

The anticonvulsant effect is due to the effect on voltage-dependent sodium channels, GAYT and glutamate receptors, inhibition of the enzyme carbonic anhydrase.

Tips. EAPA, which is indicated as monotherapy or in combination for partial or generalized seizures in both children and adults. It is effective as an adjunct in Lennox-Gasto syndrome. Has neuroprotective properties.

Contraindications: 

Increased sensitivity, severe renal failure.

Continuation of topiramate

Side effects:  Ataxia, impaired concentration, impaired thinking, dizziness, asthenia, paresthesia, drowsiness, nephrolithiasis. In rare cases: agitation, amnesia, anorexia, aphasia, depression, diplopia, emotional instability, nausea, nystagmus, speech disorders, taste disturbances, visual disturbances and weight loss.

Precautions: In mild or severe renal impairment, it takes 10-15 days to obtain a stable concentration of the drug in the blood. In patients with mild to moderate renal disease (creatinine clearance 30-69 ml / min and <30>

Reciprocal communication: Other EEP interactions of topiramate are rare, but should be considered in combination with drugs that affect the activity of liver enzymes.

Doses and setting

In adults, the total daily dose is usually 200-600 mg / day for 2 receptions. The maximum dose is 1600 mg. The starting dose is 25 mg per night, after 1 week the dose is gradually increased to 25-5 mg (2 receptions). Slow titration significantly increases the tolerance of the drug. In children older, the first week begins with 0.5-1 mg / kg (prescribed for the night), then gradually reaches 0.5-1 mg / kg / day.

Valproic acid and its derivatives

Valproic acid

Synonyms: apilepsin, valparin, encorat.

Valproate acid + Valproate sodium: Depakine-chrone

Synonyms: acedipyrol, depakin, depakin enteric, convulsive.

Valproate calcium

Synonym: convulsive

Valproate magnesium

Synonym: dipromal.

Sodium valproate (Sodium valproate)

Instructions: Lack of effect of lithium in rofilaptic therapy, the course of the disease with rapidly changing cycles (more than 4 affective episodes per year), mixed affective states.

Dosage and application: The average prophylactic dose is 600-1800 mg / day (divided into 3-4 doses). The dose is increased by 1 tablet every 2-3 days. Retard form is prescribed once a day. It has been used for many years in the prevention of schizoaffective and affective disorders.

Valproic acid and its derivatives

Highly effective in all types and seizures of epilepsy.

All forms and seizures of epilepsy (generalized, passive, as well as difficult to differentiate seizuresA). Bipolar affective disorder.

Contraindications: Liver disease (exacerbation), history of severe hepatic dysfunction, porphyria, hemorrhagic diathesis, hypersensitivity, pancreatic dysfunction.

Side effects: Dose-dependent - tremor, weight gain, hair loss, anorexia, dyspepsia, nausea, vomiting, peripheral tumors, drowsiness, hyperammonemia, menstrual disorders. Acute pancreatitis, hepatotoxicity, thrombocytopenia, encephalopathy may be possible

Precautions: It is prescribed with caution in patients with impaired liver and kidney function, prone to hemorrhage, before surgery, pregnancy, driving. It is necessary to control the picture of blood.

Reciprocal communication: Valproates inhibit the cytochrome P450 enzyme in the liver; in most cases increases the level of active metabolites of carbamazepine, lamotrigine, primidone, phenytoin. Does not interact with the hormonal component of oral contraceptives.

Doses and setting

Intravenous (adult) intake begins at 300-500 mg / day (500 mg for 2 receptions), the dose is gradually increased to 250-300 mg per week and 1000-3000 mg / day. Therapeutic concentration in the blood is 50- = 150 mcg / ml. Frequency of reception 3 times a day. It is advisable to take a retard dose. In children, 15-20 mg / kg is started, the maintenance dose is 30-50 (sometimes 80) mg / kg. Prolonged form for children is prescribed when the body weight is over 17 kg. Intravenous administration is indicated in cases of epileptic status and temporary parenteral administration of the drug is not possible. The intravenous dose is equivalent to an oral dose.

Indications for the appointment of valproates:

Biopolar disorder;

The predominance of manic episodes;

Chronic affective disorders;

Presence of "poor quality organic soil";

Diphoric manifestations of episodes;

Inversion of the circadian rhythm;

Resistance to lithium salts;

Resistance to kabamazepine.

Derivatives of vaproic acid

Unlike carbamazepine, valproates inhibit the activity of liver enzymes. It has been used in the treatment of epilepsy since 1963. Valproates are more effective than lithium and carbamazepine in the treatment and prevention of affective disorders (especially angry mania), monopolar depression, and the often changing form of bipolar phases (more than 3-4 times a year). Side effects: tremor, dyspeptic disorders, weight gain, alopecia. Valproate is taken 3 times a day (retard forms 1-2 times). The dose increase is increased until an additional effect occurs, as soon as an additional effect occurs, the previous dose is returned and treatment is continued with that dose.

