Common and Widespread Mental

Introduction:

Depression is a common and widespread mental disorder affecting millions of people worldwide; [6] Thus, this review is mainly aimed to focus upon the action mechanisms, side effects, toxicity and the logical analytical approaches possibly used in forensic toxicology for the identification of one or more Antidepressant Drugs and their metabolites from biological test matrices.

Antidepressant: Types & Functions

Antidepressant covers many varieties of drugs having different modes of actions like [16]

Figure: Mechanism action of Monoamine reuptake inhibitors (MAOIs), Tricyclic anti-deprassant (TCA) and Selective serotonin reuptake inhibitors (SSRIs).

According to the “Monoamine Theory of Depression,” (proposed by Schildkraut in 1965) the decrease in monoamine neurotransmission is thought to be responsible for inducing depression in an individual. Thus, medication with Antidepressantdrugs (TCAs, MAOIs, SSRIs, and SNRI etc.) rise in the amount of neurotransmitters. Tricyclic antidepressants (TCAs) and heterocyclic antidepressants (SSRIs, SNRIs) inhibit the norepinephrine transporter (NET) and the serotonin transporter (SERT) by competing for the binding site of the amine transporter results in the increase levels of both NE (Norepinephrine) and 5HT (5-hydroxytryptamine or Serotonine) in the synaptic cleft. In addition to this the Monoamine reuptake inhibitors (MAOIs) inhibits an enzyme MAO (monoamino oxidase) released from mitochondria (MO) which convert 5-HT to 5 hydroxyindole acetic acid (HIAA) and norepinephrine (NE) to 3-methoxy 4-hydroxy phenyl glycol (MHPG). This phenomenon increases the stores of NA and 5-HT thus contributes to higher level of Neurotransmitters in Brain. [19]

Adverse effects

Antidepressants are supposed to increase the risk of suicidal thinking and behavior, especially in children accompanying other depressive and psychiatric disorders. [17] [18] [19] The European Medicines Agency showed warning on the use of Antidepressants which might increase the risk of suicidal behavior in children and adolescents. [19] Thus, these drugs may be responsible for the fatality and intoxication and their growing rate all over the world may show threatening effects which is the matter of global concern. Thus, increasing prescription rate and adverse effects of antidepressant drugs results in a growing interest for their determination from biological matrices, proved to be very helpful in the field of Forensic.

Biological Samples use for the Screening of Antidepressant Drugs

Biological samples are the basic requirement of Forensic Toxicology as it solves several related questions which make basis of judgement, consultation and expertise for the field. The biological matrices generally encountered for analysis are urine [34], hair, nails, vitrous humour etc.

The most important and encountered biosample used for analytical purposes is Blood (plasma, serum). Toxicological effects can correlate more effectively with their concentrations in blood which can be determined qualitatively [42]

Another important biological sample is Urine which is a widely used specimen employed for screening, identification and testing of unknown drugs accompanying advantages that it forms in high amount, readily available, easy to collect and contains much useful information about the major metabolic functions of the body. [48]

A next alternative to the blood and urine specimen is the Oral fluid; for it's applications in therapeutic and toxicological drug monitoring [54]

When the analytical studies get concern with long duration of exposure to the detection window hair analysis makes a complementary approach for the detection of antidepressant drugs with the additional advantages that the hair sample can be stored at room temperature for a long time without degradation and it is easy to collect. [62]

Except from all the above described biomatrices very precise and rarely encountered biological sample is Vitreous Humor. It's a fluid mainly composed of water and hyaluronic acid (major component) found between the lens and retina of the eye proved to be the best choice for analytical examinations as it is relatively well isolated and protected from putrefaction. (Quoted reference) Two different fatality cases were reported where the extraction of drugs is done from Vitreous humor. One case has been reported of citalopram fatality where the extraction of drug is done from Vitreous humor yeilding concentration of citalopram (SSRI) less than 0.04mg/L and in second case venlafaxine fatality is reported where postmortem analysis revealed the concentrations of Fluoxetine (SSRI) and it's metabolite Norfluoxetine as 5.2 mg/l and 2.2mg/l respectively. [64]

Other than these specimens, body tissues like liver [71], cerebrospinal fluid etc. canalso encountered for toxic and therapeutic drug monitoring biological matrices.

