Table 4.
Therapeutics: drug repurposing for depression.
| A. Connectivity Map (CMAP) analyses | |||
|---|---|---|---|
| Rank | CMAP name | Score | Role |
| A1. Drugs identified using gene expression panels of biomarkers with highest evidence (CFE) for involvement in depression (BioM12 depression—12 genes—NRG1, PRPS1, GLS, DOCK10, TMEM161B, GLO1, HNRNPDL, FANCF, CD47, SMAD7, OLFM1, SLC6A4). See Table 3Aand Fig. 3. Direction of expression in high mood (CMAP). | |||
| 1 | Isoflupredone | 1 | Synthetic glucocorticoid that may be considered as an alternative to traditional corticosteroids. Isoflupredone is the only corticosteroid approved by the U.S. Food and Drug Administration for use exclusively in large animals, including lactating cattle. |
| 2 | Trichostatin A | 0.963 | HDAC inhibitor |
| 3 | Dubinidine | 0.943 | Anticonvulsant which reduces motor activity, enhances the effects of alcohol, ether and barbiturates. Quinoline alkaloid, from plants of the Rutaceae Family. |
| 4 | Ciprofibrate | 0.939 | PPAR-alpha activator, lipid lowering agent |
| 5 | Pioglitazone | 0.931 | PPAR-γ activator, anti-diabetic (*also in our work on Alzheimer [10]) |
| 6 | tropine | 0.93 | Alkaloid |
| 7 | Adiphenine* | 0.907 | Anticholinergic, antispasmodic (*also in our work on suicidality [6]) |
| 8 | Saquinavir | 0.903 | Anti-retroviral medication |
| 9 | Amitriptyline | 0.902 | Tricyclic antidepressant. |
| 10 | Chlorogenic acid* | 0.897 | Antioxidant, polyphenol found in coffee (*also in our work on suicidality [6]) |
| A2. Drugs identified using gene expression panels of biomarkers with highest evidence (CFE) for involvement in depression specific without overlap with bipolar (BioM6 Depression-specific—6 genes—GLO1, HNRNPDL, FANCF, CD47, SMAD7, OLFM1). Direction of expression in high mood (CMAP). See Fig. 3. | |||
| 1 | Pindolol | 1 | β-blocker, and is also a potent serotonin 5HT1A presynaptic receptor antagonist |
| 2 | Lansoprazole | 0.977 | Proton pump inhibitor (PPI), that works by decreasing the amount of acid produced by the stomach. |
| 3 | Xamoterol | 0.975 | Cardiac stimulant, that works by binding to the β1 adrenergic receptor. It is a 3rd generation adrenergic β receptor partial agonist. It provides cardiac stimulation at rest but it acts as a blocker during exercise. |
| 4 | Methanthelinium bromide | 0.953 | Muscarinic receptor antagonist (anticholinergic, parasympatholytic agent). Spasmolytic agent. Gastric acid secretion inhibitor. |
| 5 | Asiaticoside* | 0.927 | Triterpenoid component derived from Centella asiatica (L.) and widely used in antioxidant, anti-inflammatory, immunomodulatory, and wound healing applications. (*also in our work on suicidality [6]) |
| 6 | Estradiol | 0.924 | Female sex hormone |
| 7 | Methacholine | 0.923 | Muscarinic agonist |
| 8 | Isoflupredone | 0.916 | Steroid |
| 9 | Carteolol | 0.913 | Beta blocker |
| 10 | Chlorcyclizine | 0.911 | First-generation antihistamine. It is used primarily to treat allergy symptoms such as rhinitis, urticaria, and pruritus, and may also be used as an antiemetic. |
| A3. Drugs identified using gene expression panels of biomarkers overlapping between depression and bipolar (BioM6 bipolar depression—6 genes—NRG1, DOCK10, GLS, PRPS1, TMEM161B, and SLC6A4). Direction of expression in high mood. (CMAP). See Table 3B and Fig. 3. | |||
| 1 | Valproic acid | 1 | HDAC inhibitor, mood stabilizer |
| 2 | Atracurium besilate | 0.991 | Nicotinic antagonist muscle relaxant |
| 3 | Chicago Sky Blue 6B | 0.98 | Histological stain that also is a vesicular glutamate transporters inhibitor, attenuating methamphetamine-induced hyperactivity and behavioral sensitization in animal models |
| 4 | Enoxacin | 0.972 | Fluoroquinolone antibiotic that also elevates microRNA levels and prevents learned helplessness in animal models |
| 5 | Levobunolol | 0.969 | Beta-blocker |
| 6 | 15-delta prostaglandin J2 | 0.95 | Anti-inflammatory lipid mediator and PPAR-γ activator. It is made from prostaglandin D2. Decreased Prostaglandin D2 Levels in Major Depressive Disorder Are Associated with Depression-Like Behaviors in human and animal model studies. |
| 7 | Ciprofibrate | 0.949 | PPAR-alpha activator, lipid lowering agent |
| 8 | Pirinixic acid | 0.949 | PPAR-alpha activator, anti-lipid agent |
| 9 | Isoflupredone | 0.947 | Synthetic glucocorticoid |
| 10 | Trichostatin A | 0.946 | HDAC inhibitor |
| B. NIH LINCS L1000 characteristic direction signature search engine analyses | |||
|---|---|---|---|
| Rank | Score | Drug | Description |
| B1. Drugs identified using gene expression panels of biomarkers with highest evidence (CFE) for involvement in depression (BioM12 Depression- 12 genes). See Table 3Aand Fig. 3. Direction of expression in high mood (9 increased and 3 decreased). | |||
| 1 | 0.3 | NNC 55–0396 dihydrochloride | T-type calcium channel blocker |
| 2 | 0.3 | Nadolol | Beta blocker |
| 3 | 0.3 | MLN4924 | Inhibitor of Nedd8-Activating Enzyme |
| 4 | 0.2 | U0126 | MEK ½ inhibitor |
| 5 | 0.2 | Nortryptiline | Tricyclic antidepressant |
| 6 | 0.2 | Amcinonide | Synthetic glucocorticoid |
| 7 | 0.2 | Iopanic acid | Iodine-containing radiocontrast medium, thyroid inhibitor |
| 8 | 0.2 | Paroxetine | SSRI antidepressant |
| 9 | 0.2 | Rosuvastatin | Statin |
| 10 | 0.2 | trichostatin A | HDAC inhibitor |
Drugs that have opposite gene expression effects to the gene expression signature of our nominally significant predictive biomarkers for depression(A1–A2) and for bipolar depression(A3), using the Connectivity Map [36] (CMAP), and for depression (B1) using the NIH LINCS database. Bold—new drugs of immediate interest. Italic—natural compound. Underlined—known drugs that serve as a de facto positive control.