Sodium valproate (Sodium valproate)

In the clinical picture of monopolar manic psychosis, if the manic effect is not fully developed ("mania without mania"), patients are prescribed 9 mg of haloperidol and 150 mg of chlorpromazine per day, mainly with increased physical activity. In this case, active treatment usually lasts 4-5 months. After a steady decrease in the intensity of manic disorders, the dose of the drug is gradually reduced. Sometimes in the repetitive phase, gaperidol carbonate is combined with lithium (1200-1500 mg / water).

    In the mixed form of affective psychosis (when there are both depressive and manic components in the clinical picture), treatment should be carried out with a combination of antipsychotics and antidepressants. In this case, antipsychotics that have little effect on the inversion of affect (haloperidol - 6-12 mg / day, thioridazine - 300-500 mg / day, pyrazidol 100-300 mg / day) are prescribed. Maintenance and prophylactic treatment is carried out by means of normothymics.

Calcium channel blockers

Calcium channel blockers (nifedipine, verapamil) are used as thymostabilizers for non-psychotropic substances. Calcium channel blockers are recommended when treatment with lithium, carbamazepine, valproate is not possible and during pregnancy. On the other hand, calcium channel blockers are prescribed in combination with other thymostabilizers in cyclically frequently changing biopolar affective disorders. Unlike verapamil, nifedipine does not affect cardiac conduction and has weak antiarrhythmic properties.

Indications for the appointment of thymostabilizers

Prophylactic drug treatment should be started against the background of schizoaffective seizures or affective phase, or after the end of the main treatment. Indications for the appointment of thymostabilizer. The main indication for the appointment is the presence of at least two affective or affective-delusional seizures in the last two years. According to XBT-10, thymostabilizers are prescribed in the following diseases:

Sizoaffective disorder (F25);

Biopolar affective disorder (F30);

Recurrent depressive disorder (F33);

Mood - chronic mood disorders: cyclothymia (F34.0); dysthymia (F34.1);

Algorithms for determining thymostabilizers:

Indications for carbamazepine:

In the early stages of the disease

Frequent exacerbations (more than 4 times a year);

Dysthymia, dysphoria against the background of "poor organic soil";

Inversion of the circadian rhythm

Resistance to lithium salts;

Advantages of depression in any form;

Monopolar depression;

Angry mania

Lack of vital feeling

Co-occurring mental disorders are common, with the most frequent disorders being any substance use disorder (e.g., in our cases, methamphetamine is called glass or party in the local jargon) occur in over half of individuals with bipolar I disorder. All individuals in the infected COVID-19 whose symptoms meet criteria for bipolar disorder have abuse a party. The study did not include manic episodes associated with drug abuse (in the context of amphetamine intoxication), side effects of drugs or treatments (steroids, levodopa, antidepressants, and stimulants) and other medical conditions.

As is known from the literature, researchers mainly studied the prevalence of COVID-19 mainly in outpatients. At the same time, it was found that among mental patients, COVID-19 most often suffer from homeless people and people with mental retardation [10-14].

All of the above thymostabilizers in different combinations could not stop the psychopathological manifestations of an acute manic episode in patients suffering from COVID-19. Therefore, in addition to the appointment of carbamzepine and lithium carbonate, we added a solution of 0.5% -1.0 ml of haloperidol into the muscle within 10 days, after 10 days we switched to an injection of haloperidol deconoate 1 time for 14 days. Treatment continued for about 3 months. After the disappearance of the psychotic manifestations of the manic phase, only carbamzepine 600 mg/day and lithium carbonate 900 mg/day were left. Before the appointment of these drugs, all patients received informed consent for treatment.

Thus, for the first time we carried out a retrospective analysis, it showed that manic phase patients who were infected with COVID-19 in these clinically observed shows an fantastic paraphrenic delusion and auditory hallucinations corresponding to the mood of the patients. The limitation of our work is as follows: 1) it is necessary to carry out such studies in many centers; 2) similar research needs to be carried out on the female contingent; 3) on a large clinical material.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors declare that the article is submitted on behalf of all authors. None of the material in the article has been published previously in any form and none of the material is currently under consideration for publication elsewhere other than noted in the cover letter to the editor. Authors declare no financial and personal relationship with other people or organizations that could inappropriately influence this work. All authors contributed to and have approved the final article. The authors declare no conflicts of interest. No sponsor provided funding for this study. 

The authors would like to thank the team of doctors of the psychiatric hospital # 1 Ministry of Health of the Republic of Azerbaijan.