Techniques for Sample Preparation

The bioanalytical methods form two basic approaches that are the sample preparation step and detection of the compound of interest. Several methods have been published for the determination of one or more antidepressants in biological matrices for therapeutic monitoring or for toxicological purposes. For making biological samples suitable for analytical purposes some treatments should be given to overcome the matrix effects such that the other materials should not interfere with the analytical separation that is the extractability of the analytes in the sample inturn the results of the analysis. [96] These techniques are rapidly gaining acceptance in bioanalytical seperations to reduce time and labor producing satisfactory results with high selectivity and sensitivity over a wide dynamic range, contributing as very fine detection techniques.

Commonly Prescribed New Generation Antidepressant Drugs and their Metabolites

Several new antidepressants that inhibit the serotonine (SERT) and norepinephrine transporters (NET) have been consistently using for therapeutic purposes. [108]

Sertraline is an effective and highly utilized SSRIs group of drug, [113]

Another SSRIs group of Antidepressant drug is Fluoxetine, using worldwide in the therapy of major depression. It is metabolized via N-demethylation by the [117] nitrogen phosphorous detector (NPD) (Thesis- 103) and electron capture detector (ECD) (Thesis- 76), used for the rapid analysis of fluoxetine from biological samples, achieved detection limits up to nanogram level.

Citalopram is a selective and potent serotonine reuptake inhibitor, [78]

Another very important group of Antidepressant drug is SNRIs includes drugs like Venlafaxine which inhibits serotonine, noradrenaline, and to a lesser extent dopamine reuptake. [117] (Thesis-82) is also used for determination of venlafaxine, provided satisfactory results.

In the majority of the published analytical methods for determination of Antidepressant drugs, gas chromatography and high-performance liquid chromatography is applied in combination to different kinds of columns (operating under different separation conditions), mobile phases and detectors. High-performance liquid chromatography is described for the determination of selective serotonine reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (SNRI) and their metabolites in human plasma using fluorescence, mass and photo-diod array detector; Micellar liquid chromatography, the technique which allowed direct injection of biological samples, utilized appropriately selected surfactants in the mobile phase to maintain solubilization of interfering proteins of biological samples.Other than chromatography, separation technique like capillary electrophoresis after in-line solid-phase extraction is described for the analysis sertraline, fluoxetine and fluvoxamine from plasma samples. A survey of most recent multiresidue analytical methods developed for the determination of different kinds of Antidepressant drugs in different types of biological test matrices with their specific cleanup procedures including the choice of mobile phase, stationary phase, detector system and validation data is summarized in the tabular form below.

Abbreviations:

Thus, this table is framed for the comparative study of the major analytical approaches used in the detection and identification of Antidepressant Drugs and their metabolites in different biological matrices in order to develop the new methods with the aim to increase the sample throughput and to improve the quality of analytical methods. Analytical methods for the detection of ADs and their metabolites in biological matrices are of interest in the field of forensic toxicology which involves the analysis of drugs and poisons in biological specimens and interpretation of the results to be applied in a court of law. Several analytical methods have been developed for analysis of these antidepressants in biological matrices. These methods provide a good precision and accuracy over the entire analytical range and allowing the development of very rapid and efficient analytical methods by using newer kind of analytical techniques.

Conclusion:

As the subject of Antidepressants toxicity is evolving, newer methods for their analysis are also evolving. However, some classes of Antidepressants drugs are less toxic and well tolerated but can lead to toxic or fatal drug interactions and these also encountered in many Clinical and Forensic cases. The research in this field is very active and results in a large number of papers published every year. Therefore, this review is mainly aimed to target latest analytical and instrumental methods used in the detection and characterization of various Antidepressant drugs and their metabolites in biological test matrices in turn focused on their toxic as well as therapeutic aspects which would be definitely prove to be helpful in future research and still there is lots of work required in this area as it's prescription rate and toxicity is evolving day by day all over the world. Non-destructive and sophisticated instrumental techniques can also build a new strategy of examination and investigation for the drugs of interest. Future trials should also consider, using different kinds of detecting techniques and methods which would allow for easier comparison and interpretation of results across studies as the subject is of global concern. Despite the success of all validate methods there is a continuing need for sustained innovations in bioanalytical studies releated to forensic cases which needs fast, sensitive and non-destructive methods of analysis. Thus, future work in this area will definitely prove to be a promising from forensic prospect.

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